White adipose tissue browning and cross-talk with metabolic diseases and tumors: from molecular mechanisms to clinical translation

The process of browning of white adipose tissue has emerged as a focal point in research endeavors focused on anti-obesity and metabolic disease treatment in recent years. This process has been demonstrated to significantly increase energy expenditure and non-shivering thermogenesis, suggesting potential clinical applications. Recent research findings indicate that the process of white adipose tissue browning is governed by intricate molecular regulatory mechanisms, encompassing the interplay of hormones, signaling pathways, transcription factors, and metabolites. Despite the numerous studies that have elucidated its mechanisms, the specific regulatory process remains to be thoroughly investigated. This article systematically reviews the molecular regulatory mechanisms of white adipose tissue browning. It discusses in detail various stimulation methods, such as cold exposure, drug intervention, nutritional factors, exercise, and microbiome regulation. The article analyzes the current status of research on its role in the prevention and treatment of metabolic diseases and tumor progression based on the latest research results. This article synthesizes both traditional and contemporary research to provide a comprehensive reference for understanding the mechanisms of white adipose tissue browning and its clinical translation.

The global prevalence of obesity and related metabolic syndromes has reached an unprecedented level of severity. According to the 2023 Global Obesity Map, it is projected that by 2035, the global population of overweight or obese individuals will exceed 4 billion (accounting for 51% of the global population), with China’s adult overweight rate expected to reach 41%. 1 White adipose tissue (WAT) mainly functions as an energy storage organ, with its primary function being lipid storage. 2 Brown adipose tissue (BAT) is specialized in the production of heat and the consumption of energy. It increases heat production through the expression of highly expressed mitochondria and UCP1, which uncouples the respiratory chain. 3 Beige fat is an inducible adipocyte that is converted from WAT under specific stimulation. Beige fat combines the storage capacity of WAT with the heat production characteristics of BAT. It is widely regarded as a pivotal factor in addressing energy metabolism imbalances. 4,5 Obesity is not merely a consequence of energy metabolism imbalance; it is also an indication of adipose tissue dysfunction. In recent years, the transformation of WAT into beige fat, known as WAT browning, has emerged as a pivotal strategy in the fight against obesity. 6-10 WAT browning is a significant metabolic conversion process that is characterized by the activation of specific transcription factors, such as PRDM16, and the expression of UCP1. This process is crucial for thermogenesis. 11-13 In the field of tumor research, the process of WAT browning has been shown to impede the initiation of tumor progression by modifying the tumor microenvironment, disrupting cancer cell metabolism, and regulating proliferation mechanisms. 14,15 As indicated by the findings of several other studies, a close association exists between WAT browning and cancer-associated cachexia (CAC). CAC is characterized by accelerated fat and muscle wasting, leading to energy dissipation and weight loss. This process has been reported in multiple cancer models. 16-18 This browning process is frequently accompanied by unfavorable outcomes in the tumor environment, thereby giving rise to a contentious debate concerning whether its deleterious effects may potentially exceed its potential benefits. 19 In the field of metabolic syndrome research, the concept of WAT browning has emerged as a potential therapeutic approach for addressing obesity and enhancing metabolic syndrome outcomes. 20-23 However, this perspective is not universally accepted, and controversy has emerged regarding the potential adverse effects of browning, including its association with the exacerbation of metabolic disorders under hypermetabolic conditions or the induction of clinical challenges, and the limitations of its therapeutic effects in translational applications. 18,19 Additionally, the molecular regulatory mechanisms underlying WAT browning remain to be fully elucidated, and the regulatory involvement of multiple signaling pathways is not yet fully understood. Consequently, a comprehensive review of this field was undertaken to systematically analyze its molecular regulatory network and induction methods, explore its clinical translation in metabolic diseases and tumors, and integrate new clinical intervention strategies, with the objective of providing a theoretical basis for the development of precise and safe treatments. ADIPOSE TISSUE PLASTICITY Adipose tissue is a pivotal regulatory organ of energy metabolism, and its heterogeneity is manifested in a triple differentiation pattern of WAT, BAT, and beige adipose tissue. 24-26 White adipose tissue WAT is the primary energy storage organ in the human body, accounting for more than 90% of total adipose tissue. 27-30 Its hallmark morphological feature is a single-chambered lipid droplet structure, with lipid droplets occupying more than 90% of the cell volume and a low mitochondrial content. 31-34 Anatomically, WAT can be categorized into two distinct classifications: subcutaneous WAT (sWAT), which is distributed in the abdomen, buttocks, and thighs, and serves as the primary energy storage site, accounting for approximately 80% of total adipose tissue, and visceral WAT, which is distributed in the omentum, mesentery, and perirenal regions, accounting for approximately 5%-20%. 35,36 Visceral WAT, due to its high expression of β-adrenergic receptors (β-ARs), exhibits significantly higher lipolytic activity compared to sWAT. 37 Its excessive proliferation leads to the excessive release of free fatty acids (FFA), which, through the portal venous circulation, trigger insulin resistance(IR) in the liver and systemic inflammation. This makes it a core pathological factor in metabolic syndrome. 38-40 WAT accomplishes energy storage through the uptake and subsequent formation of lipid droplets, a process that is mediated by lipoprotein lipase (LPL). Additionally, WAT functions as a significant endocrine organ, secreting hormones such as leptin and adiponectin, which regulate appetite and insulin sensitivity, respectively. 41-44 However, browning is more prevalent in sWAT and is associated with beneficial metabolic effects, including improved insulin sensitivity and reduced obesity-related insulin secretion. 45-47 It is noteworthy that white adipose cells originate from Myf5- progenitor cells, and adipose tissue droplet expansion leading to an increase in adipose cell volume and number is a characteristic of obese adipose tissue. 48-50 Brown adipose tissue BAT originates from Myf5+ progenitor cells and is primarily found in the neck and back of newborns and adults, with a high mitochondrial content. 33,51 It has been demonstrated that this process facilitates non-shivering thermogenesis through the action of UCP1. 52,53 BAT’s thermogenic capacity is known to be activated by the sympathetic-adrenergic pathway (β3-AR/cAMP-PKA axis). This pathway is further regulated by the PGC1α-PRDM16 transcriptional axis, which plays a crucial role in mitochondrial biogenesis. 54-58 Its enhanced non-shivering thermogenesis has been demonstrated to increase energy expenditure, thereby counteracting obesity. 59 In adults, the distribution of functional BAT is primarily located in the neck, supraclavicular, mediastinal, paravertebral, and adrenal regions. 60 BAT is distinguished by the presence of small lipid droplets and a high number of mitochondria. These mitochondria decouple the electron transport chain from adenosine triphosphate (ATP) synthesis via UCP1, thereby facilitating non-shivering thermogenesis and energy expenditure. 46,61-63 The presence of BAT has been demonstrated to exhibit a negative correlation with obesity. Moreover, the thermogenic activation of BAT in adults has been shown to enhance metabolic rate, improve insulin sensitivity, and regulate lipid metabolism. 57,64-66 Beige adipocytes The transformation of beige adipocytes from WAT is a process known as ”white adipose browning,” which is induced by cold exposure, physical exertion, or pharmaceutical stimulation. These cells possess both the storage capacity of WAT and the thermogenic function of BAT. 5,67 Beige adipose cells have been found to express thermogenic genes such as UCP1 and Cidea; however, their mitochondrial density is lower than that of classic BAT. Furthermore, these cells are reversible, reverting to a white phenotype in hot environments. 51,68,69 The presence of beige adipose tissue clusters has been observed in sWAT, as well as in limited visceral WAT. 48,51 Beige adipocytes are morphologically and differentiationally intermediate between white and brown adipocytes. They contain small multilocular lipid droplets and a large number of large mitochondria, which affect energy expenditure. 61-63 In contrast, beige adipocytes are derived from a more diverse array of origins, as they are capable of transdifferentiation from white adipocytes and can be formed through alternative pathways. In mouse experiments, beige adipose cells were found to originate from progenitor cells expressing PDGFRα+ or PDGFRβ+ in vivo, smooth muscle cells expressing Myh11+, or precursor cells residing in the vascular system of adipose tissue, as well as from precursor cells expressing EBF2. 70-72 Effects of aging and environmental factors on adipose tissue Aging and environmental factors have been demonstrated to induce significant impairment to adipose tissue function, thereby affecting metabolic health and disease risk. 73 The process of aging is associated with alterations in the distribution and function of adipose tissue. 74,75 Comprehension of these age-related changes is imperative for the development of targeted interventions aimed at mitigating the effects of aging on. As individuals age, there is a decline in BAT activity, while the process of WAT browning leads to an increase in thermogenic potential and energy expenditure. 5,60 Environmental factors such as diet, physical activity, and cold exposure influence the dynamic changes in adipose tissue, including the activation of brown and beige adipose tissue, which are crucial for thermogenesis and metabolic health. 67 The ingestion of particular nutrients and bioactive compounds has been demonstrated to promote WAT browning and enhance metabolic health. 76 Physical exercise has been shown to stimulate skeletal muscle to release cytokines, such as irisin, which in turn induce WAT browning and improve insulin sensitivity. 77 These findings underscore the significance of making lifestyle modifications to enhance adipose tissue function. The presence of environmental pollutants and endocrine-disrupting chemicals has been demonstrated to have a deleterious effect on adipose tissue function, resulting in alterations in adipose cell differentiation and the promotion of metabolic dysfunction. 78,79 Furthermore, the gut microbiota is influenced by diet and the environment, playing a crucial role in adipose tissue metabolism, obesity, and the development of metabolic syndrome. 80,81 Changes in gut microbiota composition are key factors in the development of obesity, type 2 diabetes, and non-alcoholic fatty liver disease. 82,83 BIOLOGICAL BASIS OF ADIPOSE TISSUE The developmental origins and anatomical distribution of adipose tissue subtypes exhibit considerable heterogeneity, which arises from the complex interplay between lineage differentiation and microenvironmental regulation. 84 Elucidation of the underlying molecular mechanisms could facilitate the development of precision therapies for metabolic diseases. Developmental Origins of Adipose Subtypes The spatiotemporal dynamics of adipose tissue are reflected in its developmental lineage and regional specificity. Myf5+ progenitor cells primarily participate in the differentiation of BAT, while Myf5- progenitor cells differentiate into WAT and beige adipocytes. 48 Studies have demonstrated that PDGFRα+ progenitor cells expressed in WAT possess bidirectional differentiation potential and can differentiate into beige adipocytes or WAT under β-adrenergic stimulation or a high-fat diet (HFD), respectively. 85 Furthermore, studies have demonstrated that PDGFRα+ progenitor cells possess the capacity to differentiate into myofibroblast-like cells, which are known to induce fibrosis. 62 Metabolic heterogeneity in adipocytes is closely associated with the anatomical gradient distribution of their molecular markers. Research has demonstrated that elevated levels of ZFP423 in visceral WAT induce a suppression of early B-cell factors (EBF2), consequently impeding the expression of thermogenic genes (e.g., UCP1). Concurrently, this suppression enhances BMP (bone morphogenetic protein) signaling, thereby activating fibrosis-related pathways (e.g., TGF-β/Smad), resulting in excessive extracellular matrix deposition and collagen accumulation. 66,86,87 Conversely, EBF2 expression in sWAT has been shown to activate β3-adrenergic receptor signaling through cold stimulation, inducing the formation of the PRDM16-PPARγ complex and driving brown adipose differentiation and mitochondrial thermogenesis. 72,88 In addition, in cases of chronic caloric excess, visceral adipose tissue expansion is frequently accompanied by the accumulation of pro-inflammatory macrophages (M1-type macrophages). These macrophages release pro-inflammatory factors, such as IL-6 and TNF-α, which in turn exacerbate fibrosis and IR. 89 Adiponectin in sWAT binds to T-cadherin to form a local signaling axis that recruits M2-type macrophages, synergistically enhancing thermogenic adaptability. 90 This spatially specific regulatory network of molecular networks reveals the underlying mechanisms of visceral WAT metabolic vulnerability and sWAT-induced browning plasticity. Regional adipose deposition characteristics and their interactions with the tumor microenvironment The deposition of adipose tissue in distinct anatomical regions engenders unique interactive networks with the tumor microenvironment. The targeting of the regional adipose-tumor axis has the potential to emerge as a novel therapeutic strategy. The metabolic interaction network between breast cancer and the adipose microenvironment exerts a profound influence on tumor progression. Among the various cell types surrounding breast tumor epithelial cells, the most abundant are adipocytes, constituting breast adipose tissue. 91 Breast cancer cells have been observed to induce neighboring adipocytes to dedifferentiate into cancer-associated adipocytes (CAAs). CAAs are characterized by reduced surface lipid droplets and upregulation of lipolysis enzymes (ATGL/HSL). Furthermore, CAAs establish metabolic coupling via monocarboxylate transporters (MCTs). 92,93 CAAs transport lactate and ketone bodies to tumor cells via MCT4-mediated “reverse Warburg effect”, while the IL-6/JAK/STAT3 pathway enhances tumor stem cell characteristics. 94-96 In the context of lipid metabolism reprogramming, the release of FFAs by CAAs is absorbed by tumor cells via the surface transporter CD36, thereby augmenting mitochondrial β-oxidation capacity by a factor of three. 97,98 Furthermore, the role of microRNA-144 in breast cancer cells involves the regulation of beige/brown differentiation of CAA, a process that is facilitated by the downregulation of the MAP3K8/ERK1/2/PPARγ axis. 99 The interaction between pancreatic cancer and peripancreatic adipose tissue exhibits distinct characteristics. CAAs in the pancreatic cancer microenvironment support tumor progression through lipid metabolism reprogramming. CAAs not only activate PI3K/Akt, MAPK, and STAT3 signaling pathways by secreting cytokines such as IL-6, MCP-1, and M-CSF, thereby promoting cancer cell homing, proliferation, migration, and invasion. 100,101 Moreover, CAAs have been shown to upregulate proteins, including SAA1, FABP4, and CD36, thus promoting the invasiveness and drug resistance of pancreatic cancer. 102,103 Research has demonstrated that intrapancreatic adipose infiltration, also known as pancreatic steatosis, is associated with an elevated risk of developing pancreatic intraepithelial neoplasia (PanIN). The underlying mechanism involves the secretion of transforming growth factor-β (TGF-β) and hyaluronic acid by adipocytes, which remodel the extracellular matrix to establish a pro-fibrotic microenvironment. 104,105 Prostate cancer has been observed to invade the surrounding adipose tissue (PPAT), thereby forming a unique adipose-tumor interface. 106 Research has demonstrated a positive correlation between PPAT thickness and the aggressiveness of PCa. 107 Consequently, PPAT, a type of WAT, plays a pivotal role in the progression of PCa. PPAT has been shown to release various cytokines, such as IL-6, TNF-α, chemokines (e.g., CCL7), and lactotransferrin (e.g., osteopontin), which have been identified as promoting factors for PCa growth, migration, and invasion. 108-110 Furthermore, Liotti et al. utilized conditioned medium from human PPAT to treat PCa cells and discovered that IGF-1, released by PPAT, augmented TUBB2B expression and resistance to DCTX in PCa cell lines. 111 It has been demonstrated that periprostatic adipose tissue in obese patients exhibits elevated aromatase activity, resulting in increased local estrogen levels. These elevated estrogen levels have been found to be closely associated with the development of ER-positive prostate cancer. 112 Mesenteric adipocytes have been identified as the primary mediators of ovarian cancer metastasis to the omentum. Research has demonstrated that factors secreted by omental adipocytes, including IL-6, IL-8, and MCP1, promote cell migration and facilitate ovarian cancer cell colonization within the omentum. 113 Furthermore, adipocytes have been observed to induce increased expression of a specific protein, known as FABP4, in ovarian cancer cells. This induction has been shown to play a pivotal role in promoting tumor metastasis and mediating carboplatin resistance. 114 In contrast, ovarian cancer cells have been observed to induce lipolysis in adipocytes, resulting in the release of FFAs. These FFAs enter cancer cells via CD36 receptor-mediated transport, thereby promoting rapid tumor growth. 115 Wang et al. discovered that extracellular vesicles (EVs) derived from peritoneal adipose-derived stem cells (ADSCs-EVs) are abundant in epidermal growth factor receptor (EGFR) signaling molecules, including EGF and EGFR. When fused with ovarian cancer cells, ADSCs-EVs have been observed to upregulate the EGFR-NF-κB axis, thereby promoting the proliferation and migration of ovarian cancer cells. 116 Visceral adipose tissue has been shown to play a unique role in the development of liver cancer and colorectal cancer. In the case of liver cancer, the following is observed: WAT secretes leptin, which activates oncogenic pathways such as PI3K/Akt and upregulates human telomerase reverse transcriptase (hTERT) in HCC cells. 117,118 Furthermore, FFA released from visceral WAT enter the liver via the portal vein, and elevated hepatic FFA levels induce hepatic lipid synthesis, gluconeogenesis, and IR, thereby triggering oxidative stress and endoplasmic reticulum stress, and consequently promoting liver cell damage and carcinogenesis. 119 In the case of colorectal cancer, dysbiosis of the microbiota in mesenteric WAT has been demonstrated to increase intestinal barrier permeability, which may exert an additional effect on the development of colorectal cancer by inducing metabolic endotoxemia. 120 Research has demonstrated that WAT-secreted leptin facilitates tumor proliferation and survival through the ObRL/STAT3 signaling pathway in colon tumors. Moreover, tumor proliferation is suppressed even in severe obesity in the absence of leptin and its receptors. 121 A substantial body of clinical research has demonstrated a positive and significant relationship between colorectal cancer risk and body roundness index, particularly in individuals with a BMI ≥ 25 kg/m 2 . 122 MOLECULAR REGULATORY MECHANISMS OF WAT BROWNING Hormonal regulation Thyroid hormones and their signaling pathways Thyroid hormones (TH) play a crucial role in regulating energy metabolism and body temperature balance in living organisms. Research has demonstrated that TH not only stimulate the activation of BAT but also induce the browning process of WAT, thereby enhancing energy consumption and heat production. 123 Specifically, TH bind to thyroid hormone receptors (TR) within cells, activating a series of downstream signaling pathways that regulate the expression of genes associated with energy metabolism. 124 Research has demonstrated that TRβ serves as a mediator for T3-regulated Ucp1 mRNA expression, a process that occurs independently of the sympathetic nervous system. 125,126 Furthermore, the expression of Ucp1 in the inguinal WAT (iWAT) of T3-stimulated mice is contingent upon TRβ. 126 Thyrotropin regulation Elevated TSH levels have been demonstrated to significantly inhibit the browning of WAT, which is characterized by decreased energy expenditure, increased adipose accumulation, and concomitant abnormal sugar and lipid metabolism. 127 A series of experiments have demonstrated that the elimination of the thyroid-stimulating hormone receptor (TSHR) in mice has led to a substantial increase in the number of beige adipose cells within the WAT, encompassing both the epididymal and inguinal subcutaneous WAT. Concurrently, these experiments have shown a notable rise in energy expenditure. The activation of the AMPK/PRDM16/PGC1α signaling pathway has been identified as a potential mechanism underlying this process. 127 Furthermore, the regulation of adipose tissue function by TSH is observed to be tissue-specific. In adipose tissue-specific TSHR knockout mice, the thermogenic capacity of both white and BAT was impaired. 128 This metabolic abnormality has been linked to dysregulation of genes involved in lipid metabolism (e.g., ADIPOQ and LEP) and thermogenesis-related gene expression, resulting from TSH signaling deficiency. 128 β-adrenergic signaling pathway The role of β-ARs in regulating the browning of WAT has garnered significant attention in recent research. Research has demonstrated that β-AR agonists (e.g., isoproterenol) substantially enhance the gene expression of uncoupling proteins UCP1 and UCP3 by activating PGC-1α (PPARγ co-activator 1α) and PPARγ, consequently augmenting thermogenesis. 129,130 Paz et al. found that after treatment with β3-adrenergic receptor agonists, the expression of BAT-specific genes such as UCP1, PPARγ, and PGC-1α (PPARγ coactivator 1α) significantly increased in WAT, indicating that the β-AR signaling pathway activates the browning of adipocytes. 131 The specific mechanism by which this occurs may be that the activation of β3-AR increases intracellular cAMP content and activates PKA. This, in turn, leads to heterodimerization of retinoid X receptor (RXR) and nuclear receptor interaction to enhance UCP1 transcription, thereby promoting WAT browning. 132 Furthermore, the expression of β1-AR in white adipocytes has been observed to induce lipodysplasia, increased mitochondrial biogenesis, and nuclear migration. These phenotypes bear a strong resemblance to the thermogenic characteristics of brown adipocytes. 133 Regulatory network of transcription factors and coactivators Transcription factors and coactivators also play an important role in the regulation of white adipose browning. As previously mentioned, key transcription factors such as PPARγ (peroxisome proliferator-activated receptor γ) and PGC-1α (peroxisome proliferator-activated receptor γ coactivator 1α) play a crucial role in regulating the development and function of BAT. Peroxisome Proliferator-Activated Receptors (PPARs) Peroxisome proliferator-activated receptor (PPAR) agonists have been identified as critical regulators of adipocyte differentiation, glucose and lipid metabolism, and inflammation. Of particular interest are the roles of PPARα and PPARγ, which have been directly associated with thermogenesis. Rosiglitazone has been identified as a peroxisome proliferator-activated receptor gamma (PPARγ) agonist. Research findings have demonstrated that prolonged treatment with rosiglitazone leads to the browning of epididymal WAT in murine models. 134 Additionally, magnolol activates the Peroxisome Proliferator-Activated Receptor gamma (PPARγ) signaling pathway, leading to increased UCP1 expression, enhanced thermogenesis in adipose tissue, and anti-obesity effects. 135 PPARγ has been observed to interact with early B-cell factor-2 (EBF2), PRDM16, or PGC1α, thereby initiating the processes of brownification and thermogenesis in adipose tissue. 136 Xu et al. found that activation of the AMPK/silent information regulator 1 (SIRT1)/PGC1α pathway enhances peroxisome proliferator-activated receptor gamma (PPARγ)-mediated browning effects. 137 As demonstrated in prior studies, the administration of PPARα agonists has been observed to induce a lipid combustion response, superseding the anticipated glucose combustion response. The dual activation of PPARα/γ has been shown to promote the formation of a beige adipose phenotype by enhancing mitochondrial metabolism and UCP1-dependent/independent thermogenesis. 138,139 PR domain protein 16 (PRDM16) PRDM16, a pivotal transcription factor, has been demonstrated to play a critical role in the differentiation and functionality of brown and beige adipocytes. PRDM16 has been identified as a critical activator of PPARγ during WAT, forming a complex with PPARγ to regulate the expression of UCP1 and other browning genes, thereby inhibiting WAT genes and promoting WAT browning. 140 Research has demonstrated that PRDM16 enhances binding with PPARγ at the Arg240 site through methylation (mediated by PRMT4), thereby initiating the brownification and thermogenesis gene program in adipose tissue. 141 PRDM16 has been shown to promote mitochondrial biogenesis and oxidative phosphorylation by increasing the expression of UCP1 and PGC1α, thereby enhancing the thermogenic capacity of adipocytes. A multitude of experiments have demonstrated that PRDM16 overexpression results in a substantial augmentation of mitochondrial respiration and energy expenditure. This finding has been substantiated through the use of both mouse models and cell-based experiments. 142 For instance, in conditions of cold exposure, there is an increase in PRDM16 expression in iWAT, accompanied by elevated UCP1 and PGC1α levels. 143,144 In the context of microenvironment formation, researchers have determined that vascular endothelial growth factor (VEGF)-induced angiogenesis is a prerequisite for WAT browning. 145 For instance, elevated levels of vascular endothelial growth factor (VEGF) in the adipose tissue of patients with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) have been shown to promote PRDM16-dependent browning through vascular-adipocyte interactions. 18 Peroxisome proliferator-activated receptor gamma coactivator 1α (PGC-1α) PGC-1α integrates mitochondrial function, energy metabolism, and transcriptional regulatory networks, establishing it as a core regulatory node in WAT browning. PGC-1α, a pivotal regulator of mitochondrial biosynthesis, directly activates the expression of UCP1, a central protein implicated in brown adipose thermogenesis. 146 This process promotes the conversion of WAT to beige adipose tissue with thermogenic function by enhancing mitochondrial respiratory chain activity and energy expenditure. The expression and activity of PGC-1α are subject to regulation by AMPK and SIRT1. The specific mechanism by which this occurs may involve the phosphorylation of PGC-1α by AMPK, resulting in a synergistic enhancement of its transcriptional activity in conjunction with SIRT1. This, in turn, leads to an upregulation of brown adipogenesis markers, such as UCP1 and PRDM16. 137 The research has identified 5-(hydroxy)-pentadeca-5,11,15-trisenoic acid (5-HEPE) as a critical mediator in enhancing energy metabolism and promoting browning of adipocytes in mice fed a HFD. This effect is achieved through the activation of the GPR119/AMPK/PGC1α pathway. 147 Additionally, berberine administration has been shown to enhance the expression of UCP1 and thermogenic genes in WAT and primary brown adipocytes through mechanisms involving AMPK and PGC-1α. 148 In enhancing the metabolic microenvironment, PGC-1α fosters a microenvironment conducive to browning by decreasing inflammatory adipokines and suppressing NLRP3 inflammasome activity. 146,149 For instance, purple sweet potato extract (PSP) has been shown to promote visceral WAT browning by upregulating PGC-1α and UCP1 while inhibiting HIF-1α. 149 Heat shock transcription factor 1 (HSF1) The activation of HSF1 has been demonstrated to enhance the thermogenic capacity of beige adipocytes, as well as to promote the expression of other genes related to metabolism. Research has demonstrated that HSF1 enhances the transcription levels of pivotal metabolic genes through its direct interaction with the promoter region of the RNA-binding protein HNRNPA2B1 (A2B1). A2B1 has been demonstrated to stabilize the mRNA of pivotal metabolic genes (e.g., PGC1α, UCP1, etc.), thereby prolonging their half-life and enhancing the expression of these genes. 7 Furthermore, the study demonstrated that individuals carrying HSF1 functional enhancement variants (such as p.Pro365Thr) exhibited lower BMI and enhanced metabolic health markers, including blood glucose and lipid levels. These findings suggest that enhanced HSF1 function may contribute to the prevention and treatment of obesity and related metabolic diseases. 7 In addition to the aforementioned factors, studies have found that the expression of the transcription factor Kruppel-like factor 14 (KLF14) in sWAT can improve obesity by promoting WAT browning and energy expenditure, with mechanisms potentially related to fatty acid metabolism reprogramming. 150 In summary, transcription factors and co-activators play a pivotal role in the differentiation of brown adipocytes and the regulation of metabolism. Subsequent investigation into their interactions and regulatory networks will provide significant insights into the mechanisms underlying metabolic diseases and their treatment. Non-coding RNA and Epigenetic Regulation Non-coding RNA (ncRNA) and epigenetic mechanisms exert multi-level regulatory roles in WAT brown adipogenesis. Regulation by long non-coding RNA (lncRNA) LncRNA has been demonstrated to play a regulatory role in the process of browning, affecting the expression of key transcription factors, including PRDM16 and UCP1. For instance, the ncRNA AK029592 has been substantiated as a pivotal element of the thermogenic program, functioning through the modulation of beige adipose cell differentiation and WAT browning. 151 Furthermore, there is evidence to indicate that specific BAT-specific or conserved lncRNAs modulate energy metabolism by influencing browning of adipose tissue (WAT) and formation of BAT. 152 Research has demonstrated that PPARγ functions in conjunction with lncRNA to integrate classical and non-classical thermogenic pathways, thereby suppressing negative regulators of WAT thermogenesis and, consequently, inhibiting WAT storage and promoting browning. 153 Regulatory role of microRNAs MicroRNA (miRNA) is a pivotal class of ncRNA that modulates gene expression by targeting specific mRNAs, thereby playing a pivotal role in the differentiation and function of adipocytes. MiR-889-3p has been observed to exhibit significant upregulation during the process of browning of white adipose precursor cells. This upregulation has been shown to promote the expression of browning markers, including UCP1 and PRDM16, among other relevant markers. 154 Furthermore, the over-expression of miR-26a has been demonstrated to influence energy expenditure by modulating the expression levels of genes associated with adipocyte morphology and browning, including UCP1. 155 Sun et al. found that miR-155 can inhibit the gene UBQLN1 through exosome transfer, promoting WAT browning, and that downregulation of this gene can also alleviate cancer-induced adipose consumption. 156 Other studies have demonstrated that miR-133a is subject to regulation by DNA methylation, and its inhibition has been shown to increase PRDM16 and UCP-1 expression, thereby promoting browning. 157 Contrary to the findings of the aforementioned studies, miR-27b has been observed to inhibit browning by suppressing the PRDM16 pathway. In contrast, certain traditional Chinese medicine components (such as LGZG) have been shown to promote browning by regulating the miR-27b/PRDM16 axis. 158 Epigenetic regulation Epigenetic regulation principally entails the remodeling of chromatin, the methylation of RNA, and the modification of histones. The absence of nucleosome-binding proteins HMGN1 and HMGN2 has been demonstrated to induce browning of white precursor adipocytes. This process is characterized by a decrease in WAT mass and an increase in energy expenditure, which is related to gene expression reprogramming caused by changes in chromatin accessibility. 159 The most prevalent modification of mRNA is RNA methylation, m6A (N6-methyladenine), which plays a pivotal role in browning by modulating the stability or translation efficiency of genes associated with adipose formation. Alterations in m6A modification levels within adipose tissue have been demonstrated to influence the expression of thermogenic genes, including UCP1. 160 In the context of histone modification, studies have demonstrated that methyltransferase SMYD1, a histone methyltransferase, exhibits increased expression in response to cold exposure, and its expression is associated with the browning of WAT. The observed deficiency in this pathway results in a decrease in mitochondrial content and a weakening of thermogenesis. 161 Furthermore, the small ubiquitin-like modification (SUMOylation) enzyme SENP2 negatively regulates browning through de-SUMOylation, and its deficiency enhances SUMOylation, promoting the expression of thermogenic genes. 162 In summary, ncRNAs and epigenetic regulation play important regulatory roles in adipocyte differentiation and browning, providing new insights into the metabolic regulation of adipose tissue. Regulatory roles of metabolites and fatty acid metabolism In recent studies, an increasing body of research has identified fatty acid metabolites as biomarkers of BAT, underscoring their significant role in regulating energy metabolism. These metabolites have been demonstrated to play pivotal roles in both adipose synthesis and degradation as well as non-shivering thermogenesis. For instance, research has demonstrated that metabolites of omega-6 and omega-3 polyunsaturated fatty acids manifest significant signaling molecule characteristics in regulating lipid synthesis and energy balance control. The association of these lipid oxidation products with non-shivering thermogenesis in brown or brown adipocytes is a subject of active research. 163 Naringenin has been shown to activate thermogenesis and browning of iWAT by increasing intestinal acetate levels. 164 Flaxseed oil, a rich source of α-linolenic acid, has been shown to induce browning of WAT through the upregulation of β-oxidation-related factors and the downregulation of adipose synthesis factors. 165 Research has demonstrated that the absence of fatty acid synthase in adipocytes results in the accumulation of acetyl-CoA and malonyl-CoA, while palmitic acid is depleted. The scientific literature has demonstrated that these metabolic changes are critical factors in the triggering of browning. 166 Ten-Eleven Translocation-2 in endothelial cells promotes fatty acid oxidation and lipolysis in adipocytes by interacting with nuclear factor-erythroid 2-related factor 2, thereby regulating WAT browning. 167 In regard to metabolic pathways and signaling molecules, 5-HEPE has been observed to activate the GPR119/AMPK/PGC1α pathway, leading to the upregulation of brownification marker genes, including UCP1 and PRDM16. 147 In a similar manner, brain-derived neurotrophic factor has been shown to promote browning through a process involving AMPK-dependent adipose oxidation. 168 EXOGENOUS STIMULI INDUCE WAT BROWNING Cold exposure Cold exposure has been demonstrated to promote WAT browning through multiple mechanisms, involving changes in cell morphology, molecular signaling pathways, and metabolic functions. Cold stimulation has been demonstrated to elicit the release of norepinephrine (NE) through the activation of the sympathetic nervous system, which in turn activatesβ-ARs present on the surface of adipocytes. This process has been shown to result in the upregulation of UCP1 expression, thereby promoting thermogenesis and energy expenditure. 169 Cold exposure has been demonstrated to result in a significant reduction in plasma levels of retinol-binding protein (RBP). The maintenance of an intact vitamin A (retinol) transport system is imperative for the process of cold-induced adipose browning and adaptive thermogenesis. RBP-deficient mice demonstrate a heightened sensitivity to cold and exhibit browning defects. 170 Macrophages have been demonstrated to play a pivotal role in cold-induced adipose browning. Cold exposure has been demonstrated to promote the polarization of macrophages toward the M2 type, which in turn secrete cytokines (e.g., IL-4/IL-13) to activate thermogenic gene expression in adipocytes. 171 Furthermore, the absence of SIRT6 in macrophages has been shown to impede the process of cold-induced browning and thermogenesis. 172 Long ncRNAs, such as Lnc266, are induced by cold exposure, enhancing the browning of WAT through the promotion of mitochondrial biogenesis and UCP1 expression. 173 The NNAT gene encodes a small endoplasmic reticulum (ER) membrane protein that is highly expressed in WAT and low in BAT. Research has demonstrated that exposure to low temperatures suppresses the expression of neuronal nitric oxide synthase (nNOS) in mouse adipose tissue. This suppression leads to the activation of thermogenesis in beige adipose tissue through the regulation of calcium signaling. 174 In the domain of plastic surgery, the induction of cold-induced WAT browning has been employed to enhance the survival rate of autologous adipose tissue transplantation. A growing body of research suggests that adipose grafts treated with cold exhibit enhanced vascularization, reduced fibrosis and necrosis, and superior long-term retention. 175 This mechanism may be related to the enhanced angiogenic capacity of BAT, which promotes blood supply to the transplantation site through paracrine signaling. 175 Localized Hyperthermia Therapy (LHT) Hyperthermia therapy constitutes the temporary elevation of body temperature through methods such as saunas or hot baths, with the objective of treating metabolic disorders. Given its capacity for autonomous temperature sensing, beige adipose tissue functions as a metabolic target for localized hyperthermia therapy. 176 Research has demonstrated that LHT stimulates thermogenesis and the expression of browning gene programs in beige adipose cells. Moreover, long-term localized hyperthermia therapy has been shown to prevent obesity and metabolic dysfunction. 7 HSF1 is a prototypical heat-responsive protein that plays a pivotal role in orchestrating cellular responses to elevated temperatures. Local heat therapy has been shown to promote the conversion of WAT to beige adipose tissue by activating the HSF1-A2B1 axis. This activation enhances thermogenesis, thereby improving energy metabolism and reducing body fat accumulation. 7 Furthermore, LHT directly targets adipose tissue via photothermal therapy (e.g., hydrogel-based photothermal therapy) to activate beige adipose tissue. For instance, nanoparticle-enhanced local heat therapy has been shown to markedly reduce lipid accumulation in adipocytes and to induce UCP1 expression. 177 In regard to the enhancement of the microenvironment, local heat therapy has been demonstrated to generate a conducive microenvironment for adipose tissue browning. This is achieved through the promotion of angiogenesis, which increases tissue blood supply, and the regulation of inflammatory responses, which reduces pro-inflammatory factors. In clinical applications, preliminary studies have demonstrated that 1060-nm laser heat therapy can safely achieve non-invasive fat reduction with stable, long-term effects. 178 However, it is imperative to circumvent the occurrence of tissue damage due to overheating during the clinical application of this technology. Presently, targeted heating has been accomplished through the utilization of nanomaterials, including cationic albumin nanoparticles, and hydrogel photothermal therapy. 7,177,179 sWAT is more susceptible to browning than VAT, so clinical applications require optimized protocols tailored to different adipose tissue depots. 180 The validation of the stability and side effects of these methods remains contingent upon further clinical trials. Electroacupuncture (EA) Research has demonstrated that EA can elicit a substantial augmentation in the expression of browning marker proteins, such as UCP1, and induce an increase in mitochondrial number by stimulating specific acupoints (e.g., iWAT). This process serves to enhance thermogenesis and energy expenditure. 181,182 EA has been demonstrated to induce mitochondrial biogenesis by regulating the PGC-1-TFAM-UCP1 pathway through SIRT-1-dependent deacetylation of PPAR, thereby converting WAT into BAT. 181 Gao et al. discovered that EA may activate angiogenesis through the PI3K/Pten/Thbs1 signaling pathway in WAT. This, in turn, promotes adipose tissue browning and thermogenesis. 182 Furthermore, the study revealed that plasma catecholamine levels exhibited a significant increase following EV treatment, a phenomenon that may be attributable to the activation of the β3-adrenergic receptor pathway. This activation has been observed to mimic the browning processes induced by cold or exercise. 182 The therapeutic potential of acupuncture extends to the regulation of lipid metabolism, the modulation of inflammatory responses, and the promotion of WAT browning. These effects are achieved by suppressing appetite through the regulation of appetite-regulating hormones and downstream signaling pathways. 183 Researchers have found that acupuncture upregulates genes that promote lipid catabolism and oxidation while downregulating genes involved in lipid synthesis, which is essential for regulating lipid metabolism. 184 ENDOGENOUS FACTORS INDUCE WAT BROWNING Exercise Exercise has been demonstrated to promote browning through the release of various endocrine factors, including catecholamines, IL-6, insulin, and lactic acid. Research has demonstrated that lactic acid can induce browning by increasing the expression of UCP1. The specific mechanism by which this occurs may involve exercise-induced monocarboxylate transporter 1 transporting lactic acid or upregulating PPARγ. 185 Fibronectin type III domain containing 5 (Fndc5) is a transmembrane protein that exhibits high levels of expression in skeletal muscle. Exercise has been demonstrated to promote the detachment of the extracellular domain of Fndc5, thereby producing a circulating peptide (irisin) that interacts with adipose tissue to convert white adipose cells, which store lipids, into beige adipose cells that break down energy. 186 Exercise has been demonstrated to simulate the effects of cold exposure through sympathetic nerve activation, thereby promoting the differentiation of beige adipocytes in WAT. This process exhibits a degree of overlap with the cold-induced browning mechanism. 169,187,188 Exercise activates AMPK, which results in the production of ATP and a series of metabolic changes, including lipogenesis, lipolysis, BAT energy expenditure, and WAT browning. 189 Furthermore, research has demonstrated that exercise intensity exerts a significant influence on outcomes, with high-intensity interval training demonstrating superior efficacy in comparison to moderate-intensity continuous training. 190 The response of different anatomical locations of WAT to exercise is variable. For example, iWAT is more prone to browning than epididymal WAT. 191,192 During a 12-week exercise training program, non-diabetic subjects with different BMIs showed brown/beige gene expression changes in abdominal sWAT. 193 Regular exercise during pregnancy has been shown to increase irisin levels, promote WAT beige/browning, improve glucose homeostasis, and increase energy expenditure. These effects may be part of the mechanism by which exercise prevents gestational diabetes. 194 Nevertheless, numerous unresolved issues concerning the promotion of WAT browning by exercise persist. For instance, the standardization of exercise programs, encompassing the confirmation of exercise type, intensity, and duration, must be established. 195 Furthermore, given the inherent variability in human physiology, there exists a heterogeneity in fat distribution and metabolic baseline characteristics. 195 Diet and nutrition The ingestion of low-dose alcohol over an extended period of time has been shown to counteract the development of obesity in murine models. This phenomenon is characterized by the browning of WAT, which is accompanied by a reduction in body weight and an enhancement in energy expenditure. Mechanistic studies revealed that the expression levels of the browning marker UCP1 gene and protein were elevated in the alcohol-fed group, along with increased expression of proteins in the PGC1-α/PPAR-α pathway and P38 MAPK/CREB pathway. 196 Moderate alcohol consumption has been shown to increase the secretion of the chemokine protein, CXC14, in the inguinal sWAT. This, in turn, has been demonstrated to promote the recruitment of M2 macrophages. 196 Yang et al. found that capsaicin, a polyphenolic compound, can activate BAT and promote WAT browning; however, its mechanism of action requires further validation through proteomics. 197 It has been demonstrated in other studies that chitin oligosaccharides and chitosan enhance the thermogenic capacity of WAT and BAT by upregulating the expression of browning marker genes, such as UCP1 and PGC1α. 198 Malonic acid has been demonstrated to induce PRDM16 expression, a critical transcription factor that has been previously identified as a pivotal regulator of browning and UCP1 expression. This observation suggests a potential mechanism by which malonic acid may promote the browning of white adipose cells. 199 Taurine administration has been demonstrated to induce browning of iWAT in mice, accompanied by significant increases in the expression of PGC1α, UCP1, and other thermogenic genes in WAT. This phenomenon may serve as a potential mechanism underlying the anti-obesity effects of taurine. 200 A plethora of natural products (e.g., alkaloids, flavonoids, terpenoids, etc.) have been demonstrated to promote WAT browning via diverse pathways, thereby ameliorating obesity and associated metabolic disorders. 200 Furthermore, green tea extracts have been shown to counteract HFD-induced obesity by inhibiting BAT and activating browning of WAT pathways. 201 Gut microbiota The gut microbiota has been demonstrated to play a multifaceted regulatory role in the browning of WAT. Research has demonstrated that short-chain fatty acids, such as acetate, which are metabolites produced by the fermentation of gut microbiota, can promote WAT browning and increase energy expenditure. 164 For instance, naringenin has been observed to induce alterations in the composition of the gut microbiota, resulting in an increase in acetate levels within the host’s cecum and serum. This, in turn, has been shown to activate beige adipose thermogenesis. 164 In a similar manner, nobiletin has been observed to modify the composition of gut microbiota, augment serum and fecal acetate levels, and stimulate WAT browning. 202 Research has demonstrated that the process of cold-induced gut microbiota remodeling, which is governed by the gut-specific phosphodiesterase 6, results in an augmentation of ursodeoxycholic acid production. This, in turn, leads to the activation of browning-related pathways. 203 Aconite aqueous extract has been demonstrated to modulate the gut microbiota and the bile acid receptor TGR5-UCP1 signaling pathway, thereby promoting WAT browning. 204 Probiotics have also been demonstrated to play a substantial role in promoting metabolism. Lactobacillus (e.g., Lactobacillus amylovorus KU4) has been shown to ameliorate obesity induced by a HFD. The specific mechanism by which this occurs may involve increased lactate levels and stimulation of UCP1 expression through the promotion of the formation of the PPARγ-PGC-1α transcriptional complex, thereby promoting WAT browning. 205 Antibiotic treatment or fecal microbiota transplantation experiments have confirmed that the absence of gut microbiota weakens the browning-promoting effects of phytochemicals, such as genistein, which upregulates UCP1 and PGC-1α expression through a microbiota-dependent mechanism. 206 The mechanisms through which microbiota regulate adipose tissue biology are multifaceted. Specific microbiota metabolites, such as D-arabinitol, have been observed to promote WAT browning through the activation of the AMPK-PGC-1α pathway and the enhancement of mitochondrial biogenesis. 207 In diet-induced obesity, ginsenosides have been shown to regulate the gut microbiota through a mechanism that involves leptin-mediated AMPKα/STAT3 signaling. This, in turn, promotes thermogenesis and the reconstitution of brown adipocytes. 208 Moreover, research has demonstrated that plant polyphenols (e.g., resveratrol) elicit anti-obesity effects through the ”microbiota-adipose tissue” axis and can function as dietary supplements. 209 Immune cell regulation Multiple immune cells are involved in the regulation of WAT browning. 210 Macrophages have been identified as pivotal regulators of WAT browning. A body of research has demonstrated that pro-inflammatory macrophages (M1 type) secrete cytokines (e.g., TNF-α and IL-6) that suppress the expression of key browning genes (e.g., Adrb3 and PPARγ), inhibit Ucp1, and impair mitochondrial respiration in adipocytes. Consequently, this hinders WAT browning. 211 M2-type macrophages have been observed to support the growth of sympathetic nerve fibers by secreting neurotrophic factors or other molecules, thereby enhancing WAT browning. 212 However, the direct synthesis of NE by M2-type macrophages to promote browning remains a subject of controversy. 213 In states of high metabolism, such as those observed in burns, macrophage-mediated inflammatory responses are closely associated with WAT browning. However, the specific interactive mechanisms underlying these phenomena require further investigation. 214 Eosinophils have also been demonstrated to play a role in the process of WAT browning. These cells have been observed to increase the levels of IL-4 and IL-13 in WAT, thereby further activating M2-type macrophages. 212 The signaling protein, metronin (METRNL), is a hormone that is secreted by skeletal muscle and adipose tissue. This hormone increases the number of eosinophils in WAT and induces browning through these cells. 215 Regulatory T cells (Tregs) have been shown to maintain adipose tissue homeostasis by secreting IL-10, thereby suppressing the browning of WAT. 216 Invariant natural killer T cells have been shown to promote WAT browning by activating FGF21 expression in adipose tissue, thereby improving blood glucose control and weight regulation. 217 Type 2 innate lymphoid cells (ILC2) have been shown to activate eosinophils by secreting IL-5 and IL-13, thereby indirectly promoting the recruitment of M2-type macrophages and WAT browning. Furthermore, ILC2 cells exert a direct effect on PDGFRα-positive precursor cells, thereby inducing their differentiation into beige adipose cells. 218 ILC2 cells also produce methionine enkephalin (Met-Enk), an opioid peptide that directly acts on white adipocytes in sWAT to promote their browning. 219 CLINICAL INTERVENTIONS TO INDUCE WAT BROWNING Thermogenic synergistic effects of GLP-1 receptor agonists GLP-1 receptor agonists (GLP-1RAs) have been shown to promote WAT browning and thermogenic effects through multiple mechanisms. First, GLP-1 receptor agonists (e.g., liraglutide and semaglutide) have been demonstrated to directly upregulate the expression of key brownification proteins (e.g., UCP1 and PGC-1α), thereby promoting mitochondrial biogenesis and thermogenic function. 220,221 Liraglutide significantly elevated the expression of PGC-1α and UCP1 in 3T3-L1 adipocytes, thereby inducing the browning of WAT. 220 Furthermore, studies have demonstrated that GLP-1 receptor agonists promote browning by increasing the proportion of anti-inflammatory M2 macrophages and reducing pro-inflammatory M1 macrophages, thereby enhancing the microenvironment of adipose tissue. 222 GLP-1 analogues have been observed to activate the IL-6R signaling pathway through a transient upregulation of IL-6. This, in turn, has been shown to stimulate thermogenic adipocyte browning and glucose metabolism. 223 The differentiation of C3H10T1/2 mesenchymal stem cells to brown adipocytes is promoted by GLP-1 agonists through the PI3K/AKT/mTOR pathway. 224 GLP-1 receptor agonists have been demonstrated to promote the browning of WAT through multi-target, multi-pathway synergistic effects, involving mechanisms such as transcriptional regulation, inflammation modulation, and metabolic pathway activation. 221,222,225 The combined effects of these elements contribute to their clinical efficacy in the treatment of obesity and metabolic conditions. Precise beige adipose activation by photothermal nanomaterials Photothermal nanomaterials have demonstrated multifaceted potential and challenges in clinical studies targeting WAT browning. Photothermal nanomaterials (e.g., the nanocomposite pTSL@(P+I)) have been shown to activate the PPARγ/PGC1α and HSF1/PGC1α transcriptional axes through localized mild photothermal therapy. This activation results in a significant upregulation of UCP1 and COX5B expression, which, in turn, promotes WAT browning and reduces obesity. 226 In a study utilizing animal models, photothermal therapy led to a significant reduction in body mass, with a decrease of approximately 19% observed in obese mice. In contrast, the control group exhibited a weight gain of 9%. 227 A number of studies have investigated the combination of nanoparticle photothermal therapy with drugs, including mirabendron and rosiglitazone, to enhance browning efficiency through synergistic effects. 177,227 Ma et al. introduced adipose-targeted ultra-small hybrid nanoparticles (Pep-PPIX-Baic nanoparticles) composed of adipose-targeting peptides, Fe, photosensitizers (protoporphyrin IX), and browning agents (baicalin) that can specifically accumulate in WAT, especially those rich in blood supply, and drive fat reduction due to the synergistic effects of photodynamic therapy and baicalin-induced browning, thus exhibiting excellent anti-obesity potential. 228 Similar nanomaterials promote a nanoplatform for obesity treatment. The clinical application of nanomaterials offers distinct technical advantages, including enhanced targeting and safety. The delivery of nanomaterials, such as Prussian blue nanoparticles, via the transdermal route has been demonstrated to directly target sWAT, thereby mitigating systemic adverse effects. 229 The delivery of resveratrol-loaded nanoparticles to adipose matrix cells, specifically targeting these cells, could serve as an effective and low-toxicity therapeutic strategy for obesity and its comorbidities. This approach could also be targeted to sWAT. 230 Photothermal therapy, based on hydrogels, has been shown to achieve LHT, which has been confirmed to activate beige adipose tissue and improve obesity in both humans and mice. 7 Furthermore, nanomaterials offer the advantage of non-invasiveness. The penetration depth and minimal damage to surrounding tissues of near-infrared light (NIR) make it suitable for clinical translation. 231,232 NIR-activated nanomaterial-mediated phototherapy, encompassing photothermal therapy and photodynamic therapy, offers a novel approach for spatiotemporally controlled, minimally invasive cancer treatment. 233 Photothermal nanomaterials have been demonstrated to possess significant therapeutic potential in the context of WAT browning. However, to facilitate clinical translation, it is imperative to address key challenges, including enhancing efficiency, ensuring tissue specificity, and establishing long-term safety profiles. 234,235 GENDER AND AGE DIFFERENCES IN WAT BROWNING Gender differences in sensitivity to adipose tissue browning Research has demonstrated that women initiate thermogenesis at a more rapid rate than men when subjected to cold temperatures, a phenomenon that may be attributed to the heightened sensitivity of their adipose tissue to thermal stimulation. 236 Furthermore, female sex hormones (e.g., estrogen) may counteract metabolic syndrome by promoting WAT browning. 237 In a related study, Kim et al. treated mouse models with β3-adrenergic receptor agonists and observed that female mice exhibited stronger browning responses, as indicated by increased UCP1 expression and enhanced mitochondrial biogenesis, while male mice demonstrated weaker browning capacity. 237 The experimental data suggest that female mice manifest higher glucose tolerance, reduced levels of immune cell infiltration in adipose tissue, and diminished oxidative stress levels in an obese state. These findings indicate that the browning of WAT is more effective in female mice. 238 Age-related decline in brown adipose function As the body undergoes the process of aging, the browning capacity of WAT undergoes a corresponding decline. In aged mice, the capacity of WAT to undergo transformation into a brown adipose-like cell type, a process referred to as ”de-browning,” exhibits a marked decline. For instance, Pan et al. discovered that aging T cells induce ”whitening” of BAT by secreting IFN-γ. This process is characterized by increased lipid accumulation and structural dysfunction in BAT, exhibiting physiological characteristics more akin to WAT. 239 Furthermore, age-related mitochondrial dysfunction may also result in reduced BAT activity, thereby affecting the browning process of WAT. 240 These alterations may be associated with the diminished metabolic rate and reduced energy expenditure that accompanies the aging process, thereby impeding the body’s capacity to generate non-shivering heat in response to stimuli such as cold. It has been posited that the heightened activity of BAT during the aging process may contribute to an augmented lifespan in women, though further validation of these mechanisms is necessary. 241 BROWNING STRATEGIES IN THE TREATMENT OF OBESITY AND METABOLIC SYNDROME Obesity has become a global epidemic, with its prevalence nearly tripling since 1975 and currently affecting over 1 billion people. 242,243 In Western countries, approximately 25% of adults are obese. 244 The global prevalence of metabolic syndrome (MetS) is also rising, driven primarily by urbanization, sedentary lifestyles, and dietary change. 245 Obesity and metabolic syndrome are major risk factors for various chronic diseases, including type 2 diabetes, cardiovascular disease, and certain cancers. 246-248 Induced browning of WAT may hold significant potential in the prevention or treatment of obesity and obesity-related metabolic disorders. 46 Weight Loss WAT browning counteracts obesity and metabolic diseases by increasing energy expenditure, thereby exerting a significant impact on weight loss. 249 For example, long-term low-dose alcohol intake can delay obesity onset by inducing WAT browning while reducing body weight in mice. 196 In cancer cachexia (CAC), WAT browning accelerates energy expenditure, leading to adipose tissue and skeletal muscle atrophy, and is a key factor in weight loss. 16 COVID-19 infection similarly activates adipose tissue browning, resulting in adipose atrophy and weight loss. 18 VEGF inhibitors can block COVID-19-induced browning, thereby alleviating infection-associated weight loss. 18 The molecular regulatory pathways that underpin weight loss may encompass the activation of the sympathetic nervous system. For instance, the browning of WAT and the weight loss induced by a cysteine-restricted diet are contingent upon the activation of the sympathetic nervous system. 250 Furthermore, Orm2 protein, induced by intermittent fasting, has been shown to promote browning by binding to the GP130/IL23R receptor and activating the p38-MAPK pathway, resulting in a significant reduction in body weight in obese mice. 251 Tumor-derived small extracellular vesicles can also promote fat loss by regulating WAT browning. 17 WAT browning exerts a dual effect on weight loss by enhancing thermogenesis and energy expenditure. On one hand, it may serve as a potential therapeutic strategy against obesity. On the other hand, it may exacerbate catabolic syndrome under pathological conditions. Insulin Resistance WAT browning improves IR through multiple pathways (increased thermogenesis, reduced inflammation, optimized lipid metabolism, etc.), making it a potential target for treating type 2 diabetes. During WAT browning, there is an increase in mitochondrial activity, a rise in browning protein markers, and a promotion of fatty acid oxidation. These effects ultimately exert anti-obesity and anti-diabetic effects. 252 Abscisic acid (ABA) complexes have been demonstrated to significantly increase the expression of browning markers (UCP1 and PGC1-α) in WAT, enhance mitochondrial biogenesis and function, and improve glucose uptake in WAT by upregulating glucose transporter 4, thereby enhancing insulin sensitivity. 253 Furthermore, studies have demonstrated that ECH1 (enolyl coenzyme A hydratase 1) contributes to browning by modulating lipid metabolism, and its over-expression has been shown to enhance IR. 254 Myricanol treatment alleviates obesity and IR by enhancing lipid utilization and irisin production in skeletal muscle and inducing browning of inguinal adipose. 255 Atrial natriuretic peptide (ANP) improves HFD-induced IR by activating adipose tissue thermogenesis (increasing UCP1 expression) and reducing liver fat deposition. 256 Chronic inflammation in WAT plays a pivotal role in the development of IR in obesity. Conversely, WAT browning has been shown to suppress chronic inflammation, thereby enhancing insulin sensitivity. Short-term inflammation has been observed to promote browning; however, long-term chronic inflammation has been shown to inhibit this process. 257,258 A growing body of research has demonstrated that the combination of thymol (TQ) and omega-3 fatty acids promotes WAT browning, a process that may be crucial in mitigating obesity-related IR and ameliorating chronic inflammatory states. 259 Furthermore, Yu et al. discovered that local administration of diosmin to the inguinal subcutaneous adipose tissue of mice augmented the browning of WAT and energy expenditure, consequently enhancing insulin sensitivity and reducing obesity. This process also led to a reduction in inflammation within WAT and the liver. 260 Cardiovascular Diseases A clinical study found that BAT may have a potential role in promoting cardiac metabolic health. This potential role manifests as a lower risk of heart disease and metabolic disorders, including type 2 diabetes, hypertension, and coronary artery disease, particularly in obese individuals. 8 Hyperglycemia and IR have been identified as significant risk factors for the development of cardiovascular diseases. As previously indicated, WAT browning has been shown to enhance glucose tolerance and increase insulin sensitivity, suggesting that WAT browning may possess cardiovascular protective properties. 253,260 Furthermore, WAT browning has been shown to mitigate cardiovascular impairment by reducing triglyceride levels and enhancing lipid metabolism abnormalities. 261 FGF21, for instance, enhances hypercholesterolemia by activating BAT and WAT browning, thus expediting the rate of triglyceride-rich lipoproteins. Consequently, this results in a reduction of the severity of atherosclerotic lesions and an improvement in their stability index. 262 Research findings have demonstrated that following the administration of isoprenaline, UCP1 gene-knockout mice with impaired brown adipose function exhibited a greater degree of myocardial injury and fibrosis in comparison to wild-type mice. Additionally, survival rates were observed to be diminished in the former group. The transplantation of BAT from wild-type mice into UCP1 gene-knockout mice resulted in a notable improvement in myocardial injury markers and survival rates. These findings suggest that BAT may have a protective effect against ischemia-induced myocardial injury. 263 Since beige adipose, formed by the browning of WAT, has biological functions similar to those of BAT, the browning of WAT may have similar cardiovascular protective effects. Adipose tissue is distributed in the epicardium and peripheral blood vessels. WAT browning can regulate cardiovascular relaxation and contraction by maintaining normal vascular tone and blood pressure, thereby producing a cardiovascular protective effect. 261,264 STUDIES ON THE EFFECTS OF WAT BROWNING ON CANCER WAT browning can inhibit tumor progression Researchers have employed CRISPRa technology to upregulate specific genes (e.g., UCP1) in adipose cells, thereby converting white adipose cells into brown adipose-like cells. These engineered adipose cells and organoids have demonstrated efficacy in the competition for nutrients essential to the proliferation of tumors, thereby exerting a substantial inhibitory effect on the growth and progression of various tumors, including breast cancer, colon cancer, pancreatic cancer, and prostate cancer. 265 UCP1 in brown or beige adipose cells can antagonize inflammation in non-alcoholic fatty liver disease (NAFLD) by increasing energy expenditure and suppressing liver inflammation, thereby reducing the incidence of hepatocellular carcinoma. 266,267 A subsequent functional enrichment analysis revealed that the thermogenesis signaling pathway is overexpressed in hepatocellular carcinoma patients without fibrosis, which may serve as a prognostic indicator for survival rates in these patients. 268 Promoting the browning of adipose tissue in the periprostatic adipose tissue may be a way to treat the progression of prostate cancer cells. 15 Researchers have demonstrated that the browning of periprostatic adipose tissue can be promoted by blocking androgen signaling. Moreover, the effects of brown adipocytes on the proliferation mechanisms of prostate cancer cells in vitro are opposite to those of white adipocytes. 15 WAT Browning Promotes Tumor Progression In renal cancer, the process of browning of perirenal WAT has been shown to indirectly promote tumor development by increasing the expression of epithelial-mesenchymal transition (EMT) markers. 269 Breast cancer mammary globules can secrete adrenal medullary hormone to induce browning and lipolysis of adjacent adipocytes. 270 Furthermore, the activation of beige adipocytes in the breast has been shown to regulate the behavior of tumor and non-tumor mammary epithelial cells in mice, thereby favoring tumor progression. 271 Researchers identified a phenotypic transition from WAT to BAT in Kras-pancreatic cancer mice. This transition was associated with chronic inflammation and IL-6-induced upregulation of UCP1. 272 However, further investigation is necessary to determine whether pancreatic adipose undergoes browning and to explore the relationship between brown pancreatic adipose tissue and tumors. 273 In patients diagnosed with cancer cachexia, the process of WAT browning leads to adipose tissue atrophy and weight loss by increasing energy expenditure in the form of heat loss. This phenomenon may accelerate metabolic disorders and disease progression in patients with advanced tumors. 16,19,274 For instance, the browning of sWAT in patients with cachectic gastric cancer is associated with a deterioration in clinical parameters. 274 In summary, the study of WAT browning in tumors has two sides. On the one hand, it may inhibit tumors through metabolic competition and anti-inflammatory effects; on the other hand, excessive browning may also accelerate cachexia. APPLICATION CHALLENGES AND ETHICAL CONSIDERATIONS Despite the revolutionary potential of WAT browning technology in the treatment of metabolic diseases and tumors, its clinical translation is still hindered by numerous technical and ethical challenges. For instance, the clinical application of nanomaterials continues to encounter certain challenges. The primary considerations are efficiency and stability. The prevailing methodologies are plagued by deficiencies in efficiency and stability. For instance, while some nanocomposites have been observed to induce browning of 3T3-L1 adipocytes, the long-term implications remain to be elucidated. 275 Secondly, heterogeneous responses across different tissues, such as the lower sensitivity of visceral WAT to browning compared to sWAT, necessitate further addressing tissue-specific issues. 180 When examining the disparities between human and animal models, it is imperative to acknowledge the heterogeneity of human adipose tissue and the constraints inherent in such studies. Recent studies have also pointed out that human BAT shares metabolic activity similarities with mouse “beige” adipose tissue but exhibits significant differences in overall characteristics and functions. 163 In animal models, chronic low-dose alcohol consumption has been observed to induce WAT browning and resist obesity. However, human studies have yielded inconsistent results, with some studies showing positive effects and others indicating a potential association with other metabolic disorders. 196 It is imperative to comprehend the distinctions between humans and animal models to facilitate the future development of effective treatment strategies for obesity and associated metabolic diseases. In the development of personalized treatment strategies, it is imperative to consider factors such as gender, age, and lifestyle. This approach enhances the efficacy of treatment while concurrently mitigating the occurrence of adverse effects, thereby facilitating the attainment of optimal health outcomes for patients. From a technological perspective, the existing induction methods (e.g., drugs, cold exposure) are characterized by limitations, including low efficiency, poor stability, and the occurrence of side effects. While WAT browning has been demonstrated to increase energy expenditure and reduce obesity, it has the potential to trigger unpredictable metabolic consequences (e.g., cachexia or cardiovascular events). Consequently, there is a necessity for careful consideration of its applicability to specific populations (e.g., cancer patients). 276-278 While certain natural products have been observed to induce browning, the precise mechanisms through which they do so remain to be fully elucidated. Moreover, concerns regarding their long-term safety persist. 279 In summary, the exploration of new drugs and interventions shows great promise in the study of WAT browning. In the future, further elucidation of the molecular mechanisms underlying browning is imperative. This necessitates the development of tissue-specific activation strategies and the establishment of a standardized clinical evaluation system. Concurrently, the formulation of ethical guidelines through multidisciplinary collaboration is imperative to ensure the equitable and secure implementation of technology applications.

AND PERSPECTIVE The study of WAT browning has emerged as a significant area of research interest within the broader field of metabolic disease prevention and treatment, given its role as a critical biological process that enhances energy expenditure and promotes metabolic health. According to the findings of contemporary research, the manifestation of WAT browning is influenced by a multitude of hormonal factors, signaling pathways, and metabolites. Moreover, environmental influences, lifestyle choices, and individual variations have been demonstrated to play a significant role in this process. It has been demonstrated that stimuli, including cold exposure, physical exertion, and particular nutritional elements, can effectively stimulate WAT browning. This provides a range of potential intervention strategies. Nevertheless, despite the strides made in elucidating the mechanism of WAT browning, numerous controversies persist. A plethora of studies have been conducted on the subject; however, the research has not yet reached a consensus on the regulatory mechanisms, influencing factors, and physiological effects. Consequently, future research should prioritize individual differences, particularly in clinical applications, to achieve precision medicine. Emerging interventions, including electroacupuncture, nanotechnology, and the utilization of natural products, have emerged as promising avenues for the clinical translation of WAT browning. The efficacy of these methodologies in addressing obesity and metabolic syndrome is a subject of ongoing research. However, the relationship between WAT browning and tumors remains complex, and the specific mechanisms involved need to be explored further. Further research has indicated the potential for novel insights into the regulatory mechanisms and stimulation methods of WAT browning to yield new avenues for the prevention and treatment of metabolic diseases, thereby promoting the improvement of human health. In the ongoing struggle to combat global obesity and the associated metabolic diseases, conducting in-depth research on this biological process is of significant scientific value. Furthermore, it will serve as a new foundation for the development of public health policies. DECLARATION OF INTERESTS The authors declare no competing interests.

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Authors Metrics & Citations Metrics Article Usage 719views 274downloads Citations Download citation Yingjiao Wang, Diyuan Zhang, Yuqin Zhou, et al. White adipose tissue browning and cross-talk with metabolic diseases and tumors: from molecular mechanisms to clinical translation. Authorea. 26 October 2025. DOI: https://doi.org/10.22541/au.176149650.00650390/v1 DOI: https://doi.org/10.22541/au.176149650.00650390/v1 If you have the appropriate software installed, you can download article citation data to the citation manager of your choice. Simply select your manager software from the list below and click Download. For more information or tips please see 'Downloading to a citation manager' in the Help menu.