Serum secreted EMC10 (scEMC10) levels are inversely associated with metabolically active brown adipose tissue in humans

Serum secreted EMC10 (scEMC10) levels are inversely associated with metabolically active brown adipose tissue in humans | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Article Serum secreted EMC10 (scEMC10) levels are inversely associated with metabolically active brown adipose tissue in humans Xuanchun Wang, Qing Miao, Yahao Wang, Qiongyue Zhang, Wei Wu, and 8 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-4358548/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 18 Mar, 2025 Read the published version in International Journal of Obesity → Version 1 posted 11 You are reading this latest preprint version Abstract Background/Objectives: Secreted endoplasmic reticulum membrane complex subunit 10 (scEMC10) has been implicated in obesity in mice and humans. In this study, the associations of serum scEMC10 levels with thermoneutrality-modulated brown adipose tissue (BAT) activity and thyroid hormone (TH)-dependent thermogenesis were investigated in humans. Subjects/Methods: Serum scEMC10 levels were measured in participants from manifold cohorts using enzyme-linked immunosorbent assay, including participants with or without active BAT determined by PET-CT scanning, BAT-positive participants before and after thermoneutrality, and patients with hyperthyroidism before and after an anti-thyroid drug treatment. The difference in serum scEMC10 between BAT-positive and -negative participants, and the changes of serum scEMC10 in BAT-positive participants before and after thermoneutrality and in patients with Grave’s disease-caused hyperthyroidism before and after an anti-thyroid drug (ATD) treatment were determined. Results: 18 F-FDG PET–CT scanning indicated BAT-positive participants were significantly younger and leaner than BAT-negative ones. There was, however, no significant difference in serum scEMC10 between the two groups. Serum scEMC10 levels in BAT-positive participants were significantly elevated by 2-hour thermoneutrality ( P = 0.0017), concomitant with disappearance of active BAT. No significant association of serum scEMC10 with serum levels of either TSH, FT3, or FT4 was observed in participants from both Chinese and White cohorts. ATD treatment normalized thyroid function and reduced the uptake of 18 F-FDG in skeletal muscle of patients with hyperthyroidism. Serum scEMC10 concentration, however, remained unchanged in these patients before and after ATD treatment. Conclusions: Serum scEMC10 levels are inversely associated with metabolically active BAT, suggesting scEMC10 a suppressive role in facultative thermogenesis in humans. This finding implicates inhibition of scEMC10 in the treatment of obesity and its associated cardiometabolic diseases. Health sciences/Endocrinology/Endocrine system and metabolic diseases/Obesity Biological sciences/Physiology/Metabolism/Fat metabolism scEMC10 Brown adipose tissue Thyroid hormone Facultative thermogenesis Figures Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 Introduction Brown adipose tissue (BAT) plays a significant role in regulating metabolism, particularly in the regulation of systemic glucose, fatty acids, and branched-chain amino acids, contributing to improved glucose homeostasis and weight loss (ref. 1). Studies over the last decade have identified that either activating BAT or converting white adipose tissue (WAT) to a more BAT-like state can protect against obesity and its related metabolic diseases (ref. 2). In addition, BAT is regarded as the primary source of thermogenesis in infants and small mammals, and its potential to treat obesity through non-shivering thermogenesis is being explored, especially since functional BAT has been identified in adult humans (ref. 3–5). These findings collectively highlight the multifaceted role of BAT in human metabolism and its potential as a therapeutic target for metabolic disorders such as obesity and type 2 diabetes. Manifold signals have been well documented to regulate BAT thermogenesis, among which the sympathetic nervous system (SNS) is a key modulator (ref. 6). Upon binding to β3-adrenergic receptors in brown adipocyte, norepinephrine (NE) released from the nerve terminals of SNS activates cAMP-PKA signaling, which in turn phosphorylates CREB and p38 MAPK, eventually converging on the promotion of UCP1 expression (ref. 7). Thyroid hormone (TH), another key regulator of BAT thermogenesis, influences BAT activity by modulating the tissue's sensitivity to SNS stimulation and regulating the expression of UCP1. Additionally, SNS stimulation of BAT also triggers the expression of deiodinase type II, an enzyme that increases local TH availability and signaling (ref. 8). Besides NE and TH, a collection of other hormones, cytokines, and neurotransmitters have been shown to modulate BAT thermogenesis, such as insulin, glucagon, leptin, BMP7 (bone morphogenic protein 7), serotonin, and histamine (ref. 6, 8). Recently we identified a hormone-like circulating factor – scEMC10 (the secreted isoform of endoplasmic reticulum membrane complex subunit 10), as a novel modulator of BAT thermogenesis (ref. 9). Previously, we observed circulatory scEMC10 promoted, while either Emc10 gene knockout ( Emc10 KO) or antibody neutralization of circulating scEMC10 prevented diet-induced obesity and its associated metabolic disorders in mice, including impaired glucose tolerance, dyslipidemia, and fatty liver (ref. 9). These metabolic phenotypes have been linked to scEMC10-modulated BAT thermogenesis, since inhibition of scEMC10 promotes BAT thermogenesis via activation of the PKA-CREB/p38 MAPK signaling pathway in BAT (ref. 9). In humans, serum scEMC10 is upregulated in obesity, and positively correlates with insulin resistance, plasma glucose and free fatty acid. In a cohort of participants with obesity, the reduction of body weight evoked by either bariatric surgery or life-style modification is positively associated with a decrease of serum scEMC10, along with an improvement of insulin sensitivity (ref. 9). Moreover, serum scEMC10 has been identified with positive and negative associations with liver fat content and resting metabolic rate, respectively, in humans (ref. 10, 11). Collectively, these findings suggest that scEMC10 plays a critical role in the regulation of BAT activity and could be a potential therapeutic target for obesity and its related metabolic disorders. However, to date, no study has explored the association of serum scEMC10 levels with BAT activity in humans, nor have any data identified the dynamic changes of serum scEMC10 in patients with hyperthyroidism or its relationship with TH-modulated thermogenesis. In this study, we attempt to address these issues in manifold cohorts. Patients and Methods Patients Cohort 1 Totally, 38 adult participants with active BAT determined by PET-CT scan were recruited as the BAT-positive group (Table 1 ). Each BAT-positive participant was gender- and age-matched as seem as possible to a BAT-negative participant (Table 1 ). In the BAT-positive group, there were 7 participants who volunteered to stay at a climate chamber of thermoneutrality (28°C) for 2 hours. PET-CT scan and blood sampling were performed before and after thermoneutrality (Table 2 ). All subjects were healthy Chinese adults (aged between 20–50 with BMI < 30), and had no history of diabetes, hypertension, heart disease, severe infection, chronic liver or kidney disease, or cancers, and did not take any regular medications (especially adrenergic receptor blockers, antidepressants, or psychiatric drugs, et al.). Pregnant women and subjects with implantable medical electronic devices were excluded. The ethics committee of Huashan Hospital at Fudan University approved the study, and written informed consent was obtained from all volunteers. The trial was registered at ClinicalTrials.gov (NCT01387438). Table 1 Anthropometric parameters and clinical characteristics of participants with positive or negative BAT Characteristics BAT-positive (N = 38) BAT-negative (N = 38) P-value Female(%) 27(71.05) 20(52.63) 0.098 Age(year) 38.2 ± 7.0(20.0–50.0) 43.4 ± 7.8(27.0–65.0) 0.003 BMI(kg/m 2 ) 21.3 ± 2.3(17.6–26.6) 23.2 ± 3.2(17.1–30.5) 0.005 FBG(mmol/L) 4.8 ± 0.4(4.2–5.6) 4.8 ± 0.4(3.8–6.3) 0.615 SBP(mmHg) 123.6 ± 14.2(102.0-158.0) 126.1 ± 12.3(102.0-148.0) 0.410 DBP(mmHg) 79.1 ± 10.3(60.0-100.0) 80.0 ± 7.6(65.0–97.0) 0.810 HR(bpm) 73.2 ± 9.8(57.0-107.0) 71.6 ± 9.3(53.0–89.0) 0.452 Table 2 Anthropometric parameters and clinical characteristics of participants with positive BAT before and after thermoneutrality (TN) Participant Sex Age (year) BMI (kg/m 2 ) FBG (mmol/L) BP (mmHg) HR (bpm) Body temperature before TN (℃) Body temperature after TN (℃) 1 Female 41 17.8 3.4 93/59 70 36.2 36.2 2 Female 42 23.8 4.4 130/95 81 36.0 36.6 3 Female 28 19.5 5.3 104/69 67 37.2 37.5 4 Female 42 19.8 4.3 120/76 67 36.6 36.2 5 Female 45 18.9 5.3 134/96 107 36.3 36.6 6 Male 28 18.5 4.4 138/90 90 36.7 36.7 7 Male 37 21.2 4.7 116/82 81 36.2 36.2 Mean / 37.6 19.9 4.5 119/81 80.4 36.5 36.6 Cohort 2 A total of 495 Chinese subjects who underwent physical examinations were enrolled in the cross-sectional study (Table 3 ). Chinese subjects with the following conditions were excluded: diabetes, acute or chronic inflammatory disease, heart, liver or renal failure, cancer, or active use of oral hypotensive, hypolipidemic, anti-diabetic medications. The ethics committee of Huashan Hospital at Fudan University approved the study, and written informed consent was obtained from all subjects. Table 3 The association of serum scEMC10 with thyroid hormones in a Chinese physical examination cohort and a White cohort Variable cohort 1(n = 495) cohort 2(n = 76) β P-value β P-value TSH (mU/L) Model1 -0.634 0.231 0.022 0.881 Model2 -0.58 0.269 0.092 0.501 FT3 (pmol/L) Model1 -0.006 0.994 -0.088 0.615 Model2 0.093 0.905 0.07 0.674 FT4 (pmol/L) Model1 -0.051 0.821 -0.026 0.635 Model2 -0.002 0.992 -0.023 0.643 cohort 1: Chinese physical examination cohort; cohort 2: White cohort Model1: Crude model; Model2: Adjusted for gender, age, and BMI β: Regression Coefficient Cohort 3 We included 76 Caucasian individuals who underwent abdominal surgery for cholecystectomy, weight reduction surgery, abdominal injuries or explorative laparotomy into our cross-sectional study (Table 3 ). All subjects had a stable weight, defined as the absence of fluctuations of > 2% of body weight for at least 3 months before surgery. This study was approved by the ethics committee of the University of Leipzig (approval numbers: 159-12-21052012 and 017-12-23012012) following the principles of the Declaration of Helsinki. All human study participants gave written informed consent before taking part in the study. Cohort 4 Seven patients with Graves’-caused hyperthyroidism were recruited at Department of Endocrinology, Huashan Hospital affiliated with Fudan University (Table 4 ). All patients were newly diagnosed with hyperthyroidism, had no history of endocrine diseases, and were not taking any medication. After diagnosed by two independent senior investigators, all patients were subject to the first-round PET-CT scans followed by the treatment with methimazole. When their hyperthyroidic symptoms disappeared and thyroid hormone (i.e. FT3 and FT4) levels returned to the normal range, these patients were given the second-round PET-CT scans. None of the patients received beta-adrenoceptor antagonists. The ethics committee of Huashan Hospital at Fudan University approved the study, and written informed consent was obtained from all patients. Table 4 Anthropometric parameters and clinical characteristics of patients with Graves' disease-caused hyperthyroidism before and after ATD treatment (methimazole) Patients Sex Age (year) BMI HR (bpm) TSH (mIU/L) FT3 (pmol/L) FT4 (pmol/L) TRAb (U/L) T1 T2 T1 T2 T1 T2 T1 T2 T1 T2 T1 1 M 42 29.2 29.9 101 79 0.001 0.01 23.03 6.56 67.64 16.53 28.3 2 M 35 22.5 24.8 102 69 0.001 8.927 30.80 3.26 95.28 6.44 14.6 3 M 32 18.5 20.0 96 90 0.002 0.003 21.39 6.21 77.97 21.39 40 4 M 33 19.4 21.1 100 74 0.019 0.008 16.11 4.82 35.15 13.96 4.1 5 F 57 22.7 23.7 85 66 0.124 3.614 19.58 6.66 42.87 17.61 9.6 6 F 33 20.7 21.4 95 65 0.001 0.016 21.88 12.3 62.28 32.84 36.4 7 F 24 18.3 19.3 110 87 0.001 0.002 25.13 4.10 74.25 12.77 39.8 P-value 0.0013 0.0005 0.2175 0.0004 0.002 Normal range 60–100 60–100 0.35–5.5 0.35–5.5 3.5–6.5 3.5–6.5 10.2–31 10.2–31 < 1 T1: Before ATD treatment (methimazole); T2: After ATD treatment (methimazole); M: Male; F: Female Data collections Basic information about age, sex, height, body weight, medication utilization, diagnosis, smoking and drinking histories were obtained from all of the subjects. Levels of serum free T3 (FT3), free T4 (FT4), TSH, and anti-thyroid stimulating hormone receptor antibodies (TRAb) were measured by radioimmunoassay with commercially available kits (Roche Diagnostics GmbH, Sandhofer Strasse 116, 68305 Mannhelm, Germany). Fasting plasma glucose levels were measured using the glucose oxidase method (7600 automatic biochemical analyzer, Hitachi High-Tech Science Systems Corporation, Japan). PET-CT scan In this study, metabolically active BAT was quantified using PET-CT scan. Room temperature in the PET-CT center (31°12′ N, 121°30′ E) was maintained at 21–23°C. All subjects stayed in the room at least for 1 h before the injection of 18 F-FDG at a dose of 5.55–7.40 MBq/kg body weight through the cubital vein. One hour after the injection, whole-body scans were performed with Biograph 64 PET-CT scanner (SIEMENS, Germany). Calculations were completed with Open PACS and PET-CT Viewer software ( http://www.med.harvard.edu/JPNM/DisplayFreeware/ ) (ref. 12). The presence of adipose tissue and the uptake of 18 F-FDG were identified by CT (-250 to -50 Hounsfield units) and PET, respectively. Areas of adipose tissue larger than 4 mm in diameter and with the maximum 18 F-FDG SUV (SUV max) of ≥ 2.0 were identified as the active BAT regions (ref. 4). The example of two PET-CT images of subjects with and without active BAT is shown in Fig. 2 . Measurement of scEMC10 in human serum Serum scEMC10 was measured using a double sandwich ELISA kit (PZ0101, Phrenzer Biotechnology, Shanghai, China). Briefly, add 50 µL of assay buffer, scEMC10 standard or human serum samples, and detecting antibody conjugated with HRP sequentially to each well of 96-well immunoplates from the ELISA kit. Seal the immunoplates with sealer film, and then incubate them at room temperature on a microplate shaker set at 500 rpm for 2 hours. Aspirate each well and wash with 300 µL of 1X washing buffer for 4 times. After the last wash, remove any remaining washing buffer by aspirating or decanting. Invert the plates and blot them against clean paper towels. Add 100 µL of TMB substrate to each well and then incubate for 5–30 minutes at room temperature. Add 100 µL of stop solution to each well. Determine the optical density using a microplate reader set to 450 nm corrected with 570 nm or 630 nm. The ELISA system had an intra- and inter-assay coefficient of variation at 4.9–6.2% and 3.6–7.5%, respectively. Statistical Analysis All analyses were performed with Statistical Package for Social Sciences (version 26, SPSS, Chicago, IL, USA) and figures were generated with GraphPad prism (version 8.0, GraphPad Software Inc.). Normally distributed data were described as means ± standard deviation (SD). Data that are not normally distributed, as determined using Kolmogorov–Smirnov test, were logarithmically transformed and expressed as median with interquartile range. Student’s paired t test was used to compare the differences between different groups. A two-tailed P value less than 0.05 is considered significant. Results Serum scEMC10 levels in participants with positive or negative BAT A total of 38 healthy participants with detectable BAT by PET-CT scan were enrolled into the BAT-positive group, and 38 well-matched participants without detectable BAT at ambient temperature were served as the BAT-negative control group. Clinical characteristics between the two groups, such as FBG, SBP, DBP, and heart rate were not statistically different. Although the age and BMI were matched as much as possible, the overall age and BMI of participants with positive BAT were still significantly lower than those with negative BAT (Table 1 ). Serum scEMC10 levels were evaluated in participants of the two groups. There was no statistical difference in serum scEMC10 between BAT-positive and -negative groups regardless of unadjusted (P = 0.818) or adjusted (P = 0.738) for age, and BMI (Fig. 1 ). Changes in BAT activity and serum scEMC10 levels of participants with positive BAT before and after thermoneutrality Seven participants in the BAT-positive cohort were subject to thermoneutrality (TN) (28°C) for 2 hours. Their clinical characteristics were shown in Table 2 . Metabolically active BAT, which was identified in cervical and supraclavicular areas by 18 F-FDG PET–CT scanning before thermoneutrality, disappeared in all these participants after 2-h thermoneutrality (Fig. 2 ). Strikingly, serum scEMC10 levels were robustly elevated by thermoneutrality in all participants, with medians of the cohort at 2.34 and 4.25 ng/mL before and after thermoneutrality, respectively. Statistical analysis revealed the difference significant ( P = 0.0017) (Fig. 3 ). These data suggest scEMC10 exerts an inhibitory effect on human BAT thermogenesis, congruent with its role in mouse models (ref. 9). The impact of scEMC10 on thyroid hormone-associated thermogenesis Thyroid hormones (THs) have been shown an important role in both BAT and whole-body thermogenesis (ref. 8). To determine the possible impact of scEMC10 on thyroid hormone-associated thermogenesis, we firstly investigated the association of serum scEMC10 with THs in a Chinese physical examination cohort and a White cohort. There was no significant association of serum scEMC10 levels with either TSH, free T3, or free T4 in both cohorts regardless of unadjusted or adjusted for gender, age, and BMI (Table 3 ). We next assessed the change of serum scEMC10 in patients with hyperthyroidism due to Graves' disease who underwent 18 F-FDG PET–CT scanning before and after the treatment with methimazole, an anti-thyroid drug (ATD). As shown in Table 4 , the ATD treatment normalized thyroid functions, along with amelioration of thyrotoxic symptoms in these patients. No active BAT was detected by 18 F-FDG PET–CT scanning in all patients both before and after the ATD treatment, except one who had no active BAT before the treatment, but exhibited active BAT after the treatment (Fig. 4 ). All patients showed increased 18 F-FDG uptake in their skeletal muscle before the ATD treatment followed by almost loss of 18 F-FDG deposit after the treatment (Fig. 4 ). There was no statistical difference in serum scEMC10 levels of these patients between before and after the ATD treatment ( P = 0.927) (Fig. 5 ). Taken together, these observations suggest scEMC10 isn’t involved in thyroid hormone-modulated thermogenesis. Discussion A major advance in the understanding of adipose biology during the past decades is the identification of functionally active BAT in adult humans. The BAT activity in human is determined by multiple factors, including sex, age, BMI, and ambient temperature (ref. 4, 5, 13, 14). In this study, we observed BAT-positive participants are significantly younger and leaner than BAT-negative ones, consistent with other previous studies (ref. 4, 15). However, there was no significant difference in serum scEMC10 between the BAT-negative and -positive groups at room temperature. In BAT-positive participants, serum scEMC10 levels were significantly elevated by thermoneutrality, concomitant with suppression of active BAT determined by PET-CT scan, suggesting scEMC10 acts as a suppressor of BAT activity in humans which is congruent with its inhibitory role in BAT thermogenesis in mice (ref. 9). These findings also suggest scEMC10 a regulatory role in facultative thermogenesis, rather than a role in determining BAT mass in humans. Facultative thermogenesis, which cold exposure activates, while thermoneutrality inactivates, has been linked to human BAT (ref. 14, 16, 17). It has been shown that the regulation of facultative thermogenesis involves the SNS in both rodents and humans (ref. 18, 19). EMC10 has been implicated in the SNS-regulated BAT thermogenesis. Emc10 KO potentiated β3 adrenoceptor agonist-evoked UCP1 expression in brown adipocytes through PKA-CREB/p38 MAPK signaling in vitro and energy expenditure in mice in vivo (ref. 9). Collectively, these data suggest scEMC10 suppresses facultative thermogenesis via inhibition of SNS-PKA signaling in humans. It is well established that facultative thermogenesis, a quick-response form of nonshivering thermogenesis emanating from BAT, is blunted in obesity, and even its small increases can significantly affect the long-term energy homeostasis, making BAT a promising therapeutic target to treat obesity and its associated metabolic diseases, such as type 2 diabetes (ref. 16, 20, 21). We have proven that a scEMC10-neutralizing antibody is effective in treating diet-induced obesity, impaired glucose tolerance, and fatty liver in mouse, which is mainly attributed to heightened BAT thermogenesis (ref. 9). Consistent with the inhibitory effect of scEMC10 on human BAT activity at thermoneutrality, Emc10 KO prevents diet-induced obesity in mouse under thermoneutral condition (30°C) (ref. 9). Taken together, these observations suggest inhibition of scEMC10 will be a therapeutic strategy to treat obesity and its associated cardiometabolic diseases via enhancing facultative thermogenesis. PET-CT scanning analysis didn’t identify active BAT in patients with hyperthyroidism, which accounts for the observation that serum scEMC10 levels remained unchanged before and after ATD treatment. Of note, there was an apparent reduction in the uptake of 18 F-FDG in whole body, especially in skeletal muscle, after ATD treatment, which coincides with a previous study showing patients with elevated levels of THs exhibited increased whole-body thermogenesis together with an increase in skeletal muscle mitochondrial uncoupling (ref. 22). This may be accounted for by the fact that deiodinase II, a key enzyme converting cellular T4 to more active T3 which in turn increases thermogenesis, is predominantly expressed in skeletal muscle in adult humans (ref. 16, 23). A larger cohort consisting of BAT-positive patients with hyperthyroidism is needed to investigate whether there is an association between serum scEMC10 and TH-regulated BAT activity. It has been shown that both BAT and skeletal muscle contribute to nonshivering thermogenesis in humans (ref. 24). The findings of this study that serum scEMC10 is inversely associated with BAT activity, while doesn’t correlate with skeletal muscle thermogenesis suggest scEMC10-modulated facultative thermogenesis is BAT-specific and independent of skeletal muscle in humans. This may be explained by different subtypes of β adrenergic receptors present in BAT and skeletal muscle where β3 subtype predominates in BAT, while β2 receptor is the most subtype in skeletal muscle (ref. 7, 25). We have shown that scEMC10 is involved in the β3 adrenoceptor-modulated thermogenesis in BAT (ref. 9). Further experiments are needed to determine whether scEMC10 regulates β2-adrenoceptor signaling in skeletal muscle. In conclusion, our data link scEMC10 to BAT facultative thermogenesis, but not to thyroid hormone-associated skeletal muscle thermogenesis in humans. This study renders inhibition of scEMC10 a translational significance in treating obesity and its associated cardiometabolic diseases via activation of BAT activity. Declarations Competing interests MB received honoraria as a consultant and speaker from Amgen, AstraZeneca, Bayer, Boehringer-Ingelheim, Lilly, Novo Nordisk, Novartis, Pfizer and Sanofi. Fundings The work was supported by National Natural Science Foundation of China (No. 81800691 to QM, No. 82200952 to QZ, No. 82000790 to WW.) and Science and Technology Commission of Shanghai Municipality (No. 22140902700 to XW). Author Contributions QM and XW conceived the research idea, designed the study, and wrote the manuscript. YW measured serum scEMC10 in humans. QZ, WW, FZ, YYa and MB collected the data. QM, YYu and MB analyzed data and performed the statistical analysis. CZ and YG performed PET-CT scans and analyzed the data. CWL and YL proofread the manuscript for clarity and correctness. All authors have agreed to submit the manuscription. Acknowledgements We thank Samuel M. Lockhart for his help in discussing the data and preparing the manuscript. Data availability The data that support the findings of this study are available upon request from the corresponding authors. References Brown Z, Yoneshiro T. Brown fat thermogenesis and branched-chain amino acids in metabolic disease. Endocr J. 2024; 71:89–100. Liu X, Zhang Z, Song Y, Xie H, Dong M. An update on brown adipose tissue and obesity intervention: Function, regulation and therapeutic implications. Front Endocrinol (Lausanne). 2023; 13:1065263. Singh R, Barrios A, Dirakvand G, Pervin S. Human Brown Adipose Tissue and Metabolic Health: Potential for Therapeutic Avenues. Cells. 2021; 10:3030. Cypess AM, Lehman S, Williams G, Tal I, Rodman D, Goldfine AB, et al. Identification and importance of brown adipose tissue in adult humans. N Engl J Med. 2009; 360:1509–17. van Marken Lichtenbelt WD, Vanhommerig JW, Smulders NM, Drossaerts JM, Kemerink GJ, Bouvy ND, et al. Cold-activated brown adipose tissue in healthy men. N Engl J Med. 2009; 360:1500–8. Morrison SF, Madden CJ, Tupone D. Central neural regulation of brown adipose tissue thermogenesis and energy expenditure. Cell Metab. 2014; 19:741–56. Cannon B, Nedergaard J. Brown adipose tissue: function and physiological significance. Physiol Rev. 2004; 84:277–359. Silva JE. Thermogenic mechanisms and their hormonal regulation. Physiol Rev. 2006; 86:435–64. Wang X, Li Y, Qiang G, Wang K, Dai J, McCann M, et al. Secreted EMC10 is upregulated in human obesity and its neutralizing antibody prevents diet-induced obesity in mice. Nat Commun. 2022; 13:7323. Chen K, Wang Y, Yang J, Klöting N, Liu C, Dai J, et al. EMC10 modulates hepatic ER stress and steatosis in an isoform specific manner. J Hepatol. 2024; doi: 10.1016/j.jhep.2024.03.047 . Chen K, Dai J, Klöting N, Cao X, Jin S, Chen L, et al. Serum scEMC10 Levels are Negatively Associated With Resting Metabolic Rate and age in Humans. J Clin Endocrinol Metab. 2023; 108:e1074-e1081. Barbaras L, Tal I, Palmer MR, Parker JA, Kolodny GM. Shareware program for nuclear medicine and PET/CT PACS display and processing. AJR Am J Roentgenol. 2007; 188:W565-8. Nedergaard J, Bengtsson T, Cannon B. Unexpected evidence for active brown adipose tissue in adult humans. Am J Physiol Endocrinol Metab. 2007; 293:E444-52. Saito M, Okamatsu-Ogura Y, Matsushita M, Watanabe K, Yoneshiro T, Nio-Kobayashi J, et al. High incidence of metabolically active brown adipose tissue in healthy adult humans: effects of cold exposure and adiposity. Diabetes. 2009; 58:1526–31. Zhang Q, Ye H, Miao Q, Zhang Z, Wang Y, Zhu X, et al. Differences in the metabolic status of healthy adults with and without active brown adipose tissue. Wien Klin Wochenschr. 2013; 125:687–95. van Marken Lichtenbelt WD, Schrauwen P. Implications of nonshivering thermogenesis for energy balance regulation in humans. Am J Physiol Regul Integr Comp Physiol. 2011; 301:R285-96. Vijgen GH, Bouvy ND, Teule GJ, Brans B, Schrauwen P, van Marken Lichtenbelt WD. Brown adipose tissue in morbidly obese subjects. PLoS One. 2011; 6:e17247. Thomas SA, Palmiter RD. Thermoregulatory and metabolic phenotypes of mice lacking noradrenaline and adrenaline. Nature. 1997; 387:94–7. Celi FS, Brychta RJ, Linderman JD, Butler PW, Alberobello AT, Smith S, et al. Minimal changes in environmental temperature result in a significant increase in energy expenditure and changes in the hormonal homeostasis in healthy adults. Eur J Endocrinol. 2010; 163:863–72. Lidell ME, Betz MJ, Enerbäck S. Brown adipose tissue and its therapeutic potential. J Intern Med. 2014; 276:364–77. Cannon B, Nedergaard J. Nonshivering thermogenesis and its adequate measurement in metabolic studies. J Exp Biol. 2011; 214:242–53. Mitchell CS, Savage DB, Dufour S, Schoenmakers N, Murgatroyd P, Befroy D, et al. Resistance to thyroid hormone is associated with raised energy expenditure, muscle mitochondrial uncoupling, and hyperphagia. J Clin Invest. 2010; 120:1345–54. Salvatore D, Bartha T, Harney JW, Larsen PR. Molecular biological and biochemical characterization of the human type 2 selenodeiodinase. Endocrinology. 1996; 137:3308–15. Wijers SL, Schrauwen P, van Baak MA, Saris WH, van Marken Lichtenbelt WD. Beta-adrenergic receptor blockade does not inhibit cold-induced thermogenesis in humans: possible involvement of brown adipose tissue. J Clin Endocrinol Metab. 2011; 96:E598-605. Lynch GS, Ryall JG. Role of beta-adrenoceptor signaling in skeletal muscle: implications for muscle wasting and disease. Physiol Rev. 2008; 88:729–67. Additional Declarations (Not answered) Cite Share Download PDF Status: Published Journal Publication published 18 Mar, 2025 Read the published version in International Journal of Obesity → Version 1 posted Editorial decision: revise 15 Oct, 2024 Review # 3 received at journal 09 Sep, 2024 Review # 2 received at journal 01 Sep, 2024 Reviewer # 3 agreed at journal 15 Aug, 2024 Reviewer # 2 agreed at journal 26 Jul, 2024 Review # 1 received at journal 17 Jun, 2024 Reviewer # 1 agreed at journal 05 Jun, 2024 Reviewers invited by journal 20 May, 2024 Submission checks completed at journal 07 May, 2024 Editor assigned by journal 02 May, 2024 First submitted to journal 02 May, 2024 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-4358548","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Article","associatedPublications":[],"authors":[{"id":304650613,"identity":"75abbeb0-209f-4364-8ab8-664d983a1279","order_by":0,"name":"Xuanchun Wang","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA4ElEQVRIiWNgGAWjYPCCA3LsDQwGIBZjA7FajHkOkKolsYdoLQbHzx5+zVNzJ71HInnj5wIGG9kNB5ifPcCr5UxemuWMY89yeyTSiqVnMKQZbzjAZm6AT4vZgRwzg48Nh3P3S+QYSPMwHE7ccICHTQKvlvNvzAwSGw6n80jkGP/mYfhPhJYbOcYPgLYkALWYAW05QFiL/Y03Zowzjh027OF5VmbNY5BsPPMwmxleLZL9OcafeWoOy/OwJ2++zVNhJ9t3vPkZXi1AgOwMUFAxE1APUvKBsJpRMApGwSgY0QAAiYJLfXObhUMAAAAASUVORK5CYII=","orcid":"https://orcid.org/0000-0003-2980-4363","institution":"Huashan Hospital, Fudan University","correspondingAuthor":true,"prefix":"","firstName":"Xuanchun","middleName":"","lastName":"Wang","suffix":""},{"id":304650614,"identity":"c810fa75-74c8-4411-be7f-a9eb40194e01","order_by":1,"name":"Qing Miao","email":"","orcid":"","institution":"Huashan Hospital","correspondingAuthor":false,"prefix":"","firstName":"Qing","middleName":"","lastName":"Miao","suffix":""},{"id":304650615,"identity":"0719a7bc-f28f-4941-8af8-f277c07c83d2","order_by":2,"name":"Yahao Wang","email":"","orcid":"","institution":"Huashan Hospital","correspondingAuthor":false,"prefix":"","firstName":"Yahao","middleName":"","lastName":"Wang","suffix":""},{"id":304650616,"identity":"9673ed7f-8c4e-4731-a668-cc39c407a333","order_by":3,"name":"Qiongyue Zhang","email":"","orcid":"","institution":"Huashan Hospital","correspondingAuthor":false,"prefix":"","firstName":"Qiongyue","middleName":"","lastName":"Zhang","suffix":""},{"id":304650617,"identity":"80bcb8f9-f9ac-41ce-b898-bdf40a95bf51","order_by":4,"name":"Wei Wu","email":"","orcid":"","institution":"Huashan Hospital","correspondingAuthor":false,"prefix":"","firstName":"Wei","middleName":"","lastName":"Wu","suffix":""},{"id":304650618,"identity":"e5bded5c-bb18-4632-b588-89bd36136262","order_by":5,"name":"Yifei Yu","email":"","orcid":"","institution":"Huashan Hospital","correspondingAuthor":false,"prefix":"","firstName":"Yifei","middleName":"","lastName":"Yu","suffix":""},{"id":304650619,"identity":"c4cf784f-d011-48f3-91b6-97ed0223d360","order_by":6,"name":"Fangfang Zeng","email":"","orcid":"","institution":"Huashan Hospital","correspondingAuthor":false,"prefix":"","firstName":"Fangfang","middleName":"","lastName":"Zeng","suffix":""},{"id":304650620,"identity":"44b582a3-daac-45ce-8d3a-52bbe6734999","order_by":7,"name":"Yehong Yang","email":"","orcid":"","institution":"Huashan Hospital","correspondingAuthor":false,"prefix":"","firstName":"Yehong","middleName":"","lastName":"Yang","suffix":""},{"id":304650621,"identity":"43066d59-4ad6-4673-9614-5cda5d7ddfbb","order_by":8,"name":"Chuantao Zuo","email":"","orcid":"","institution":"Huashan Hospital","correspondingAuthor":false,"prefix":"","firstName":"Chuantao","middleName":"","lastName":"Zuo","suffix":""},{"id":304650622,"identity":"51b61039-0aaf-41f6-ac63-6fbba879465e","order_by":9,"name":"Yihui Guan","email":"","orcid":"","institution":"Key Laboratory of Molecular Medicine, the Ministry of Education, Shanghai Medical School and Institutes of Biomedical Sciences, Fudan University, Shanghai 200032, PR Chin","correspondingAuthor":false,"prefix":"","firstName":"Yihui","middleName":"","lastName":"Guan","suffix":""},{"id":304650623,"identity":"aaf1036d-a6a7-49f4-b5e7-2cf82114dfab","order_by":10,"name":"Chong Wee Liew","email":"","orcid":"","institution":"University of Illinois at Chicago","correspondingAuthor":false,"prefix":"","firstName":"Chong","middleName":"Wee","lastName":"Liew","suffix":""},{"id":304650624,"identity":"49ffdcb4-ba2f-44e1-b7a2-40acced4e000","order_by":11,"name":"Matthias Blüher","email":"","orcid":"https://orcid.org/0000-0003-0208-2065","institution":"University of Leipzig and University Hospital","correspondingAuthor":false,"prefix":"","firstName":"Matthias","middleName":"","lastName":"Blüher","suffix":""},{"id":304650625,"identity":"4f207e85-36b9-45cc-9704-a5dad5679486","order_by":12,"name":"Yiming Li","email":"","orcid":"","institution":"","correspondingAuthor":false,"prefix":"","firstName":"Yiming","middleName":"","lastName":"Li","suffix":""}],"badges":[],"createdAt":"2024-05-02 10:31:38","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-4358548/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-4358548/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1038/s41366-025-01744-2","type":"published","date":"2025-03-18T04:00:00+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":57802020,"identity":"cf49b6f2-85c4-4063-b093-e69badcd5b2a","added_by":"auto","created_at":"2024-06-05 22:28:03","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":29942,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eSerum scEMC10 levels in participants with positive (+) or negative (-) BAT\u003c/strong\u003e\u003c/p\u003e","description":"","filename":"1.png","url":"https://assets-eu.researchsquare.com/files/rs-4358548/v1/627380ac42a3fbe30c70d9ff.png"},{"id":57802651,"identity":"b6123f3e-7227-4382-89b0-9596e5465961","added_by":"auto","created_at":"2024-06-05 22:36:03","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":696743,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eThe images of a participant before (left) and after 2-hour thermoneutrality (right) generated by PET-CT scanning with \u003c/strong\u003e\u003csup\u003e\u003cstrong\u003e18\u003c/strong\u003e\u003c/sup\u003e\u003cstrong\u003eF-FDG\u003c/strong\u003e\u003c/p\u003e","description":"","filename":"floatimage2.png","url":"https://assets-eu.researchsquare.com/files/rs-4358548/v1/f58f7316d2efeb7743d9ef06.png"},{"id":57802019,"identity":"6bca3603-e446-4920-a37d-5067f071b7a2","added_by":"auto","created_at":"2024-06-05 22:28:03","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":30038,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eSerum scEMC10 levels in participants with positive BAT before and after thermoneutrality (TN)\u003c/strong\u003e\u003c/p\u003e","description":"","filename":"3.png","url":"https://assets-eu.researchsquare.com/files/rs-4358548/v1/5c79733b58e036dd48ccc070.png"},{"id":57802023,"identity":"ed1c605a-1e29-4f62-bc88-ba21fb0ded8c","added_by":"auto","created_at":"2024-06-05 22:28:03","extension":"png","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":305146,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eThe images of a patient with Graves’ disease-caused hyperthyroidism before (left) and after (right) ATD treatment (methimazole) generated by PET-CT scanning with \u003c/strong\u003e\u003csup\u003e\u003cstrong\u003e18\u003c/strong\u003e\u003c/sup\u003e\u003cstrong\u003eF-FDG\u003c/strong\u003e\u003c/p\u003e","description":"","filename":"floatimage4.png","url":"https://assets-eu.researchsquare.com/files/rs-4358548/v1/5bb65f51e7d2a7bc3c3db9c0.png"},{"id":57802021,"identity":"30ba9362-2cf7-4ffc-8817-845db61ad4ad","added_by":"auto","created_at":"2024-06-05 22:28:03","extension":"png","order_by":5,"title":"Figure 5","display":"","copyAsset":false,"role":"figure","size":25400,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eSerum scEMC10 levels in\u003c/strong\u003e \u003cstrong\u003epatients with Graves' disease-caused hyperthyroidism before and after ATD treatment (methimazole)\u003c/strong\u003e\u003c/p\u003e","description":"","filename":"5.png","url":"https://assets-eu.researchsquare.com/files/rs-4358548/v1/bd8104b1ecd1041c5545808f.png"},{"id":78802786,"identity":"6ab848e8-91a8-42d8-8adc-193785c6d029","added_by":"auto","created_at":"2025-03-19 07:07:26","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":2567373,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-4358548/v1/65a92e52-9314-4215-b69b-ad7c9bb3cd72.pdf"}],"financialInterests":"(Not answered)","formattedTitle":"Serum secreted EMC10 (scEMC10) levels are inversely associated with metabolically active brown adipose tissue in humans","fulltext":[{"header":"Introduction","content":"\u003cp\u003eBrown adipose tissue (BAT) plays a significant role in regulating metabolism, particularly in the regulation of systemic glucose, fatty acids, and branched-chain amino acids, contributing to improved glucose homeostasis and weight loss (ref. 1). Studies over the last decade have identified that either activating BAT or converting white adipose tissue (WAT) to a more BAT-like state can protect against obesity and its related metabolic diseases (ref. 2). In addition, BAT is regarded as the primary source of thermogenesis in infants and small mammals, and its potential to treat obesity through non-shivering thermogenesis is being explored, especially since functional BAT has been identified in adult humans (ref. 3\u0026ndash;5). These findings collectively highlight the multifaceted role of BAT in human metabolism and its potential as a therapeutic target for metabolic disorders such as obesity and type 2 diabetes.\u003c/p\u003e \u003cp\u003eManifold signals have been well documented to regulate BAT thermogenesis, among which the sympathetic nervous system (SNS) is a key modulator (ref. 6). Upon binding to β3-adrenergic receptors in brown adipocyte, norepinephrine (NE) released from the nerve terminals of SNS activates cAMP-PKA signaling, which in turn phosphorylates CREB and p38 MAPK, eventually converging on the promotion of UCP1 expression (ref. 7). Thyroid hormone (TH), another key regulator of BAT thermogenesis, influences BAT activity by modulating the tissue's sensitivity to SNS stimulation and regulating the expression of UCP1. Additionally, SNS stimulation of BAT also triggers the expression of deiodinase type II, an enzyme that increases local TH availability and signaling (ref. 8). Besides NE and TH, a collection of other hormones, cytokines, and neurotransmitters have been shown to modulate BAT thermogenesis, such as insulin, glucagon, leptin, BMP7 (bone morphogenic protein 7), serotonin, and histamine (ref. 6, 8). Recently we identified a hormone-like circulating factor \u0026ndash; scEMC10 (the secreted isoform of endoplasmic reticulum membrane complex subunit 10), as a novel modulator of BAT thermogenesis (ref. 9).\u003c/p\u003e \u003cp\u003ePreviously, we observed circulatory scEMC10 promoted, while either \u003cem\u003eEmc10\u003c/em\u003e gene knockout (\u003cem\u003eEmc10\u003c/em\u003e KO) or antibody neutralization of circulating scEMC10 prevented diet-induced obesity and its associated metabolic disorders in mice, including impaired glucose tolerance, dyslipidemia, and fatty liver (ref. 9). These metabolic phenotypes have been linked to scEMC10-modulated BAT thermogenesis, since inhibition of scEMC10 promotes BAT thermogenesis via activation of the PKA-CREB/p38 MAPK signaling pathway in BAT (ref. 9). In humans, serum scEMC10 is upregulated in obesity, and positively correlates with insulin resistance, plasma glucose and free fatty acid. In a cohort of participants with obesity, the reduction of body weight evoked by either bariatric surgery or life-style modification is positively associated with a decrease of serum scEMC10, along with an improvement of insulin sensitivity (ref. 9). Moreover, serum scEMC10 has been identified with positive and negative associations with liver fat content and resting metabolic rate, respectively, in humans (ref. 10, 11).\u003c/p\u003e \u003cp\u003eCollectively, these findings suggest that scEMC10 plays a critical role in the regulation of BAT activity and could be a potential therapeutic target for obesity and its related metabolic disorders. However, to date, no study has explored the association of serum scEMC10 levels with BAT activity in humans, nor have any data identified the dynamic changes of serum scEMC10 in patients with hyperthyroidism or its relationship with TH-modulated thermogenesis. In this study, we attempt to address these issues in manifold cohorts.\u003c/p\u003e"},{"header":"Patients and Methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003ePatients\u003c/h2\u003e \u003cdiv id=\"Sec4\" class=\"Section3\"\u003e \u003ch2\u003eCohort 1\u003c/h2\u003e \u003cp\u003eTotally, 38 adult participants with active BAT determined by PET-CT scan were recruited as the BAT-positive group (Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e). Each BAT-positive participant was gender- and age-matched as seem as possible to a BAT-negative participant (Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e). In the BAT-positive group, there were 7 participants who volunteered to stay at a climate chamber of thermoneutrality (28\u0026deg;C) for 2 hours. PET-CT scan and blood sampling were performed before and after thermoneutrality (Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e). All subjects were healthy Chinese adults (aged between 20\u0026ndash;50 with BMI\u0026thinsp;\u0026lt;\u0026thinsp;30), and had no history of diabetes, hypertension, heart disease, severe infection, chronic liver or kidney disease, or cancers, and did not take any regular medications (especially adrenergic receptor blockers, antidepressants, or psychiatric drugs, et al.). Pregnant women and subjects with implantable medical electronic devices were excluded. The ethics committee of Huashan Hospital at Fudan University approved the study, and written informed consent was obtained from all volunteers. The trial was registered at ClinicalTrials.gov (NCT01387438).\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eAnthropometric parameters and clinical characteristics of participants with positive or negative BAT\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"4\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cem\u003eCharacteristics\u003c/em\u003e\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u003cem\u003eBAT-positive (N\u0026thinsp;=\u0026thinsp;38)\u003c/em\u003e\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u003cem\u003eBAT-negative (N\u0026thinsp;=\u0026thinsp;38)\u003c/em\u003e\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u003cem\u003eP-value\u003c/em\u003e\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eFemale(%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e27(71.05)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e20(52.63)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.098\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAge(year)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e38.2\u0026thinsp;\u0026plusmn;\u0026thinsp;7.0(20.0\u0026ndash;50.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e43.4\u0026thinsp;\u0026plusmn;\u0026thinsp;7.8(27.0\u0026ndash;65.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e\u003cb\u003e0.003\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBMI(kg/m\u003csup\u003e2\u003c/sup\u003e)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e21.3\u0026thinsp;\u0026plusmn;\u0026thinsp;2.3(17.6\u0026ndash;26.6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e23.2\u0026thinsp;\u0026plusmn;\u0026thinsp;3.2(17.1\u0026ndash;30.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e\u003cb\u003e0.005\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eFBG(mmol/L)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e4.8\u0026thinsp;\u0026plusmn;\u0026thinsp;0.4(4.2\u0026ndash;5.6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e4.8\u0026thinsp;\u0026plusmn;\u0026thinsp;0.4(3.8\u0026ndash;6.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.615\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSBP(mmHg)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e123.6\u0026thinsp;\u0026plusmn;\u0026thinsp;14.2(102.0-158.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e126.1\u0026thinsp;\u0026plusmn;\u0026thinsp;12.3(102.0-148.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.410\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDBP(mmHg)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e79.1\u0026thinsp;\u0026plusmn;\u0026thinsp;10.3(60.0-100.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e80.0\u0026thinsp;\u0026plusmn;\u0026thinsp;7.6(65.0\u0026ndash;97.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.810\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHR(bpm)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e73.2\u0026thinsp;\u0026plusmn;\u0026thinsp;9.8(57.0-107.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e71.6\u0026thinsp;\u0026plusmn;\u0026thinsp;9.3(53.0\u0026ndash;89.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.452\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab2\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eAnthropometric parameters and clinical characteristics of participants with positive BAT before and after thermoneutrality (TN)\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"9\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c7\" colnum=\"7\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c8\" colnum=\"8\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c9\" colnum=\"9\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eParticipant\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eSex\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eAge (year)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eBMI\u003c/p\u003e \u003cp\u003e(kg/m\u003csup\u003e2\u003c/sup\u003e)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003eFBG\u003c/p\u003e \u003cp\u003e(mmol/L)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c6\"\u003e \u003cp\u003eBP\u003c/p\u003e \u003cp\u003e(mmHg)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c7\"\u003e \u003cp\u003eHR\u003c/p\u003e \u003cp\u003e(bpm)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c8\"\u003e \u003cp\u003eBody temperature before TN (℃)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c9\"\u003e \u003cp\u003eBody temperature\u003c/p\u003e \u003cp\u003eafter TN (℃)\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eFemale\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e41\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e17.8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e3.4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e93/59\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e70\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e36.2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e \u003cp\u003e36.2\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eFemale\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e42\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e23.8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e4.4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e130/95\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e81\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e36.0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e \u003cp\u003e36.6\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eFemale\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e28\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e19.5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e5.3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e104/69\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e67\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e37.2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e \u003cp\u003e37.5\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eFemale\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e42\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e19.8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e4.3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e120/76\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e67\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e36.6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e \u003cp\u003e36.2\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eFemale\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e45\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e18.9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e5.3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e134/96\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e107\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e36.3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e \u003cp\u003e36.6\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eMale\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e28\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e18.5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e4.4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e138/90\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e90\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e36.7\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e \u003cp\u003e36.7\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e7\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eMale\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e37\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e21.2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e4.7\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e116/82\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e81\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e36.2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e \u003cp\u003e36.2\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMean\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e/\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e37.6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e19.9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e4.5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e119/81\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e80.4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e36.5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e \u003cp\u003e36.6\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv id=\"Sec5\" class=\"Section2\"\u003e \u003ch2\u003eCohort 2\u003c/h2\u003e \u003cp\u003eA total of 495 Chinese subjects who underwent physical examinations were enrolled in the cross-sectional study (Table\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e). Chinese subjects with the following conditions were excluded: diabetes, acute or chronic inflammatory disease, heart, liver or renal failure, cancer, or active use of oral hypotensive, hypolipidemic, anti-diabetic medications. The ethics committee of Huashan Hospital at Fudan University approved the study, and written informed consent was obtained from all subjects.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab3\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 3\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eThe association of serum scEMC10 with thyroid hormones in a Chinese physical examination cohort and a White cohort\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"7\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c7\" colnum=\"7\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colspan=\"2\" morerows=\"1\" nameend=\"c2\" namest=\"c1\" rowspan=\"2\"\u003e \u003cp\u003eVariable\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colspan=\"2\" nameend=\"c4\" namest=\"c3\"\u003e \u003cp\u003ecohort 1(n\u0026thinsp;=\u0026thinsp;495)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colspan=\"2\" nameend=\"c6\" namest=\"c5\"\u003e \u003cp\u003ecohort 2(n\u0026thinsp;=\u0026thinsp;76)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colspan=\"1\" nameend=\"c7\" namest=\"c7\"\u003e\u0026nbsp;\u003c/th\u003e \u003c/tr\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eβ\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u003cem\u003eP-value\u003c/em\u003e\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003eβ\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c6\"\u003e \u003cp\u003e\u003cem\u003eP-value\u003c/em\u003e\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colspan=\"1\" nameend=\"c7\" namest=\"c7\"\u003e\u0026nbsp;\u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTSH (mU/L)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eModel1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e-0.634\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.231\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.022\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0.881\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eModel2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e-0.58\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.269\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.092\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0.501\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eFT3 (pmol/L)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eModel1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e-0.006\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.994\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e-0.088\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0.615\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eModel2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.093\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.905\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.07\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0.674\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eFT4 (pmol/L)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eModel1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e-0.051\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.821\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e-0.026\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0.635\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eModel2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e-0.002\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.992\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e-0.023\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0.643\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"7\"\u003ecohort 1: Chinese physical examination cohort; cohort 2: White cohort\u003c/td\u003e\u003c/tr\u003e \u003ctr\u003e\u003ctd colspan=\"7\"\u003eModel1: Crude model; Model2: Adjusted for gender, age, and BMI\u003c/td\u003e\u003c/tr\u003e \u003ctr\u003e\u003ctd colspan=\"7\"\u003eβ: Regression Coefficient\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cdiv id=\"Sec6\" class=\"Section3\"\u003e \u003ch2\u003eCohort 3\u003c/h2\u003e \u003cp\u003eWe included 76 Caucasian individuals who underwent abdominal surgery for cholecystectomy, weight reduction surgery, abdominal injuries or explorative laparotomy into our cross-sectional study (Table\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e). All subjects had a stable weight, defined as the absence of fluctuations of \u0026gt;\u0026thinsp;2% of body weight for at least 3 months before surgery. This study was approved by the ethics committee of the University of Leipzig (approval numbers: 159-12-21052012 and 017-12-23012012) following the principles of the Declaration of Helsinki. All human study participants gave written informed consent before taking part in the study.\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv id=\"Sec7\" class=\"Section2\"\u003e \u003ch2\u003eCohort 4\u003c/h2\u003e \u003cp\u003eSeven patients with Graves\u0026rsquo;-caused hyperthyroidism were recruited at Department of Endocrinology, Huashan Hospital affiliated with Fudan University (Table\u0026nbsp;\u003cspan refid=\"Tab4\" class=\"InternalRef\"\u003e4\u003c/span\u003e). All patients were newly diagnosed with hyperthyroidism, had no history of endocrine diseases, and were not taking any medication. After diagnosed by two independent senior investigators, all patients were subject to the first-round PET-CT scans followed by the treatment with methimazole. When their hyperthyroidic symptoms disappeared and thyroid hormone (i.e. FT3 and FT4) levels returned to the normal range, these patients were given the second-round PET-CT scans. None of the patients received beta-adrenoceptor antagonists. The ethics committee of Huashan Hospital at Fudan University approved the study, and written informed consent was obtained from all patients.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab4\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 4\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eAnthropometric parameters and clinical characteristics of patients with Graves' disease-caused hyperthyroidism before and after ATD treatment (methimazole)\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"14\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c7\" colnum=\"7\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c8\" colnum=\"8\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c9\" colnum=\"9\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c10\" colnum=\"10\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c11\" colnum=\"11\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c12\" colnum=\"12\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c13\" colnum=\"13\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c14\" colnum=\"14\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePatients\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eSex\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eAge (year)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colspan=\"2\" nameend=\"c5\" namest=\"c4\"\u003e \u003cp\u003eBMI\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colspan=\"2\" nameend=\"c7\" namest=\"c6\"\u003e \u003cp\u003eHR (bpm)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colspan=\"2\" nameend=\"c9\" namest=\"c8\"\u003e \u003cp\u003eTSH (mIU/L)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colspan=\"2\" nameend=\"c11\" namest=\"c10\"\u003e \u003cp\u003eFT3 (pmol/L)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colspan=\"2\" nameend=\"c13\" namest=\"c12\"\u003e \u003cp\u003eFT4 (pmol/L)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c14\"\u003e \u003cp\u003eTRAb (U/L)\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eT1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eT2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eT1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eT2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eT1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003eT2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003eT1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003eT2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\"\u003e \u003cp\u003eT1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c13\"\u003e \u003cp\u003eT2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c14\"\u003e \u003cp\u003eT1\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eM\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e42\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e29.2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e29.9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e101\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e79\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e0.001\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e0.01\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e23.03\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003e6.56\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\"\u003e \u003cp\u003e67.64\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c13\"\u003e \u003cp\u003e16.53\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c14\"\u003e \u003cp\u003e28.3\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eM\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e35\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e22.5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e24.8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e102\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e69\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e0.001\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e8.927\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e30.80\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003e3.26\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\"\u003e \u003cp\u003e95.28\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c13\"\u003e \u003cp\u003e6.44\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c14\"\u003e \u003cp\u003e14.6\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eM\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e32\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e18.5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e20.0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e96\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e90\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e0.002\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e0.003\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e21.39\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003e6.21\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\"\u003e \u003cp\u003e77.97\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c13\"\u003e \u003cp\u003e21.39\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c14\"\u003e \u003cp\u003e40\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eM\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e33\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e19.4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e21.1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e100\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e74\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e0.019\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e0.008\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e16.11\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003e4.82\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\"\u003e \u003cp\u003e35.15\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c13\"\u003e \u003cp\u003e13.96\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c14\"\u003e \u003cp\u003e4.1\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eF\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e57\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e22.7\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e23.7\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e85\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e66\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e0.124\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e3.614\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e19.58\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003e6.66\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\"\u003e \u003cp\u003e42.87\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c13\"\u003e \u003cp\u003e17.61\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c14\"\u003e \u003cp\u003e9.6\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eF\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e33\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e20.7\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e21.4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e95\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e65\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e0.001\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e0.016\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e21.88\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003e12.3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\"\u003e \u003cp\u003e62.28\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c13\"\u003e \u003cp\u003e32.84\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c14\"\u003e \u003cp\u003e36.4\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e7\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eF\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e24\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e18.3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e19.3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e110\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e87\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e0.001\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e0.002\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e25.13\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003e4.10\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\"\u003e \u003cp\u003e74.25\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c13\"\u003e \u003cp\u003e12.77\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c14\"\u003e \u003cp\u003e39.8\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eP-value\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c5\" namest=\"c4\"\u003e \u003cp\u003e\u003cb\u003e0.0013\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c7\" namest=\"c6\"\u003e \u003cp\u003e\u003cb\u003e0.0005\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c9\" namest=\"c8\"\u003e \u003cp\u003e0.2175\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c11\" namest=\"c10\"\u003e \u003cp\u003e\u003cb\u003e0.0004\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c13\" namest=\"c12\"\u003e \u003cp\u003e\u003cb\u003e0.002\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c14\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNormal range\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e60\u0026ndash;100\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e60\u0026ndash;100\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e0.35\u0026ndash;5.5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e0.35\u0026ndash;5.5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e3.5\u0026ndash;6.5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003e3.5\u0026ndash;6.5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\"\u003e \u003cp\u003e10.2\u0026ndash;31\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c13\"\u003e \u003cp\u003e10.2\u0026ndash;31\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c14\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;1\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"14\"\u003eT1: Before ATD treatment (methimazole); T2: After ATD treatment (methimazole); M: Male; F: Female\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec8\" class=\"Section2\"\u003e \u003ch2\u003eData collections\u003c/h2\u003e \u003cp\u003eBasic information about age, sex, height, body weight, medication utilization, diagnosis, smoking and drinking histories were obtained from all of the subjects. Levels of serum free T3 (FT3), free T4 (FT4), TSH, and anti-thyroid stimulating hormone receptor antibodies (TRAb) were measured by radioimmunoassay with commercially available kits (Roche Diagnostics GmbH, Sandhofer Strasse 116, 68305 Mannhelm, Germany). Fasting plasma glucose levels were measured using the glucose oxidase method (7600 automatic biochemical analyzer, Hitachi High-Tech Science Systems Corporation, Japan).\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec9\" class=\"Section2\"\u003e \u003ch2\u003ePET-CT scan\u003c/h2\u003e \u003cp\u003eIn this study, metabolically active BAT was quantified using PET-CT scan. Room temperature in the PET-CT center (31\u0026deg;12\u0026prime; N, 121\u0026deg;30\u0026prime; E) was maintained at 21\u0026ndash;23\u0026deg;C. All subjects stayed in the room at least for 1 h before the injection of \u003csup\u003e18\u003c/sup\u003eF-FDG at a dose of 5.55\u0026ndash;7.40 MBq/kg body weight through the cubital vein. One hour after the injection, whole-body scans were performed with Biograph 64 PET-CT scanner (SIEMENS, Germany). Calculations were completed with Open PACS and PET-CT Viewer software (\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttp://www.med.harvard.edu/JPNM/DisplayFreeware/\u003c/span\u003e\u003cspan address=\"http://www.med.harvard.edu/JPNM/DisplayFreeware/\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e) (ref. 12). The presence of adipose tissue and the uptake of \u003csup\u003e18\u003c/sup\u003eF-FDG were identified by CT (-250 to -50 Hounsfield units) and PET, respectively. Areas of adipose tissue larger than 4 mm in diameter and with the maximum \u003csup\u003e18\u003c/sup\u003eF-FDG SUV (SUV max) of \u0026ge;\u0026thinsp;2.0 were identified as the active BAT regions (ref. 4). The example of two PET-CT images of subjects with and without active BAT is shown in Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e2\u003c/span\u003e.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cdiv id=\"Sec10\" class=\"Section3\"\u003e \u003ch2\u003eMeasurement of scEMC10 in human serum\u003c/h2\u003e \u003cp\u003eSerum scEMC10 was measured using a double sandwich ELISA kit (PZ0101, Phrenzer Biotechnology, Shanghai, China). Briefly, add 50 \u0026micro;L of assay buffer, scEMC10 standard or human serum samples, and detecting antibody conjugated with HRP sequentially to each well of 96-well immunoplates from the ELISA kit. Seal the immunoplates with sealer film, and then incubate them at room temperature on a microplate shaker set at 500 rpm for 2 hours. Aspirate each well and wash with 300 \u0026micro;L of 1X washing buffer for 4 times. After the last wash, remove any remaining washing buffer by aspirating or decanting. Invert the plates and blot them against clean paper towels. Add 100 \u0026micro;L of TMB substrate to each well and then incubate for 5\u0026ndash;30 minutes at room temperature. Add 100 \u0026micro;L of stop solution to each well. Determine the optical density using a microplate reader set to 450 nm corrected with 570 nm or 630 nm. The ELISA system had an intra- and inter-assay coefficient of variation at 4.9\u0026ndash;6.2% and 3.6\u0026ndash;7.5%, respectively.\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv id=\"Sec11\" class=\"Section2\"\u003e \u003ch2\u003eStatistical Analysis\u003c/h2\u003e \u003cp\u003eAll analyses were performed with Statistical Package for Social Sciences (version 26, SPSS, Chicago, IL, USA) and figures were generated with GraphPad prism (version 8.0, GraphPad Software Inc.). Normally distributed data were described as means\u0026thinsp;\u0026plusmn;\u0026thinsp;standard deviation (SD). Data that are not normally distributed, as determined using Kolmogorov\u0026ndash;Smirnov test, were logarithmically transformed and expressed as median with interquartile range. Student\u0026rsquo;s paired \u003cem\u003et\u003c/em\u003e test was used to compare the differences between different groups. A two-tailed \u003cem\u003eP\u003c/em\u003e value less than 0.05 is considered significant.\u003c/p\u003e \u003c/div\u003e"},{"header":"Results","content":"\u003cdiv id=\"Sec13\" class=\"Section2\"\u003e \u003ch2\u003eSerum scEMC10 levels in participants with positive or negative BAT\u003c/h2\u003e \u003cp\u003eA total of 38 healthy participants with detectable BAT by PET-CT scan were enrolled into the BAT-positive group, and 38 well-matched participants without detectable BAT at ambient temperature were served as the BAT-negative control group. Clinical characteristics between the two groups, such as FBG, SBP, DBP, and heart rate were not statistically different. Although the age and BMI were matched as much as possible, the overall age and BMI of participants with positive BAT were still significantly lower than those with negative BAT (Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e). Serum scEMC10 levels were evaluated in participants of the two groups. There was no statistical difference in serum scEMC10 between BAT-positive and -negative groups regardless of unadjusted (P\u0026thinsp;=\u0026thinsp;0.818) or adjusted (P\u0026thinsp;=\u0026thinsp;0.738) for age, and BMI (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e1\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003e \u003cb\u003eChanges in BAT activity and serum scEMC10 levels of participants with positive BAT before and after thermoneutrality\u003c/b\u003e \u003c/p\u003e \u003cp\u003eSeven participants in the BAT-positive cohort were subject to thermoneutrality (TN) (28\u0026deg;C) for 2 hours. Their clinical characteristics were shown in Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e. Metabolically active BAT, which was identified in cervical and supraclavicular areas by \u003csup\u003e18\u003c/sup\u003eF-FDG PET\u0026ndash;CT scanning before thermoneutrality, disappeared in all these participants after 2-h thermoneutrality (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e2\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eStrikingly, serum scEMC10 levels were robustly elevated by thermoneutrality in all participants, with medians of the cohort at 2.34 and 4.25 ng/mL before and after thermoneutrality, respectively. Statistical analysis revealed the difference significant (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.0017) (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003e). These data suggest scEMC10 exerts an inhibitory effect on human BAT thermogenesis, congruent with its role in mouse models (ref. 9).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec14\" class=\"Section2\"\u003e \u003ch2\u003eThe impact of scEMC10 on thyroid hormone-associated thermogenesis\u003c/h2\u003e \u003cp\u003eThyroid hormones (THs) have been shown an important role in both BAT and whole-body thermogenesis (ref. 8). To determine the possible impact of scEMC10 on thyroid hormone-associated thermogenesis, we firstly investigated the association of serum scEMC10 with THs in a Chinese physical examination cohort and a White cohort. There was no significant association of serum scEMC10 levels with either TSH, free T3, or free T4 in both cohorts regardless of unadjusted or adjusted for gender, age, and BMI (Table\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eWe next assessed the change of serum scEMC10 in patients with hyperthyroidism due to Graves' disease who underwent \u003csup\u003e18\u003c/sup\u003eF-FDG PET\u0026ndash;CT scanning before and after the treatment with methimazole, an anti-thyroid drug (ATD). As shown in Table\u0026nbsp;\u003cspan refid=\"Tab4\" class=\"InternalRef\"\u003e4\u003c/span\u003e, the ATD treatment normalized thyroid functions, along with amelioration of thyrotoxic symptoms in these patients. No active BAT was detected by \u003csup\u003e18\u003c/sup\u003eF-FDG PET\u0026ndash;CT scanning in all patients both before and after the ATD treatment, except one who had no active BAT before the treatment, but exhibited active BAT after the treatment (Fig.\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e4\u003c/span\u003e). All patients showed increased \u003csup\u003e18\u003c/sup\u003eF-FDG uptake in their skeletal muscle before the ATD treatment followed by almost loss of \u003csup\u003e18\u003c/sup\u003eF-FDG deposit after the treatment (Fig.\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e4\u003c/span\u003e). There was no statistical difference in serum scEMC10 levels of these patients between before and after the ATD treatment (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.927) (Fig.\u0026nbsp;\u003cspan refid=\"Fig5\" class=\"InternalRef\"\u003e5\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eTaken together, these observations suggest scEMC10 isn\u0026rsquo;t involved in thyroid hormone-modulated thermogenesis.\u003c/p\u003e \u003c/div\u003e"},{"header":"Discussion","content":"\u003cp\u003eA major advance in the understanding of adipose biology during the past decades is the identification of functionally active BAT in adult humans. The BAT activity in human is determined by multiple factors, including sex, age, BMI, and ambient temperature (ref. 4, 5, 13, 14). In this study, we observed BAT-positive participants are significantly younger and leaner than BAT-negative ones, consistent with other previous studies (ref. 4, 15). However, there was no significant difference in serum scEMC10 between the BAT-negative and -positive groups at room temperature. In BAT-positive participants, serum scEMC10 levels were significantly elevated by thermoneutrality, concomitant with suppression of active BAT determined by PET-CT scan, suggesting scEMC10 acts as a suppressor of BAT activity in humans which is congruent with its inhibitory role in BAT thermogenesis in mice (ref. 9). These findings also suggest scEMC10 a regulatory role in facultative thermogenesis, rather than a role in determining BAT mass in humans. Facultative thermogenesis, which cold exposure activates, while thermoneutrality inactivates, has been linked to human BAT (ref. 14, 16, 17). It has been shown that the regulation of facultative thermogenesis involves the SNS in both rodents and humans (ref. 18, 19). EMC10 has been implicated in the SNS-regulated BAT thermogenesis. \u003cem\u003eEmc10\u003c/em\u003e KO potentiated β3 adrenoceptor agonist-evoked UCP1 expression in brown adipocytes through PKA-CREB/p38 MAPK signaling \u003cem\u003ein vitro\u003c/em\u003e and energy expenditure in mice \u003cem\u003ein vivo\u003c/em\u003e (ref. 9). Collectively, these data suggest scEMC10 suppresses facultative thermogenesis via inhibition of SNS-PKA signaling in humans.\u003c/p\u003e \u003cp\u003eIt is well established that facultative thermogenesis, a quick-response form of nonshivering thermogenesis emanating from BAT, is blunted in obesity, and even its small increases can significantly affect the long-term energy homeostasis, making BAT a promising therapeutic target to treat obesity and its associated metabolic diseases, such as type 2 diabetes (ref. 16, 20, 21). We have proven that a scEMC10-neutralizing antibody is effective in treating diet-induced obesity, impaired glucose tolerance, and fatty liver in mouse, which is mainly attributed to heightened BAT thermogenesis (ref. 9). Consistent with the inhibitory effect of scEMC10 on human BAT activity at thermoneutrality, \u003cem\u003eEmc10\u003c/em\u003e KO prevents diet-induced obesity in mouse under thermoneutral condition (30\u0026deg;C) (ref. 9). Taken together, these observations suggest inhibition of scEMC10 will be a therapeutic strategy to treat obesity and its associated cardiometabolic diseases via enhancing facultative thermogenesis.\u003c/p\u003e \u003cp\u003ePET-CT scanning analysis didn\u0026rsquo;t identify active BAT in patients with hyperthyroidism, which accounts for the observation that serum scEMC10 levels remained unchanged before and after ATD treatment. Of note, there was an apparent reduction in the uptake of \u003csup\u003e18\u003c/sup\u003eF-FDG in whole body, especially in skeletal muscle, after ATD treatment, which coincides with a previous study showing patients with elevated levels of THs exhibited increased whole-body thermogenesis together with an increase in skeletal muscle mitochondrial uncoupling (ref. 22). This may be accounted for by the fact that deiodinase II, a key enzyme converting cellular T4 to more active T3 which in turn increases thermogenesis, is predominantly expressed in skeletal muscle in adult humans (ref. 16, 23). A larger cohort consisting of BAT-positive patients with hyperthyroidism is needed to investigate whether there is an association between serum scEMC10 and TH-regulated BAT activity.\u003c/p\u003e \u003cp\u003eIt has been shown that both BAT and skeletal muscle contribute to nonshivering thermogenesis in humans (ref. 24). The findings of this study that serum scEMC10 is inversely associated with BAT activity, while doesn\u0026rsquo;t correlate with skeletal muscle thermogenesis suggest scEMC10-modulated facultative thermogenesis is BAT-specific and independent of skeletal muscle in humans. This may be explained by different subtypes of β adrenergic receptors present in BAT and skeletal muscle where β3 subtype predominates in BAT, while β2 receptor is the most subtype in skeletal muscle (ref. 7, 25). We have shown that scEMC10 is involved in the β3 adrenoceptor-modulated thermogenesis in BAT (ref. 9). Further experiments are needed to determine whether scEMC10 regulates β2-adrenoceptor signaling in skeletal muscle.\u003c/p\u003e \u003cp\u003eIn conclusion, our data link scEMC10 to BAT facultative thermogenesis, but not to thyroid hormone-associated skeletal muscle thermogenesis in humans. This study renders inhibition of scEMC10 a translational significance in treating obesity and its associated cardiometabolic diseases via activation of BAT activity.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e \u003ch2\u003eCompeting interests\u003c/h2\u003e \u003cp\u003eMB received honoraria as a consultant and speaker from Amgen, AstraZeneca, Bayer, Boehringer-Ingelheim, Lilly, Novo Nordisk, Novartis, Pfizer and Sanofi.\u003c/p\u003e \u003c/p\u003e\u003ch2\u003eFundings\u003c/h2\u003e \u003cp\u003eThe work was supported by National Natural Science Foundation of China (No. 81800691 to QM, No. 82200952 to QZ, No. 82000790 to WW.) and Science and Technology Commission of Shanghai Municipality (No. 22140902700 to XW).\u003c/p\u003e\u003ch2\u003eAuthor Contributions\u003c/h2\u003e \u003cp\u003eQM and XW conceived the research idea, designed the study, and wrote the manuscript. YW measured serum scEMC10 in humans. QZ, WW, FZ, YYa and MB collected the data. QM, YYu and MB analyzed data and performed the statistical analysis. CZ and YG performed PET-CT scans and analyzed the data. CWL and YL proofread the manuscript for clarity and correctness. All authors have agreed to submit the manuscription.\u003c/p\u003e\u003ch2\u003eAcknowledgements\u003c/h2\u003e \u003cp\u003eWe thank Samuel M. Lockhart for his help in discussing the data and preparing the manuscript.\u003c/p\u003e\u003ch2\u003eData availability\u003c/h2\u003e \u003cp\u003eThe data that support the findings of this study are available upon request from the corresponding authors.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eBrown Z, Yoneshiro T. Brown fat thermogenesis and branched-chain amino acids in metabolic disease. Endocr J. 2024; 71:89\u0026ndash;100.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLiu X, Zhang Z, Song Y, Xie H, Dong M. An update on brown adipose tissue and obesity intervention: Function, regulation and therapeutic implications. Front Endocrinol (Lausanne). 2023; 13:1065263.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSingh R, Barrios A, Dirakvand G, Pervin S. Human Brown Adipose Tissue and Metabolic Health: Potential for Therapeutic Avenues. Cells. 2021; 10:3030.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eCypess AM, Lehman S, Williams G, Tal I, Rodman D, Goldfine AB, et al. Identification and importance of brown adipose tissue in adult humans. N Engl J Med. 2009; 360:1509\u0026ndash;17.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003evan Marken Lichtenbelt WD, Vanhommerig JW, Smulders NM, Drossaerts JM, Kemerink GJ, Bouvy ND, et al. Cold-activated brown adipose tissue in healthy men. N Engl J Med. 2009; 360:1500\u0026ndash;8.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMorrison SF, Madden CJ, Tupone D. Central neural regulation of brown adipose tissue thermogenesis and energy expenditure. Cell Metab. 2014; 19:741\u0026ndash;56.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eCannon B, Nedergaard J. Brown adipose tissue: function and physiological significance. Physiol Rev. 2004; 84:277\u0026ndash;359.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSilva JE. Thermogenic mechanisms and their hormonal regulation. Physiol Rev. 2006; 86:435\u0026ndash;64.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eWang X, Li Y, Qiang G, Wang K, Dai J, McCann M, et al. Secreted EMC10 is upregulated in human obesity and its neutralizing antibody prevents diet-induced obesity in mice. Nat Commun. 2022; 13:7323.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eChen K, Wang Y, Yang J, Kl\u0026ouml;ting N, Liu C, Dai J, et al. EMC10 modulates hepatic ER stress and steatosis in an isoform specific manner. J Hepatol. 2024; doi: \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1016/j.jhep.2024.03.047\u003c/span\u003e\u003cspan address=\"10.1016/j.jhep.2024.03.047\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eChen K, Dai J, Kl\u0026ouml;ting N, Cao X, Jin S, Chen L, et al. Serum scEMC10 Levels are Negatively Associated With Resting Metabolic Rate and age in Humans. J Clin Endocrinol Metab. 2023; 108:e1074-e1081.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBarbaras L, Tal I, Palmer MR, Parker JA, Kolodny GM. Shareware program for nuclear medicine and PET/CT PACS display and processing. AJR Am J Roentgenol. 2007; 188:W565-8.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eNedergaard J, Bengtsson T, Cannon B. Unexpected evidence for active brown adipose tissue in adult humans. Am J Physiol Endocrinol Metab. 2007; 293:E444-52.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSaito M, Okamatsu-Ogura Y, Matsushita M, Watanabe K, Yoneshiro T, Nio-Kobayashi J, et al. High incidence of metabolically active brown adipose tissue in healthy adult humans: effects of cold exposure and adiposity. Diabetes. 2009; 58:1526\u0026ndash;31.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eZhang Q, Ye H, Miao Q, Zhang Z, Wang Y, Zhu X, et al. Differences in the metabolic status of healthy adults with and without active brown adipose tissue. Wien Klin Wochenschr. 2013; 125:687\u0026ndash;95.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003evan Marken Lichtenbelt WD, Schrauwen P. Implications of nonshivering thermogenesis for energy balance regulation in humans. Am J Physiol Regul Integr Comp Physiol. 2011; 301:R285-96.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eVijgen GH, Bouvy ND, Teule GJ, Brans B, Schrauwen P, van Marken Lichtenbelt WD. Brown adipose tissue in morbidly obese subjects. PLoS One. 2011; 6:e17247.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eThomas SA, Palmiter RD. Thermoregulatory and metabolic phenotypes of mice lacking noradrenaline and adrenaline. Nature. 1997; 387:94\u0026ndash;7.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eCeli FS, Brychta RJ, Linderman JD, Butler PW, Alberobello AT, Smith S, et al. Minimal changes in environmental temperature result in a significant increase in energy expenditure and changes in the hormonal homeostasis in healthy adults. Eur J Endocrinol. 2010; 163:863\u0026ndash;72.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLidell ME, Betz MJ, Enerb\u0026auml;ck S. Brown adipose tissue and its therapeutic potential. J Intern Med. 2014; 276:364\u0026ndash;77.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eCannon B, Nedergaard J. Nonshivering thermogenesis and its adequate measurement in metabolic studies. J Exp Biol. 2011; 214:242\u0026ndash;53.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMitchell CS, Savage DB, Dufour S, Schoenmakers N, Murgatroyd P, Befroy D, et al. Resistance to thyroid hormone is associated with raised energy expenditure, muscle mitochondrial uncoupling, and hyperphagia. J Clin Invest. 2010; 120:1345\u0026ndash;54.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSalvatore D, Bartha T, Harney JW, Larsen PR. Molecular biological and biochemical characterization of the human type 2 selenodeiodinase. Endocrinology. 1996; 137:3308\u0026ndash;15.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eWijers SL, Schrauwen P, van Baak MA, Saris WH, van Marken Lichtenbelt WD. Beta-adrenergic receptor blockade does not inhibit cold-induced thermogenesis in humans: possible involvement of brown adipose tissue. J Clin Endocrinol Metab. 2011; 96:E598-605.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLynch GS, Ryall JG. Role of beta-adrenoceptor signaling in skeletal muscle: implications for muscle wasting and disease. Physiol Rev. 2008; 88:729\u0026ndash;67.\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"international-journal-of-obesity","isNatureJournal":false,"hasQc":false,"allowDirectSubmit":false,"externalIdentity":"ijo","sideBox":"Learn more about [International Journal of Obesity](http://www.nature.com/ijo/)","snPcode":"41366","submissionUrl":"https://mts-ijo.nature.com/cgi-bin/main.plex","title":"International Journal of Obesity","twitterHandle":"@intjobesity","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"ejp","reportingPortfolio":"Nature AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":false},"keywords":"scEMC10, Brown adipose tissue, Thyroid hormone, Facultative thermogenesis","lastPublishedDoi":"10.21203/rs.3.rs-4358548/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-4358548/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eBackground/Objectives:\u003c/strong\u003e Secreted endoplasmic reticulum membrane complex subunit 10 (scEMC10) has been implicated in obesity in mice and humans. In this study, the associations of serum scEMC10 levels with thermoneutrality-modulated brown adipose tissue (BAT) activity and thyroid hormone (TH)-dependent thermogenesis were investigated in humans.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eSubjects/Methods: \u003c/strong\u003eSerum scEMC10 levels were measured in participants from manifold cohorts using enzyme-linked immunosorbent assay, including participants with or without active BAT determined by PET-CT scanning, BAT-positive participants before and after thermoneutrality, and patients with hyperthyroidism before and after an anti-thyroid drug treatment. The difference in serum scEMC10 between BAT-positive and -negative participants, and the changes of serum scEMC10 in BAT-positive participants before and after thermoneutrality and in patients with Grave’s disease-caused hyperthyroidism before and after an anti-thyroid drug (ATD) treatment were determined.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eResults:\u003c/strong\u003e \u003csup\u003e18\u003c/sup\u003eF-FDG PET–CT scanning indicated BAT-positive participants were significantly younger and leaner than BAT-negative ones. There was, however, no significant difference in serum scEMC10 between the two groups. Serum scEMC10 levels in BAT-positive participants were significantly elevated by 2-hour thermoneutrality (\u003cem\u003eP\u003c/em\u003e = 0.0017), concomitant with disappearance of active BAT. No significant association of serum scEMC10 with serum levels of either TSH, FT3, or FT4 was observed in participants from both Chinese and White cohorts. ATD treatment normalized thyroid function and reduced the uptake of \u003csup\u003e18\u003c/sup\u003eF-FDG in skeletal muscle of patients with hyperthyroidism. Serum scEMC10 concentration, however, remained unchanged in these patients before and after ATD treatment.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConclusions: \u003c/strong\u003eSerum scEMC10 levels are inversely associated with metabolically active BAT, suggesting scEMC10 a suppressive role in facultative thermogenesis in humans. This finding implicates inhibition of scEMC10 in the treatment of obesity and its associated cardiometabolic diseases.\u003c/p\u003e","manuscriptTitle":"Serum secreted EMC10 (scEMC10) levels are inversely associated with metabolically active brown adipose tissue in humans","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-06-05 22:27:58","doi":"10.21203/rs.3.rs-4358548/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"revise","date":"2024-10-15T13:41:54+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"This content is not available.","date":"2024-09-09T18:48:34+00:00","index":3,"fulltext":"This content is not available."},{"type":"editorInvitedReview","content":"This content is not available.","date":"2024-09-02T01:18:55+00:00","index":2,"fulltext":"This content is not available."},{"type":"reviewerAgreed","content":"This content is not available.","date":"2024-08-15T16:47:43+00:00","index":3,"fulltext":"This content is not available."},{"type":"reviewerAgreed","content":"This content is not available.","date":"2024-07-26T05:19:34+00:00","index":2,"fulltext":"This content is not available."},{"type":"editorInvitedReview","content":"This content is not available.","date":"2024-06-17T14:28:01+00:00","index":1,"fulltext":"This content is not available."},{"type":"reviewerAgreed","content":"This content is not available.","date":"2024-06-05T13:57:30+00:00","index":1,"fulltext":"This content is not available."},{"type":"reviewersInvited","content":"","date":"2024-05-20T16:18:16+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2024-05-07T10:41:43+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2024-05-02T10:27:32+00:00","index":"","fulltext":""},{"type":"submitted","content":"International Journal of Obesity","date":"2024-05-02T10:27:32+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"international-journal-of-obesity","isNatureJournal":false,"hasQc":false,"allowDirectSubmit":false,"externalIdentity":"ijo","sideBox":"Learn more about [International Journal of Obesity](http://www.nature.com/ijo/)","snPcode":"41366","submissionUrl":"https://mts-ijo.nature.com/cgi-bin/main.plex","title":"International Journal of Obesity","twitterHandle":"@intjobesity","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"ejp","reportingPortfolio":"Nature AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":false}}],"origin":"","ownerIdentity":"07f4a933-bc90-4d32-95a8-9e2d9b6226d4","owner":[],"postedDate":"June 5th, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[{"id":32163673,"name":"Health sciences/Endocrinology/Endocrine system and metabolic diseases/Obesity"},{"id":32163674,"name":"Biological sciences/Physiology/Metabolism/Fat metabolism"}],"tags":[],"updatedAt":"2025-03-19T07:07:20+00:00","versionOfRecord":{"articleIdentity":"rs-4358548","link":"https://doi.org/10.1038/s41366-025-01744-2","journal":{"identity":"international-journal-of-obesity","isVorOnly":false,"title":"International Journal of Obesity"},"publishedOn":"2025-03-18 04:00:00","publishedOnDateReadable":"March 18th, 2025"},"versionCreatedAt":"2024-06-05 22:27:58","video":"","vorDoi":"10.1038/s41366-025-01744-2","vorDoiUrl":"https://doi.org/10.1038/s41366-025-01744-2","workflowStages":[]},"version":"v1","identity":"rs-4358548","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-4358548","identity":"rs-4358548","version":["v1"]},"buildId":"qtupq5eGEP_6zYnWcrvyt","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}