Diet-Driven Inflammatory Signalling in Cardio-Metabolic Physiology: Molecular Pathways, Sex Differences, and Cardiovascular Consequences

Diet-Driven Inflammatory Signalling in Cardio-Metabolic Physiology: Molecular Pathways, Sex Differences, and Cardiovascular Consequences | 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 Research Article Diet-Driven Inflammatory Signalling in Cardio-Metabolic Physiology: Molecular Pathways, Sex Differences, and Cardiovascular Consequences V M Nandhini, K M Priyadharshini This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-8782385/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Dietary patterns enriched in saturated fats and refined carbohydrates exert profound effects on metabolic and cardiovascular physiology by promoting chronic low-grade inflammation. Accumulating evidence indicates that diet-induced inflammatory signalling acts as a central integrator linking adipose tissue dysfunction, insulin resistance, endothelial impairment, and cardiovascular pathology. In this review, we synthesize current physiological insights into how pro-inflammatory diets activate innate immune pathways, including Toll-like receptor 4, nuclear factor-κB, mitogen-activated protein kinases, and the NLRP3 inflammasome thereby disrupting metabolic and vascular homeostasis. We highlight the coordinated roles of inflammatory cytokines, oxidative stress, lipid signalling, and immune–metabolic crosstalk in the pathogenesis of obesity, metabolic syndrome, hypertension, and atherosclerotic cardiovascular disease. Emerging evidence suggests that biological sex modifies inflammatory and metabolic responses to dietary excess through differences in adipose distribution, sex hormone signalling, immune regulation, and interactions with the gut microbiota. Together, these findings position diet-induced inflammation as a fundamental physiological mechanism linking nutrition to cardio-metabolic dysfunction and cardiovascular risk. Understanding these pathways provides a framework for developing targeted, physiology-informed dietary and therapeutic strategies aimed at reducing inflammation-driven cardiovascular disease. Diet-induced inflammation Cardio-metabolic physiology Immune-metabolic signalling Innate immune pathways Endothelial dysfunction Adipose tissue inflammation Oxidative stress Sex differences Cardiovascular physiology Figures Figure 1 Figure 2 Figure 3 Figure 4 1. Background Cardiovascular diseases (CVDs) represent the leading cause of mortality worldwide and remain a major public health challenge. Recent global estimates indicate a substantial and continuing rise in cardiovascular mortality, driven largely by modifiable metabolic risk factors including obesity, hypertension, dyslipidaemia, and diabetes (Di Cesare et al., 2024 ). In India, national health data further emphasize the growing burden of CVD and highlight diet-related metabolic risks such as elevated blood pressure, abnormal lipid profiles, and excess adiposity as key contributors to cardiovascular morbidity and mortality. These trends underscore the critical role of dietary patterns in shaping cardio-metabolic health and cardiovascular risk. The modern Western dietary pattern, often characterized as a high-fat diet (HFD), is dominated by excessive intake of saturated and trans fatty acids, refined carbohydrates, added sugars, and ultra-processed foods, including processed meats, sugar-sweetened beverages, fried foods, and packaged snacks (Chen et al., 2020 ). Increasing evidence suggests that habitual consumption of such diets induces oxidative stress, disrupts gut microbiota composition, and promotes chronic low-grade inflammation, thereby precipitating metabolic ddysfunctions such as obesity, insulin resistance, dyslipidemia, and hypertension (Clemente-Suárez et al., 2023 ; Silveira Rossi et al., 2022 ). These cardio-metabolic abnormalities are well-recognized precursors of atherosclerosis, heart failure, cardiomyopathy, and other cardiovascular complications. A central feature linking HFD consumption to cardio-metabolic dysfunction and CVD is inflammation. Excess dietary fat intake leads to elevated circulating triglycerides and low-density lipoprotein cholesterol, accompanied by reduced high-density lipoprotein levels, thereby favouring lipid accumulation within vascular and cardiac tissues (Vekic et al., 2023 ). Concurrently, saturated fatty acids disrupt metabolic homeostasis by activating inflammatory signalling pathways, resulting in endothelial dysfunction, oxidative stress, and progressive vascular injury. Over time, these alterations facilitate atherosclerotic plaque formation, impair myocardial function, and increase susceptibility to coronary artery disease, myocardial infarction, and stroke (Clapp et al., 2004 ; Duan et al., 2018 ). At the cellular level, prolonged exposure to an HFD promotes excessive accumulation of free fatty acids in adipose tissue and ectopic lipid deposition in non-adipose organs such as the liver, skeletal muscle, and heart. Adipocyte hypertrophy and dysfunction lead to increased secretion of pro-inflammatory cytokines, including tumour necrosis factor-α (TNF-α), interleukin-6 (IL-6), and monocyte chemoattractant protein-1 (MCP-1), which recruit immune cells and enhance macrophage infiltration into adipose tissue (Cullberg et al., 2014 ). These processes amplify systemic inflammation and interfere with insulin signalling pathways, thereby contributing to insulin resistance and impaired glucose metabolism. Smith et al. ( 2022 ) comprehensively reviewed the determinants of health behaviour change, highlighting the role of individual, social, and environmental factors. Innate immune activation plays a critical role in mediating diet-induced inflammation. Saturated fatty acids and gut-derived lipopolysaccharides activate Toll-like receptor-4 (TLR4), triggering downstream signalling cascades involving nuclear factor-κB (NF-κB) and c-Jun N-terminal kinase (JNK). Activation of these pathways promotes transcription of pro-inflammatory genes and perpetuates chronic inflammatory responses, which are closely linked to obesity, type 2 diabetes, and metabolic syndrome (Duan et al., 2018 ). Chronic inflammation further exacerbates oxidative stress by increasing reactive oxygen species production and reducing nitric oxide bioavailability, leading to impaired vasodilation, arterial stiffness, and endothelial dysfunction (Clapp et al., 2004 ). Systemic inflammation induced by unhealthy dietary patterns therefore, acts as a unifying mechanism connecting metabolic abnormalities with cardiovascular pathology. Elevated circulating inflammatory mediators and dysregulated lipid metabolism accelerate lipid deposition within arterial walls, promote plaque instability, and increase the risk of atherosclerotic cardiovascular disease and cardiovascular mortality (Vekic et al., 2023 ). Epidemiological evidence using dietary inflammatory indices further supports the association between pro-inflammatory diets and increased cardio-metabolic and cardiovascular risk across diverse populations. Emerging literature also suggests that biological sex may influence inflammatory and metabolic responses to dietary exposures. Differences in sex hormone regulation, adipose tissue distribution, immune function, and gut microbiota composition may modify susceptibility to diet-induced inflammation and cardio-metabolic dysfunction, although sex-stratified evidence remains limited (Silveira Rossi et al., 2022 ). Recognizing sex-related biological considerations is therefore important for understanding variability in cardio-metabolic risk and cardiovascular outcomes. Despite growing recognition of the role of diet-induced inflammation in cardiometabolic and cardiovascular disease, an integrated synthesis focusing on inflammatory genes, enzymes, and molecular pathways within a nutrition, metabolism and cardiovascular framework remains limited. Therefore, this review aims to systematically summarize current evidence linking high-fat and pro-inflammatory dietary patterns to inflammation-mediated cardio-metabolic dysfunction and associated cardiovascular risk, with emphasis on key inflammatory pathways and emerging sex-related considerations relevant to prevention and clinical practice. 2. Methodology This study was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Data were retrieved from standard electronic databases and screened using predefined inclusion and exclusion criteria. Following the initial screening, eligible articles were further assessed for relevance, and studies meeting all criteria were included in the final analysis. The study selection process is illustrated in Fig. 01 . 2.1. Research Approach This review employed a systematic evidence-based approach to examine the role of high-fat and pro-inflammatory dietary patterns in driving inflammation-mediated cardiometabolic dysfunction and subsequent cardiovascular risk. The methodological framework followed the principles outlined in the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) to ensure methodological transparency and reproducibility. The review integrates findings from population-based studies, clinical investigations, and mechanistic research to elucidate how dietary fat excess influences inflammatory signalling, metabolic disturbances, and cardiovascular pathology. Special consideration was given to sex-specific biological responses, allowing comparison of inflammatory and metabolic outcomes between males and females. The focus was placed on molecular mediators, including inflammatory genes, enzymes, and pathways that connect dietary exposure to cardiometabolic and cardiovascular outcomes. 2.2. Literature Screening Process A comprehensive literature search was conducted using the electronic databases PubMed, Web of Science, Scopus, Embase, and ScienceDirect. Search strategies combined relevant keywords and Boolean operators related to diet, inflammation, metabolism, and cardiovascular disease. The search was not restricted by study design to allow inclusion of both observational and interventional research. All retrieved records were compiled, and duplicate articles were removed before screening. Initial screening was performed by reviewing titles and abstracts to exclude studies clearly unrelated to the research objective. Full-text evaluation was subsequently carried out for potentially eligible articles to confirm relevance and methodological suitability. Only studies meeting all predefined criteria were included in the final synthesis. The selection process and study flow are presented in the PRISMA diagram. All the literature is collected using the keywords: “cardiovascular disease associated inflammation with high fat diet or western diet in India, only in terms of gene or enzyme regulation, a comparison between male and female.” 2.3. Criteria for Inclusion and Exclusion Studies were considered eligible for inclusion if they were peer-reviewed articles published in English that investigated high-fat, Western, or pro-inflammatory dietary patterns, including evaluations based on the dietary inflammatory index, and examined their associations with inflammation-related cardiometabolic and cardiovascular outcomes. Included studies involved adult human populations of either or both sexes and reported data on inflammatory mediators, molecular pathways, or enzymatic regulators relevant to metabolic and cardiovascular physiology, together with cardiometabolic outcomes such as obesity, insulin resistance, dyslipidaemia, metabolic syndrome, or hypertension, and cardiovascular outcomes or risk indicators including atherosclerosis, atherosclerotic cardiovascular disease, heart failure, or cardiovascular mortality. Studies were excluded if they did not assess dietary exposure in relation to inflammation or cardiometabolic health, focused exclusively on inflammatory conditions unrelated to metabolic or cardiovascular disease, lacked relevant metabolic or cardiovascular endpoints, or were published as case reports, editorials, conference abstracts, or other non-peer-reviewed sources. Experimental animal studies and in vitro investigations without direct translational relevance to human cardiometabolic or cardiovascular disease were also excluded. 2.4. In-silico pathway enrichment analysis To support the mechanistic interpretation of diet-induced cardiometabolic inflammation, an in-silico pathway enrichment analysis was performed using Shiny GO v0.8 (Ge et al., 2020). Key inflammatory genes repeatedly identified across the reviewed studies (CRP, IL-6, TNF-α, and IL-1β) were used as input. Gene Ontology (GO), Kyoto Encyclopaedia of Genes and Genomes (KEGG), and Reactive databases were queried to identify enriched biological processes and signalling pathways relevant to lipid metabolism, inflammation, cardiometabolic dysfunction, and cardiovascular disease. 2.5. Standardized data extraction To ensure methodological consistency and reduce the potential for selection bias, a standardized data extraction framework was applied uniformly across all included studies. Relevant information was systematically collected and categorized according to predefined variables, including authorship and year of publication, journal source, study population characteristics with sex distribution, type of dietary pattern or nutritional exposure, inflammatory genes, enzymes, or molecular pathways investigated, reported cardiometabolic alterations, associated cardiovascular outcomes or risk indicators, and corresponding DOI and database sources. The extracted data were compiled into a structured summary table to facilitate direct comparison across studies. This standardized process enabled coherent integration of molecular, metabolic, and clinical evidence, thereby supporting mechanistic interpretation of diet-induced inflammatory processes and their role in cardiometabolic dysfunction and cardiovascular disease. 3. Results The results of the collected data are presented in Table 01. The results depict that HFD may induce inflammation at a lower level, which in turn induces any of the cardiometabolic dysfunctions, leading to the long-term process of Cardiovascular risk. Any of these may include alterations by the inhibition or induction of genes or enzymes in any related pathway. Most of the inflammatory genes related were CRP, IL-6, IL-1β, TNF-α, and NF-κB, which in turn release the proinflammatory cytokines resulting in the cardiometabolic ailments such as Obesity, diabetes, hypertension, and hypercholesterolemia. This endured exposure to this diet, with associated metabolic problems, would lead to certain cardiovascular risk, particularly ASCVD, heart failure, heart attack, fatty liver, etc., depending on the kind and term of exposure, may or may not lead to mortality as presented in the following table. Table.01 Cardiovascular risk linked to High Fat Diet- induced cardiometabolic dysfunction through inflammatory genes, enzymes, and pathways. S. No Author, Year- Journal Sex M/ F HFD Genes/ Enzyme/ Pathway Cardio Metabolic dysfunction Cardiovascular risk DOI Database Inflammation 1 Yang M et al., 2024 - Nutrition, Metabolism and Cardiovasc Disease M F PI diet Inflammatory biomarkers- CRP, IL-6, TNF-α and possibly IL-1β ASCVD driven Metabolic dysfunctions Cardiovascular mortality due to the causes of ASCVD 10.1016/j.numecd.2023.11.015 PubMed, WOS, Scopus 2 Tuttolomondo et al., 2019 - Int J Mol Sci M F High NF-κB Cytokines NA Atherosclerosis 10.3390/ijms20194716 PubMed 3 Rooney et al., 2025 - Eur J Nutr M F Dairy Endothelial function biomarkers; inflammation indices Vascular endothelial function (FMD) Implications of CVD via FMD 10.1007/s00394-024-03574-w PubMed 4 Schulz, Michael Tobias et al., 2025- Immunity and Ageing M F NA Immune aging/inflammation markers Inflammaging Cardiovascular risk 10.1186/s12979-025-00511-1 Scopus 5 Ansari P et al., 2024 - Nutrients M F Plant based CRP, IL-6, TNF-α, IL-1β Dyslipidaemia, Insulin resistance with inflammation CMR with CVD 10.3390/nu16213709 Scopus 6 Carbone F, et al., 2025 - European Journal of Clinical Investigation M F NA Pro-inflammatory adipocytokines: leptin, resisting; Cytokines: IL-6, TNF-α Obesity, increased inflammatory adipokines, and hypertension Atherosclerosis Heart failure with Increased CVD 10.1111/eci.70059 PubMed, WOS, Scopus 7 Vissers LET et al., 2017- Nutrition, Metabolism and Cardiovasc Disease F PI diet Inflammatory mediators, including CRP, IL-6, and TNF-α, are further implicated in DII Hypertension and Metabolic Syndrome A proinflammatory diet may increase the risk of CVD 10.1016/j.numecd.2017.03.005 PubMed, WOS, Scopus 8 Halabitska I. et al., 2024 - Nutrients M F High Inflammatory cytokines, oxidative stress pathways (IL-6, CRP T2DM inflammatory phenotype Cardiometabolic risk via inflammation and metabolic dysregulation 10.3390/nu16193349 PubMed, WOS, Scopus 9 Toledo E et al., 2015- Nutrients M F High CRP, IL-6, TNF-α All associated metabolic risk Increasing DII scores are associated with higher CVD incidence (HRs − 1.42 to 1.85) 10.3390/nu7064124 PubMed, WOS, Scopus 10 Mohammadi et al., 2025 - Nutrition, Metabolism & Cardiovascular Diseases M F High Hyperhomocysteinemia, Impairment of renal function, abnormal ABI Inflammation with metabolic disturbances Incidence of CVD & Mortality (HR- 1.43 to 1.45) 10.1016/j.numecd.2025.01.007 PubMed, WOS, Scopus 11 Bhattacharya K., 2024 - Biomolecular Concepts F PC-OS diet, High Oxidative stress, TNF-α, IL- 6, Insulin signaling mediators Obesity, Insulin resistance, central adiposity, dyslipidemia PCOS is linked with an increased risk of CVD via the process of inflammation 10.1515/bmc-2022-0038 Scopus 12 Carrasco-Marín F et al., 2024 -Nutrition, Metabolism & Cardiovascular Diseases M F NA Pro-inflammatory markers- CRP, Proinflammatory score by DII DII impaired with Cardio-metabolic associations Higher DII may aggravate the risk of CVD markers 10.1016/j.numecd.2024.03.010 PubMed, WOS, Scopus 13 Mancia G. et al., 2023 - Journal of Hypertension M F High salt food Hypertension, including the RAS pathway, endothelial dysfunction, and inflammatory markers All metabolic dysfunctions, especially obesity related hypertension High BP is associated with obesity, leading to the risk of CVD 10.1097/HJH.0000000000003480 Scopus 14 Santos-Marcos J.A. et al., 2023- Biology of Sex Differences M F High Gut microbiota pathways, with LPS to TLR4 inflammation, sex steroid pathways, and inflammatory cytokines IL-6, TNF-α Obesity, Insulin resistance Diet influenced gut microbiota, triggering metabolic dysfunction as a foremost high risk of CVD 10.1186/s13293-023-00490-2 Scopus 15 Vasincu A. et al., 2023 -Biomedicines M F High Immune metabolic signaling with CB1R and CB2R Obesity, Insulin Resistance, and Dyslipidemia Inflammation with metabolic dysfunctions increases the risk of CVD 10.3390/biomedicines11061667 Scopus 16 Naryzhnaya N.V., 2022- J Biomed Res. M F NA Ischemia reperfusion pathway and oxidative stress enzymes (SOD, CAT) Cardiac tolerance or vulnerability and Metabolic Stress Cardiac Injury and CVD 10.7555/JBR.36.20220125 Scopus 17 Mohanta Y.K. et al., 2023- Frontiers in Pharmacology M F Natural products Anti-oxidant, Anti-inflammatory, and modulating NF-κB, IL-6, TNF-α Inflammation with diabetes and oxidative stress Metabolic inflammation driving CVD 10.3389/fphar.2023.1153600 Scopus 18 Daniele A. et al., 2022 - Frontiers in Physiology M F High Vascular Inflammation pathway, Endothelial NO Synthase, Oxidative stress with cytokines and VCAM-1, ICAM-1, and IL-6, TNF-α Endothelial dysfunction, Impaired Vaso- dilation, Metabolic syndrome Sedentary life with unhealthy food leads to an increased risk of CVD 10.3389/fphys.2022.998380 Scopus 19 Bays H.E. et al., 2022- Obesity Pillars M F High Adipokines and inflammatory markers with leptin, adiponectin, IL-6, CRP, and TNF-α Obesity, Insulin Resistance, and Dyslipidemia Obesity may increase the risk of CVD by increasing inflammation and metabolic mechanisms 10.1016/j.obpill.2022.100034 Scopus 20 Berger M.M. et al., 2022- Clinical Nutrition M F NA Oxidative stress with the inflammatory pathway by inflammation due to micronutrients like Vitamin D,C, and trace elements like Zn, Se Deficiency due to Mal or overnutrition Appropriate levels of micronutrients may increase the risk of CVD 10.1016/j.clnu.2022.02.015 Scopus 21 Dardiotis E. et al., 2021- Journal of Neurology M F NA Neuroinflammatory pathway and cytokines (IL-6, TNF-α) NA NA 10.1007/s00415-021-10928-5 Scopus 22 Hall J.E. et al., 2021- Comprehensive Physiology M F NA RAAS with inflammatory pathways Pathophysiology and Hypertension Hypertension is a major leading factor of CVD 10.1002/cphy.c200033 Scopus 23 López-Moreno M. et al., 2024- Nutrition, Metabolism & Cardiovascular Diseases M F High Inflammatory biomarkers like CRP, IL-6, TNF-α and the cardiometabolic panel marker, including lipid and glucose Proinflammatory biomarkers may impact metabolic syndrome features Increased risk of CVD may lead to even mortality with a proinflammatory diet quality profile 10.1016/j.numecd.2024.03.010 PubMed, WOS, Scopus 24 Martens C.R. et al., 2021- Physiology & Behavior M F High Inflammatory Signaling, Oxidative stress with IL-6 and TNF-α Insulin Resistance and Obesity Increased CMR 10.1016/j.phyplu.2021.100161 Scopus 25 Calder P.C. et al., 2021- Critical Reviews in Food Science & Nutrition M F High NF-κB, IL-6, CRP, TNF-α, and the eicosanoid pathway Chronic low-grade inflammation and Insulin resistance Fatal CVD due to the risk of increasing inflammation 10.1080/10408398.2021.1895054 Scopus 26 Sardu C. et al., 2021- Frontiers in Medicine M F NA Endothelial inflammation pathway with IL-6, CRP, and TNF-α Obesity and Insulin Resistance Heart failure and vascular dysfunction 10.3389/fmed.2021.667315 Scopus 27 Franceschi C. et al., 2020- Biogerontology M F High Inflammatory pathway NF-κB, IL-6, CRP and TNF-α Age-related metabolic dysfunction Increased age-related CVD risk 10.1007/s11357-020-00295-w Scopus 28 Pourrajab et al., 2025- Nutrition Reviews M F Low CRP IL6 Endothelial function NA 10.1093/nutrit/nuae166 PubMed 29 Tuttolomondo et al., 2019 - Int J Mol Sci M F High NF-ĸB Cytokines NA Atherosclerosis 10.3390/ijms20194716 PubMed 30 Mouliou D.S., 2023- Diseases M F NA CRP, IL-6, IL-1β, TNF-α Inflammation leading to metabolic dysfunctions CRP as a marker of CVD via inflammation 10.3390/diseases11040132 Scopus 31 Tsao C.W. et al., 2022- Circulation M F High Population-level markers with associated metabolic stress and syndrome Obesity and diabetes CVD relevance with increasing mortality 10.1161/CIR.0000000000001052 Scopus 32 Neufcourt L et al., 2015 - Nutrition, Metabolism & Cardiovascular Diseases M F PI diet NA Metabolic syndrome features A higher inflammatory diet with metabolic syndrome may lead to fatal conditions of CVD 10.1016/j.numecd.2015.09.002 PubMed, WOS, Scopus 3.1. Literature search strategy The literature search yielded a total of 2,195 records across all electronic databases, including PubMed, Web of Science, Scopus, Embase, and Science Direct. Following the removal of 642 duplicate records and 10 records excluded for non-relevant reasons, 1,543 articles were retained for title and abstract screening. Of these, 1,213 records were excluded due to lack of relevance to high-fat or pro-inflammatory diets, inflammation, cardio-metabolic dysfunction, or cardiovascular outcomes. Full-text assessment was conducted for 330 articles, of which 295 studies were excluded because they did not address high-fat diet–related cardiovascular disease (n = 196) or cardio-metabolic dysfunction linked to cardiovascular outcomes (n = 99). Ultimately, 32 studies met all eligibility criteria and were included in the final qualitative synthesis. The detailed study selection process is illustrated in the PRISMA flow diagram (Fig. 01 ). 3.2. Characteristic of inclusion studies The total of 32 studies included in the review comprised a diverse range of observational, clinical, and mechanistic investigations evaluating the relationship between dietary patterns, inflammation, cardio-metabolic dysfunction, and cardiovascular risk. The majority of studies involved adult human populations and included both male and female participants, although sex-stratified analyses were inconsistently reported. Dietary exposures primarily encompassed high-fat diets, Western dietary patterns, pro-inflammatory diets, and dietary inflammatory index–based assessments, with a smaller number of studies evaluating plant-based or anti-inflammatory dietary patterns for comparative context. Across the included studies, commonly assessed inflammatory markers included C-reactive protein (CRP), interleukin-6 (IL-6), tumour necrosis factor-α (TNF-α), interleukin-1β (IL-1β), and signalling pathways such as NF-κB, TLR4, MAPK, and NLRP3 inflammasome activation. Cardio-metabolic outcomes frequently reported were obesity, insulin resistance, dyslipidemia, metabolic syndrome, and hypertension, while cardiovascular endpoints included atherosclerosis, atherosclerotic cardiovascular disease, endothelial dysfunction, heart failure, and cardiovascular mortality. The key characteristics and findings of the included studies are summarized in Table 01, providing an integrated overview of diet-induced inflammatory mechanisms and their association with cardio-metabolic and cardiovascular risk. 3.3. In-silico pathway enrichment analysis Pathway enrichment analysis using Shiny GO v0.8 revealed significant enrichment of CRP, IL-6, TNF-α, and IL-1β in inflammation-related pathways, including cytokine–cytokine receptor interaction, NF-κB signalling, JAK–STAT signalling, NLRP3 inflammasome activation, and lipid-associated atherosclerosis pathways. These pathways are implicated in immune activation, endothelial dysfunction, oxidative stress, and metabolic dysregulation, providing mechanistic support for the observed association between pro-inflammatory diets, cardio-metabolic risk, and cardiovascular disease, as shown in Figs. 01 and 02 . 4. Discussion This review provides a comprehensive synthesis of evidence demonstrating that high-fat and pro-inflammatory dietary patterns are major drivers of chronic low-grade inflammation, which serves as a central mechanistic link between cardiometabolic dysfunction and cardiovascular disease. Across population-based, clinical, and mechanistic studies, poor diet quality characterized by high intake of saturated fats, refined carbohydrates, and ultra-processed foods was consistently associated with elevated inflammatory biomarkers and adverse metabolic profiles, reinforcing the role of diet-induced inflammation in cardiovascular risk. 4.1. Full section-by-section narrative 4.2. Diet-induced inflammation as a mechanistic link The collective findings summarized in Table 1 highlight inflammation as a primary biological consequence of high-fat and pro-inflammatory diets. Elevated circulating levels of C-reactive protein, interleukin-6, tumour necrosis factor-α, and interleukin-1β were consistently observed across diverse populations, indicating systemic immune activation. These inflammatory responses appear to originate largely from adipose tissue dysfunction, where excess lipid accumulation promotes adipocyte hypertrophy, immune cell infiltration, and increased secretion of pro-inflammatory cytokines. Importantly, inflammatory activation was frequently reported to precede or accompany cardio-metabolic abnormalities, including obesity, insulin resistance, dyslipidaemia, metabolic syndrome, and hypertension. This temporal and mechanistic relationship supports inflammation as a key mediator linking dietary exposure to metabolic dysregulation, rather than a secondary consequence of established disease, consistent with findings reported by Shivappa and Hébert in Preventive Medicine (2014). Conversely, studies evaluating plant-based or less inflammatory dietary patterns reported lower inflammatory biomarker levels and more favourable metabolic profiles, further supporting diet quality as a modifiable determinant of inflammation-driven cardio-metabolic risk. 4.3. Molecular pathways and inflammatory signalling mechanisms At the molecular level, the reviewed studies identify several interconnected pathways through which high-fat diets promote inflammation and cardio-metabolic dysfunction. Activation of innate immune signalling pathways, particularly Toll-like receptor 4 by saturated fatty acids and gut-derived lipopolysaccharides, initiates downstream cascades involving nuclear factor-κB, mitogen-activated protein kinase, and the NOD-like receptor protein 3 inflammasome. These pathways collectively drive transcriptional upregulation of pro-inflammatory cytokines and sustain chronic inflammatory signalling. Oxidative stress emerged as an important complementary mechanism, with increased reactive oxygen species production and impaired antioxidant defences contributing to endothelial dysfunction and vascular inflammation. Dysregulation of endothelial nitric oxide synthase, increased expression of vascular adhesion molecules, and activation of the renin–angiotensin–aldosterone system further link metabolic inflammation to hypertension, arterial stiffness, and atherosclerotic progression. In addition, immune-metabolic crosstalk involving adipokines, eicosanoid signalling, and cannabinoid receptor pathways underscores the complexity of interactions between lipid metabolism and inflammation. Collectively, these molecular mechanisms provide a biologically plausible explanation for epidemiological findings showing that pro-inflammatory dietary patterns are associated with increased risk of cardio-metabolic disorders and cardiovascular disease, as reported in large cohort analyses published in Preventive Medicine (Wirth et al., 2016 ). 4.4. Sex-related biological considerations Although most included studies involved both male and female participants, explicit sex-stratified analyses were limited. Nevertheless, emerging evidence suggests that biological sex may modify inflammatory and metabolic responses to high-fat and pro-inflammatory diets. Differences in sex hormone signalling, adipose tissue distribution, immune responsiveness, and gut microbiota composition may influence susceptibility to diet-induced inflammation and cardiometabolic dysfunction. Female-specific conditions, such as polycystic ovary syndrome, demonstrated heightened inflammatory sensitivity and metabolic impairment in response to unhealthy dietary patterns, potentially increasing long-term cardiovascular risk. In contrast, males often exhibit greater visceral adiposity and macrophage infiltration, which may amplify inflammatory responses and insulin resistance. These observations support the interpretation of sex as a biological modifier of diet-induced cardio-metabolic risk rather than an independent determinant, highlighting the need for more consistent sex-stratified reporting in future research. 4.5. Cardio-metabolic outcomes and cardiovascular risk The convergence of inflammatory signalling, oxidative stress, and metabolic dysregulation culminates in a spectrum of cardiometabolic outcomes that substantially increase cardiovascular risk. High-fat and pro-inflammatory diets were consistently associated with obesity, insulin resistance, type 2 diabetes mellitus, dyslipidaemia, metabolic syndrome, and hypertension, conditions that collectively constitute cardiometabolic risk. Endothelial dysfunction, impaired flow-mediated dilation, arterial stiffness, and chronic vascular inflammation were frequently reported as intermediate phenotypes linking metabolic abnormalities to cardiovascular pathology. Chronic exposure to inflammatory mediators facilitates lipid deposition within arterial walls, accelerates atherosclerotic plaque formation, and promotes plaque instability, thereby increasing the risk of atherosclerotic cardiovascular disease, heart failure, and cardiovascular mortality. Longitudinal studies employing dietary inflammatory indices further demonstrated dose-response relationships between higher dietary inflammatory potential and increased incidence of cardiovascular events and mortality, reinforcing the clinical relevance of dietary inflammation in cardiovascular disease progression. 4.6. Clinical and public health implications From a clinical perspective, the findings of this review underscore the importance of targeting diet-induced inflammation as a preventive and therapeutic strategy for cardio-metabolic and cardiovascular disease. Inflammatory biomarkers such as C-reactive protein, interleukin-6, and tumour necrosis factor-α may serve as accessible indicators for early risk stratification and monitoring of cardio-metabolic health. Dietary interventions emphasizing anti-inflammatory patterns, including plant-based, Mediterranean, or nutrient-dense diets, have the potential to attenuate inflammatory signalling, improve metabolic profiles, and reduce cardiovascular risk. Incorporating dietary inflammatory assessment tools into clinical practice may enhance personalized nutrition strategies and support early prevention. Recognition of sex-related biological differences may further refine risk assessment and intervention strategies, supporting more tailored approaches to cardio-metabolic and cardiovascular disease prevention. 4.7. In-silico pathway enrichment analysis The convergence of lipid-driven and innate immune inflammatory pathways provides a mechanistic basis for how high-fat diets translate into increased cardio-metabolic risk and overt cardiovascular disease. Excess dietary fat and lipid overload generate metabolic stress signals that activate the NOD-like receptor family pyrin domain containing 3 (NLRP3) inflammasome via oxidative stress, mitochondrial dysfunction, and the accumulation of lipid crystals in metabolic tissues, leading to caspase-1-mediated release of IL-1β and IL-18. These cytokines, together with IL-6, TNF-α, and C-reactive protein (CRP), act systemically and within vascular and metabolic tissues to impair insulin sensitivity, promote endothelial dysfunction, and perpetuate low-grade chronic inflammation. Concurrently, elevated LDL and oxidized LDL activate endothelial receptors such as LOX-1, TLR4, and RAGE, amplifying NF-κB and JAK/STAT-dependent inflammatory gene expression, leukocyte recruitment, foam cell formation, and atherosclerotic plaque development and instability. Clinically, this integrated inflammatory milieu helps explain epidemiological observations linking pro-inflammatory dietary patterns with higher incidence of metabolic syndrome, hypertension, type 2 diabetes, and atherosclerotic cardiovascular disease (ASCVD), as well as increased cardiovascular mortality; for example, Preventive Medicine has documented how dietary patterns with high inflammatory potential are associated with elevated cardiovascular risk and adverse outcomes linked to chronic inflammation and metabolic dysregulation (Shivappa et al., 2018 ). In this context, inflammatory mediators such as IL-1β, IL-6, TNF-α, and CRP serve as actionable biomarkers and therapeutic targets, supporting dietary modulation (e.g., reducing saturated fats and pro-inflammatory foods) and anti-inflammatory strategies as integral components of cardio-metabolic and cardiovascular disease prevention. Integrated interpretation Overall, this review consolidates evidence that high-fat and pro-inflammatory dietary patterns act as potent triggers of chronic low-grade inflammation, which mediates the progression from metabolic dysfunction to cardiovascular disease. At the molecular level, diet-induced activation of innate immune pathways, oxidative stress, and endothelial dysfunction converge to impair metabolic and vascular homeostasis. These processes manifest clinically as cardio-metabolic disorders that substantially elevate cardiovascular risk. By integrating molecular, metabolic, and clinical evidence within a nutrition-focused framework, this review highlights inflammation as a unifying pathological process linking diet quality to cardio-metabolic and cardiovascular outcomes. These findings reinforce the critical role of dietary modulation as a cornerstone of cardiovascular disease prevention and management (Smith et al., 2022 ). 5. Conclusion and Future Perspectives Current evidence supports the concept that pro-inflammatory dietary patterns fundamentally reprogram cardio-metabolic physiology through sustained activation of innate immune and inflammatory signalling pathways. Excess dietary fat and poor diet quality initiate a cascade involving TLR4-dependent immune activation, NF-κB and MAPK signalling, inflammasome assembly, and oxidative stress, collectively impairing insulin sensitivity, adipose tissue function, and vascular homeostasis. These physiological disturbances converge to accelerate the development of cardiometabolic disorders and cardiovascular disease. Importantly, emerging data indicate that inflammatory responses to dietary exposure are not uniform, with biological sex acting as a critical modifier of immune–metabolic signalling, adiposity, and cardiovascular vulnerability. Incorporating sex as a biological variable will be essential for refining mechanistic understanding and improving translational relevance. From a physiological perspective, diet-induced inflammation represents a modifiable node within the integrated network linking metabolism, immunity, and cardiovascular function. Future research should prioritize mechanistic human studies, integrative multi-omics approaches, and longitudinal designs to clarify causal pathways and adaptive versus maladaptive inflammatory responses. Such insights will support the development of personalized nutritional and therapeutic strategies aimed at restoring immune-metabolic balance and reducing inflammation-driven cardiovascular disease. 6. Limitation of Resources available Despite providing a comprehensive synthesis of current evidence, this review has several limitations that should be acknowledged. First, substantial heterogeneity existed across the included studies with respect to dietary assessment methods, inflammatory biomarkers measured, study populations, and cardio-metabolic and cardiovascular endpoints. This variability limited direct comparison across studies and precluded quantitative meta-analysis. Although most studies included both male and female participants, sex-stratified analyses were inconsistently reported. As a result, conclusions regarding sex-related differences in diet-induced inflammation and cardio-metabolic risk remain largely inferential rather than definitive. Third, most included studies were observational in nature, which limits causal inference between dietary patterns, inflammatory processes, and cardiovascular outcomes. Additionally, differences in follow-up duration, population characteristics, confounding adjustment, and dietary measurement error may have influenced reported associations. Finally, restriction to peer-reviewed English-language publications may have introduced publication bias and limited representation of diverse dietary patterns across global populations. Abbreviations HFD High Fat Diet WHO World Health Organisation CMR Cardio Metabolic Risk CVD Cardiovascular Dysfunction TG Triglycerides HDL High Density Lipoproteins LDL Low Density Lipoproteins M/F Male / Female PI Diet Pro-inflammatory Diet HFD High Fat Diet CRP C- Reactive Protein IL Interleukin TNF- α Tumour Necrosis Factor NF-κB Nuclear Factor kappa-light-chain-enhancer of activated B cells ASCVD Atherosclerotic cardiovascular disease WOS Web Of Science NA Not Applicable FMD Flow-mediated dilation TLR4 Toll-Like Receptor 4 MAPK Mitogen-Activated Protein Kinase NLRP3 NOD-Like Receptor Family, Pyrin Domain-Containing 3 DII Dietary Inflammatory Index LPS Lipopolysaccharide CB1R Cannabinoid Receptor 1 CB2R Cannabinoid Receptor 2 SOD Superoxide Dismutase CAT Catalase ROS Reactive Oxygen Species MCP Monocyte Chemoattractant Protein CAD Coronary Artery Disease MI Myocardial Infarction Declarations Future directions Future research should prioritize well-designed longitudinal and interventional studies to establish causal relationships between high-fat and pro-inflammatory dietary patterns, inflammatory signalling pathways, and cardio-metabolic and cardiovascular outcomes. Greater emphasis on standardized dietary assessment tools, including dietary inflammatory indices, and harmonized biomarker panels would enhance comparability across studies. Importantly, future investigations should incorporate consistent sex-stratified analyses to clarify sex-related biological mechanisms influencing inflammatory and metabolic responses to dietary exposure. Integration of multi-omics approaches such as genomics, epigenomics, metabolomics, and gut microbiome profiling may further elucidate molecular pathways linking diet-induced inflammation to cardio-metabolic dysfunction. From a clinical perspective, future studies should explore the utility of inflammatory biomarkers and dietary inflammatory scores in risk stratification, personalized nutrition, and prevention strategies aimed at reducing cardio-metabolic dysfunction and cardiovascular disease burden. Funding Statement We acknowledge that the work was financially supported by “Savitribai Jyotirao Phule Fellowship for Single Girl Child” under “University Grants Commission” of grant number: UGCES-22-OB-TAM-F-SJSGC-8474. Author Contribution V.M - Framing concepts, original draftK.M - Formal analysis, Validation, Correction References Ansari P, Khan JT, Chowdhury S, Reberio AD, Kumar S, Seidel V, Abdel-Wahab YH, Flatt PR. Plant-based diets and phytochemicals in the management of diabetes mellitus and prevention of its complications: a review. Nutrients. 2024;16(21):3709. Bays HE, Golden A, Tondt J. Thirty obesity myths, misunderstandings, and/or oversimplifications: an obesity medicine association (OMA) clinical practice statement (CPS) 2022. Obes Pillars. 2022;3:100034. Berger MM, Shenkin A, Schweinlin A, Amrein K, Augsburger M, Biesalski HK, Bischoff SC, Casaer MP, Gundogan K, Lepp HL, De Man AM. ESPEN micronutrient guideline. Clin Nutr. 2022;41(6):1357-1424. Bhattacharya K, Dey R, Sen D, Paul N, Basak AK, Purkait MP, Shukla N, Chaudhuri GR, Bhattacharya A, Maiti R, Adhikary K. Polycystic ovary syndrome and its management: in view of oxidative stress. Biomol Concepts. 2024;15(1):20220038. Carbone F, Després JP, Ioannidis JP, Neeland IJ, Garruti G, Busetto L, Liberale L, Ministrini S, Vilahur G, Schindler TH, Macedo MP. Bridging the gap in obesity research: a consensus statement from the European Society for Clinical Investigation. Eur J Clin Invest. 2025;e70059. Carrasco-Marín F, Zhao L, Hébert JR, Wirth MD, Petermann-Rocha F, Phillips N, Malcomson FC, Mathers JC, Ferguson LD, Ho F, Pell J. Association of a dietary inflammatory index with cardiometabolic, endocrine, liver, renal and bone biomarkers: cross-sectional analysis of the UK Biobank study. Nutr Metab Cardiovasc Dis. 2024;34(7):1731-1740. Chen X, Zhang Z, Yang H, et al. Consumption of ultra-processed foods and health outcomes: a systematic review of epidemiological studies. Nutr J. 2020;19:86. Clapp BR, Hingorani AD, Kharbanda RK, Mohamed-Ali V, Stephens JW, Vallance P, MacAllister RJ. Inflammation-induced endothelial dysfunction involves reduced nitric oxide bioavailability and increased oxidant stress. Cardiovasc Res. 2004;64(1):172-178. Clemente-Suárez VJ, Beltrán-Velasco AI, Redondo-Flórez L, Martín-Rodríguez A, Tornero-Aguilera JF. Global impacts of Western diet and its effects on metabolism and health: a narrative review. Nutrients. 2023;15(12):2749. Cullberg K, Larsen J, Pedersen S, et al. Effects of LPS and dietary free fatty acids on MCP-1 in 3T3-L1 adipocytes and macrophages in vitro. Nutr Diabetes. 2014;4:e113. Daniele A, Lucas SJ, Rendeiro C. Detrimental effects of physical inactivity on peripheral and brain vasculature in humans: insights into mechanisms, long-term health consequences and protective strategies. Front Physiol. 2022;13:998380. Di Cesare M, Perel P, Taylor S, et al. The heart of the world. Glob Heart. 2024;19(1):11. Duan Y, Zeng L, Zheng C, Song B, Li F, Kong X, Xu K. Inflammatory links between high fat diets and diseases. Front Immunol. 2018;9:2649. Garcia-Arellano A, Ramallal R, Ruiz-Canela M, Salas-Salvado J, Corella D, Shivappa N, Schröder H, Hébert JR, Ros E, Gomez-Garcia E, Estruch R. Dietary inflammatory index and incidence of cardiovascular disease in the PREDIMED study. Nutrients. 2015;7(6):4124-4138. Halabitska I, Oksenych V, Kamyshnyi O. Exploring the efficacy of alpha-lipoic acid in comorbid osteoarthritis and type 2 diabetes mellitus. Nutrients. 2024;16(19):3349. Jhanji M, Rao CN, Sajish M. Towards resolving the enigma of the dichotomy of resveratrol: cis- and trans-resveratrol have opposite effects on TyrRS-regulated PARP1 activation. GeroScience. 2021;43(3):1171-1200. Kuiper-Makris C, Selle J, Nüsken E, Dötsch J, Alejandre Alcazar MA. Perinatal nutritional and metabolic pathways: early origins of chronic lung diseases. Front Med. 2021;8:667315. Lavin KM, Coen PM, Baptista LC, Bell MB, Drummer D, Harper SA, Lixandrão ME, McAdam JS, O'Bryan SM, Ramos S, Roberts LM. State of knowledge on molecular adaptations to exercise in humans: historical perspectives and future directions. Compr Physiol. 2022;12(2):3193-3279. Mancia G, Chairperson; Brunström M, Burnier M, Grassi G, Januszewicz A, Muiesan ML, Tsioufis K, Agabiti-Rosei E, Azizi M, Benetos A, et al. 2023 ESH guidelines for the management of arterial hypertension. J Hypertens. 2023;41(12):1874-2071. Messina M, Mejia SB, Cassidy A, Duncan A, Kurzer M, Nagato C, Ronis M, Rowland I, Sievenpiper J, Barnes S. Neither soyfoods nor isoflavones warrant classification as endocrine disruptors: a technical review of the observational and clinical data. Crit Rev Food Sci Nutr. 2022;62(21):5824-5885. Mohammadi S, Heshmati J, Baziar N, Ziaei S, Farsi F, Ebrahimi S, Mobaderi T, Mohammadi T, Mir H. Impacts of supplementation with pomegranate on cardiometabolic risk factors: a systematic review and dose-response meta-analysis. Nutr Metab Cardiovasc Dis. 2025; Article 104154. Mohanta YK, Mishra AK, Nongbet A, Chakrabartty I, Mahanta S, Sarma B, Panda J, Panda SK. Potential use of the Asteraceae family as a cure for diabetes: a review of ethnopharmacology to modern day drug and nutraceuticals developments. Front Pharmacol. 2023;14:1153600. Mouliou DS. C-reactive protein: pathophysiology, diagnosis, false test results and a novel diagnostic algorithm for clinicians. Diseases. 2023;11(4):132. Naryzhnaya NV, Maslov LN, Derkachev IA, Ma H, Zhang Y, Prasad NR, Singh N, Fu F, Pei J, Sarybaev A, Sydykov A. The effect of an adaptation to hypoxia on cardiac tolerance to ischemia/reperfusion. J Biomed Res. 2022;37(4):230. Neufcourt L, Assmann KE, Fezeu LK, Touvier M, Graffouillère L, Shivappa N, Hébert JR, Wirth MD, Hercberg S, Galan P, Julia C. Prospective association between the dietary inflammatory index and metabolic syndrome: findings from the SU.VI.MAX study. Nutr Metab Cardiovasc Dis. 2015;25(11):988-996. Rani R, Hajam YA, Kumar R, Bhat RA, Rai S, Rather MA. A landscape analysis of the potential role of polyphenols for the treatment of polycystic ovarian syndrome (PCOS). Phytomed Plus. 2022;2(1):100161. Re DB, Yan B, Calderón-Garcidueñas L, Andrew AS, Tischbein M, Stommel EW. A perspective on persistent toxicants in veterans and amyotrophic lateral sclerosis: identifying exposures determining higher ALS risk. J Neurol. 2022;269(5):2359-2377. Rooney M, Lambe J, O’Connor A, Dunne S, Mills A, Feeney EL, Gibney ER. Bovine dairy products and flow mediated dilation (FMD): a systematic review of the published evidence. Eur J Nutr. 2025;64(2):66. Santos-Marcos JA, Mora-Ortiz M, Tena-Sempere M, Lopez-Miranda J, Camargo A. Interaction between gut microbiota and sex hormones and their relation to sexual dimorphism in metabolic diseases. Biol Sex Differ. 2023;14(1):4. Schulz MT, Rink L. Zinc deficiency as possible link between immunosenescence and age-related diseases. Immun Ageing. 2025;22(1):19. Shivappa, N., & Hébert, J. R. (2014). Dietary inflammatory index and associations with inflammatory biomarkers. Preventive Medicine , 69, 234–240. Shivappa, N., Godos, J., Hébert, J.R., Wirth, M.D., Piuri, G., Speciani, A.F. and Grosso, G. (2018) ‘Dietary inflammatory index and cardiovascular risk and mortality: A meta-analysis’, Preventive Medicine , 112, pp. 23–31. https://doi.org/10.1016/j.ypmed.2018.03.016. Silveira Rossi JL, Barbalho SM, Reverete de Araujo R, Bechara MD, Sloan KP, Sloan LA. Metabolic syndrome and cardiovascular diseases: going beyond traditional risk factors. Diabetes Metab Res Rev. 2022;38(3):e3502. Smith J, Lee A, et al. Determinants of health behaviour change: a comprehensive review. Preventive Medicine . 2022;154:106879. Tsao CW, Aday AW, Almarzooq ZI, Alonso A, Beaton AZ, Bittencourt MS, Boehme AK, Buxton AE, Carson AP, Commodore-Mensah Y, Elkind MS. Heart disease and stroke statistics-2022 update: a report from the American Heart Association. Circulation. 2022;145(8):e153-e639. Tuttolomondo A, Simonetta I, Daidone M, Mogavero A, Ortello A, Pinto A. Metabolic and vascular effect of the Mediterranean diet. Int J Mol Sci. 2019;20(19):4716. Vasincu A, Rusu RN, Ababei DC, Neamțu M, Arcan OD, Macadan I, Beșchea Chiriac S, Bild W, Bild V. Exploring the therapeutic potential of cannabinoid receptor antagonists in inflammation, diabetes mellitus, and obesity. Biomedicines. 2023;11(6):1667. Vekic J, Stromsnes K, Mazzalai S, Zeljkovic A, Rizzo M, Gambini J. Oxidative stress, atherogenic dyslipidemia, and cardiovascular risk. Biomedicines. 2023;11(11):2897. Vissers LE, Waller M, van der Schouw YT, Hebert JR, Shivappa N, Schoenaker DAJM, Mishra GD. A pro-inflammatory diet is associated with increased risk of developing hypertension among middle-aged women. Nutr Metab Cardiovasc Dis. 2017;27(6):564-570. Wirth MD, Shivappa N, Davis L, et al. Construct validation of the Dietary Inflammatory Index among African Americans. Preventive Medicine. 2016;83:1–8. Yang M, Miao S, Hu W, Yan J. Association between the dietary inflammatory index and all-cause and cardiovascular mortality in patients with atherosclerotic cardiovascular disease. Nutr Metab Cardiovasc Dis. 2024;34(4):1046-1053. Additional Declarations No competing interests reported. Cite Share Download PDF Status: Posted Version 1 posted 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. 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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-8782385","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":591175113,"identity":"40371a8b-b2df-4267-af9d-5d5c59b5e1cb","order_by":0,"name":"V M Nandhini","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA/ElEQVRIiWNgGAWjYJACaQiVw3Ag4cc/ORDzwAOitTzsOWAM1pJArBbGB2wHEhtAbHxazNnPHrxd2HZH3pw99+CBBJ476fPDDj8E2mInp9uAXYtlT16y9cy2Z4Y7e94lHEiweJa78XaaAVBLsrHZAexaDA7kmEnzth1m3HAjB6iShzl34+wEkJYDidtwaTn/BqzFHqKFjTndcHb6B/xabkBsSYRqOZwgL51DwJYbb4ytec4dTt5w5o3BgcSeNMMN0jkFBxIM8PjlfI7hbZ6yw7YbjucYf/zxw0Zefnb65g8fKuzkcGnBFiBgkljlICDfQIrqUTAKRsEoGAkAANGtbVAOOh+XAAAAAElFTkSuQmCC","orcid":"","institution":"PSG College of Arts \u0026 Science","correspondingAuthor":true,"prefix":"","firstName":"V","middleName":"M","lastName":"Nandhini","suffix":""},{"id":591175114,"identity":"28b22fa3-a19f-4b0f-800b-984b1d2230ba","order_by":1,"name":"K M Priyadharshini","email":"","orcid":"","institution":"PSG College of Arts \u0026 Science","correspondingAuthor":false,"prefix":"","firstName":"K","middleName":"M","lastName":"Priyadharshini","suffix":""}],"badges":[],"createdAt":"2026-02-04 06:09:31","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-8782385/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-8782385/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":102781856,"identity":"dd7857db-85e4-445b-a100-143468e516a2","added_by":"auto","created_at":"2026-02-16 15:12:55","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":59213,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003ePRISMA flow diagram illustrating the identification, screening, eligibility assessment, and inclusion of the review.\u003c/strong\u003e\u003c/p\u003e","description":"","filename":"1.png","url":"https://assets-eu.researchsquare.com/files/rs-8782385/v1/fdd75a5ce1199adb4c936949.png"},{"id":102781853,"identity":"8bc8b339-6745-440f-a11a-eb290da0619d","added_by":"auto","created_at":"2026-02-16 15:12:55","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":433424,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eIn-silico pathway enrichment analysis (Shiny GO v0.8) demonstrating the involvement in lipid and atherosclerosis pathways\u003c/strong\u003e\u003c/p\u003e","description":"","filename":"2.png","url":"https://assets-eu.researchsquare.com/files/rs-8782385/v1/603c76dc914c7fc42ea209af.png"},{"id":102962851,"identity":"e421494d-b227-4b4b-8e2a-6605d6564825","added_by":"auto","created_at":"2026-02-19 04:11:41","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":209827,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eIn silico pathway enrichment analysis (Shiny GO v0.8) illustrating the enrichment in NOD-like receptor signalling pathways.\u003c/strong\u003e\u003c/p\u003e","description":"","filename":"3.png","url":"https://assets-eu.researchsquare.com/files/rs-8782385/v1/1f493821f8addd452f155daa.png"},{"id":102781854,"identity":"149a2f5e-da7f-410a-8f0a-aa22ea5ebaae","added_by":"auto","created_at":"2026-02-16 15:12:55","extension":"png","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":185602,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eIntegrated factors spanning from high-fat diet induced inflammation to cardio-metabolic dysfunction, and cardiovascular disease.\u003c/strong\u003e\u003c/p\u003e","description":"","filename":"4.png","url":"https://assets-eu.researchsquare.com/files/rs-8782385/v1/9ae6afe0f466cf62609682e8.png"},{"id":105600571,"identity":"59191664-eac4-4823-9e90-f83f7cbb67b2","added_by":"auto","created_at":"2026-03-27 19:39:49","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1988549,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-8782385/v1/37900c43-5d29-4597-adfb-9159be8ee71c.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Diet-Driven Inflammatory Signalling in Cardio-Metabolic Physiology: Molecular Pathways, Sex Differences, and Cardiovascular Consequences","fulltext":[{"header":"1. Background","content":"\u003cp\u003eCardiovascular diseases (CVDs) represent the leading cause of mortality worldwide and remain a major public health challenge. Recent global estimates indicate a substantial and continuing rise in cardiovascular mortality, driven largely by modifiable metabolic risk factors including obesity, hypertension, dyslipidaemia, and diabetes (Di Cesare et al., \u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e2024\u003c/span\u003e). In India, national health data further emphasize the growing burden of CVD and highlight diet-related metabolic risks such as elevated blood pressure, abnormal lipid profiles, and excess adiposity as key contributors to cardiovascular morbidity and mortality. These trends underscore the critical role of dietary patterns in shaping cardio-metabolic health and cardiovascular risk.\u003c/p\u003e \u003cp\u003eThe modern Western dietary pattern, often characterized as a high-fat diet (HFD), is dominated by excessive intake of saturated and trans fatty acids, refined carbohydrates, added sugars, and ultra-processed foods, including processed meats, sugar-sweetened beverages, fried foods, and packaged snacks (Chen et al., \u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e2020\u003c/span\u003e). Increasing evidence suggests that habitual consumption of such diets induces oxidative stress, disrupts gut microbiota composition, and promotes chronic low-grade inflammation, thereby precipitating metabolic ddysfunctions such as obesity, insulin resistance, dyslipidemia, and hypertension (Clemente-Su\u0026aacute;rez et al., \u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e2023\u003c/span\u003e; Silveira Rossi et al., \u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e2022\u003c/span\u003e). These cardio-metabolic abnormalities are well-recognized precursors of atherosclerosis, heart failure, cardiomyopathy, and other cardiovascular complications.\u003c/p\u003e \u003cp\u003eA central feature linking HFD consumption to cardio-metabolic dysfunction and CVD is inflammation. Excess dietary fat intake leads to elevated circulating triglycerides and low-density lipoprotein cholesterol, accompanied by reduced high-density lipoprotein levels, thereby favouring lipid accumulation within vascular and cardiac tissues (Vekic et al., \u003cspan citationid=\"CR38\" class=\"CitationRef\"\u003e2023\u003c/span\u003e). Concurrently, saturated fatty acids disrupt metabolic homeostasis by activating inflammatory signalling pathways, resulting in endothelial dysfunction, oxidative stress, and progressive vascular injury. Over time, these alterations facilitate atherosclerotic plaque formation, impair myocardial function, and increase susceptibility to coronary artery disease, myocardial infarction, and stroke (Clapp et al., \u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e2004\u003c/span\u003e; Duan et al., \u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e2018\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eAt the cellular level, prolonged exposure to an HFD promotes excessive accumulation of free fatty acids in adipose tissue and ectopic lipid deposition in non-adipose organs such as the liver, skeletal muscle, and heart. Adipocyte hypertrophy and dysfunction lead to increased secretion of pro-inflammatory cytokines, including tumour necrosis factor-α (TNF-α), interleukin-6 (IL-6), and monocyte chemoattractant protein-1 (MCP-1), which recruit immune cells and enhance macrophage infiltration into adipose tissue (Cullberg et al., \u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e2014\u003c/span\u003e). These processes amplify systemic inflammation and interfere with insulin signalling pathways, thereby contributing to insulin resistance and impaired glucose metabolism. Smith et al. (\u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e2022\u003c/span\u003e) comprehensively reviewed the determinants of health behaviour change, highlighting the role of individual, social, and environmental factors.\u003c/p\u003e \u003cp\u003eInnate immune activation plays a critical role in mediating diet-induced inflammation. Saturated fatty acids and gut-derived lipopolysaccharides activate Toll-like receptor-4 (TLR4), triggering downstream signalling cascades involving nuclear factor-κB (NF-κB) and c-Jun N-terminal kinase (JNK). Activation of these pathways promotes transcription of pro-inflammatory genes and perpetuates chronic inflammatory responses, which are closely linked to obesity, type 2 diabetes, and metabolic syndrome (Duan et al., \u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e2018\u003c/span\u003e). Chronic inflammation further exacerbates oxidative stress by increasing reactive oxygen species production and reducing nitric oxide bioavailability, leading to impaired vasodilation, arterial stiffness, and endothelial dysfunction (Clapp et al., \u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e2004\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eSystemic inflammation induced by unhealthy dietary patterns therefore, acts as a unifying mechanism connecting metabolic abnormalities with cardiovascular pathology. Elevated circulating inflammatory mediators and dysregulated lipid metabolism accelerate lipid deposition within arterial walls, promote plaque instability, and increase the risk of atherosclerotic cardiovascular disease and cardiovascular mortality (Vekic et al., \u003cspan citationid=\"CR38\" class=\"CitationRef\"\u003e2023\u003c/span\u003e). Epidemiological evidence using dietary inflammatory indices further supports the association between pro-inflammatory diets and increased cardio-metabolic and cardiovascular risk across diverse populations.\u003c/p\u003e \u003cp\u003eEmerging literature also suggests that biological sex may influence inflammatory and metabolic responses to dietary exposures. Differences in sex hormone regulation, adipose tissue distribution, immune function, and gut microbiota composition may modify susceptibility to diet-induced inflammation and cardio-metabolic dysfunction, although sex-stratified evidence remains limited (Silveira Rossi et al., \u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e2022\u003c/span\u003e). Recognizing sex-related biological considerations is therefore important for understanding variability in cardio-metabolic risk and cardiovascular outcomes.\u003c/p\u003e \u003cp\u003eDespite growing recognition of the role of diet-induced inflammation in cardiometabolic and cardiovascular disease, an integrated synthesis focusing on inflammatory genes, enzymes, and molecular pathways within a nutrition, metabolism and cardiovascular framework remains limited. Therefore, this review aims to systematically summarize current evidence linking high-fat and pro-inflammatory dietary patterns to inflammation-mediated cardio-metabolic dysfunction and associated cardiovascular risk, with emphasis on key inflammatory pathways and emerging sex-related considerations relevant to prevention and clinical practice.\u003c/p\u003e"},{"header":"2. Methodology","content":"\u003cp\u003eThis study was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Data were retrieved from standard electronic databases and screened using predefined inclusion and exclusion criteria. Following the initial screening, eligible articles were further assessed for relevance, and studies meeting all criteria were included in the final analysis. The study selection process is illustrated in Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e01\u003c/span\u003e.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003e2.1. Research Approach\u003c/h2\u003e \u003cp\u003eThis review employed a systematic evidence-based approach to examine the role of high-fat and pro-inflammatory dietary patterns in driving inflammation-mediated cardiometabolic dysfunction and subsequent cardiovascular risk. The methodological framework followed the principles outlined in the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) to ensure methodological transparency and reproducibility.\u003c/p\u003e \u003cp\u003eThe review integrates findings from population-based studies, clinical investigations, and mechanistic research to elucidate how dietary fat excess influences inflammatory signalling, metabolic disturbances, and cardiovascular pathology. Special consideration was given to sex-specific biological responses, allowing comparison of inflammatory and metabolic outcomes between males and females. The focus was placed on molecular mediators, including inflammatory genes, enzymes, and pathways that connect dietary exposure to cardiometabolic and cardiovascular outcomes.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec4\" class=\"Section2\"\u003e \u003ch2\u003e2.2. Literature Screening Process\u003c/h2\u003e \u003cp\u003eA comprehensive literature search was conducted using the electronic databases PubMed, Web of Science, Scopus, Embase, and ScienceDirect. Search strategies combined relevant keywords and Boolean operators related to diet, inflammation, metabolism, and cardiovascular disease. The search was not restricted by study design to allow inclusion of both observational and interventional research. All retrieved records were compiled, and duplicate articles were removed before screening. Initial screening was performed by reviewing titles and abstracts to exclude studies clearly unrelated to the research objective. Full-text evaluation was subsequently carried out for potentially eligible articles to confirm relevance and methodological suitability. Only studies meeting all predefined criteria were included in the final synthesis. The selection process and study flow are presented in the PRISMA diagram. All the literature is collected using the keywords: \u0026ldquo;cardiovascular disease associated inflammation with high fat diet or western diet in India, only in terms of gene or enzyme regulation, a comparison between male and female.\u0026rdquo;\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec5\" class=\"Section2\"\u003e \u003ch2\u003e2.3. Criteria for Inclusion and Exclusion\u003c/h2\u003e \u003cp\u003eStudies were considered eligible for inclusion if they were peer-reviewed articles published in English that investigated high-fat, Western, or pro-inflammatory dietary patterns, including evaluations based on the dietary inflammatory index, and examined their associations with inflammation-related cardiometabolic and cardiovascular outcomes. Included studies involved adult human populations of either or both sexes and reported data on inflammatory mediators, molecular pathways, or enzymatic regulators relevant to metabolic and cardiovascular physiology, together with cardiometabolic outcomes such as obesity, insulin resistance, dyslipidaemia, metabolic syndrome, or hypertension, and cardiovascular outcomes or risk indicators including atherosclerosis, atherosclerotic cardiovascular disease, heart failure, or cardiovascular mortality. Studies were excluded if they did not assess dietary exposure in relation to inflammation or cardiometabolic health, focused exclusively on inflammatory conditions unrelated to metabolic or cardiovascular disease, lacked relevant metabolic or cardiovascular endpoints, or were published as case reports, editorials, conference abstracts, or other non-peer-reviewed sources. Experimental animal studies and in vitro investigations without direct translational relevance to human cardiometabolic or cardiovascular disease were also excluded.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec6\" class=\"Section2\"\u003e \u003ch2\u003e2.4. In-silico pathway enrichment analysis\u003c/h2\u003e \u003cp\u003eTo support the mechanistic interpretation of diet-induced cardiometabolic inflammation, an in-silico pathway enrichment analysis was performed using Shiny GO v0.8 (Ge et al., 2020). Key inflammatory genes repeatedly identified across the reviewed studies (CRP, IL-6, TNF-α, and IL-1β) were used as input. Gene Ontology (GO), Kyoto Encyclopaedia of Genes and Genomes (KEGG), and Reactive databases were queried to identify enriched biological processes and signalling pathways relevant to lipid metabolism, inflammation, cardiometabolic dysfunction, and cardiovascular disease.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec7\" class=\"Section2\"\u003e \u003ch2\u003e2.5. Standardized data extraction\u003c/h2\u003e \u003cp\u003eTo ensure methodological consistency and reduce the potential for selection bias, a standardized data extraction framework was applied uniformly across all included studies. Relevant information was systematically collected and categorized according to predefined variables, including authorship and year of publication, journal source, study population characteristics with sex distribution, type of dietary pattern or nutritional exposure, inflammatory genes, enzymes, or molecular pathways investigated, reported cardiometabolic alterations, associated cardiovascular outcomes or risk indicators, and corresponding DOI and database sources. The extracted data were compiled into a structured summary table to facilitate direct comparison across studies. This standardized process enabled coherent integration of molecular, metabolic, and clinical evidence, thereby supporting mechanistic interpretation of diet-induced inflammatory processes and their role in cardiometabolic dysfunction and cardiovascular disease.\u003c/p\u003e \u003c/div\u003e"},{"header":"3. Results","content":"\u003cp\u003eThe results of the collected data are presented in Table\u0026nbsp;01. The results depict that HFD may induce inflammation at a lower level, which in turn induces any of the cardiometabolic dysfunctions, leading to the long-term process of Cardiovascular risk. Any of these may include alterations by the inhibition or induction of genes or enzymes in any related pathway. Most of the inflammatory genes related were CRP, IL-6, IL-1β, TNF-α, and NF-κB, which in turn release the proinflammatory cytokines resulting in the cardiometabolic ailments such as Obesity, diabetes, hypertension, and hypercholesterolemia. This endured exposure to this diet, with associated metabolic problems, would lead to certain cardiovascular risk, particularly ASCVD, heart failure, heart attack, fatty liver, etc., depending on the kind and term of exposure, may or may not lead to mortality as presented in the following table.\u003cdiv class=\"BlockQuote\"\u003e\u003cp\u003e \u003cb\u003eTable.01 Cardiovascular risk linked to High Fat Diet- induced cardiometabolic dysfunction through inflammatory genes, enzymes, and pathways.\u003c/b\u003e \u003c/p\u003e\u003c/div\u003e\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"No\" id=\"Taba\" border=\"1\"\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=\"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 \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eS.\u003c/p\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eAuthor, Year-\u003c/p\u003e \u003cp\u003eJournal\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eSex\u003c/p\u003e \u003cp\u003eM/ F\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eHFD\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003eGenes/\u003c/p\u003e \u003cp\u003eEnzyme/\u003c/p\u003e \u003cp\u003ePathway\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c6\"\u003e \u003cp\u003eCardio Metabolic dysfunction\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c7\"\u003e \u003cp\u003eCardiovascular risk\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c8\"\u003e \u003cp\u003eDOI\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c9\"\u003e \u003cp\u003eDatabase\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003ctr\u003e \u003cth align=\"left\" colspan=\"9\" nameend=\"c9\" namest=\"c1\"\u003e \u003cp\u003eInflammation\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 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\u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eM\u003c/p\u003e \u003cp\u003eF\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eHigh\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003ePopulation-level markers with associated metabolic stress and syndrome\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eObesity and diabetes\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eCVD relevance with increasing mortality\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1161/CIR.0000000000001052\u003c/span\u003e\u003cspan address=\"10.1161/CIR.0000000000001052\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003eScopus\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e32\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eNeufcourt L et al., \u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e2015\u003c/span\u003e- Nutrition, Metabolism \u0026amp; Cardiovascular Diseases\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eM\u003c/p\u003e \u003cp\u003eF\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003ePI diet\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eNA\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eMetabolic syndrome features\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eA higher inflammatory diet with metabolic syndrome may lead to fatal conditions of CVD\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1016/j.numecd.2015.09.002\u003c/span\u003e\u003cspan address=\"10.1016/j.numecd.2015.09.002\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003ePubMed, WOS, Scopus\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cdiv id=\"Sec9\" class=\"Section2\"\u003e \u003ch2\u003e3.1. Literature search strategy\u003c/h2\u003e \u003cp\u003eThe literature search yielded a total of 2,195 records across all electronic databases, including PubMed, Web of Science, Scopus, Embase, and Science Direct. Following the removal of 642 duplicate records and 10 records excluded for non-relevant reasons, 1,543 articles were retained for title and abstract screening. Of these, 1,213 records were excluded due to lack of relevance to high-fat or pro-inflammatory diets, inflammation, cardio-metabolic dysfunction, or cardiovascular outcomes. Full-text assessment was conducted for 330 articles, of which 295 studies were excluded because they did not address high-fat diet\u0026ndash;related cardiovascular disease (n\u0026thinsp;=\u0026thinsp;196) or cardio-metabolic dysfunction linked to cardiovascular outcomes (n\u0026thinsp;=\u0026thinsp;99). Ultimately, 32 studies met all eligibility criteria and were included in the final qualitative synthesis. The detailed study selection process is illustrated in the PRISMA flow diagram (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e01\u003c/span\u003e).\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec10\" class=\"Section2\"\u003e \u003ch2\u003e3.2. Characteristic of inclusion studies\u003c/h2\u003e \u003cp\u003eThe total of 32 studies included in the review comprised a diverse range of observational, clinical, and mechanistic investigations evaluating the relationship between dietary patterns, inflammation, cardio-metabolic dysfunction, and cardiovascular risk. The majority of studies involved adult human populations and included both male and female participants, although sex-stratified analyses were inconsistently reported. Dietary exposures primarily encompassed high-fat diets, Western dietary patterns, pro-inflammatory diets, and dietary inflammatory index\u0026ndash;based assessments, with a smaller number of studies evaluating plant-based or anti-inflammatory dietary patterns for comparative context.\u003c/p\u003e \u003cp\u003eAcross the included studies, commonly assessed inflammatory markers included C-reactive protein (CRP), interleukin-6 (IL-6), tumour necrosis factor-α (TNF-α), interleukin-1β (IL-1β), and signalling pathways such as NF-κB, TLR4, MAPK, and NLRP3 inflammasome activation. Cardio-metabolic outcomes frequently reported were obesity, insulin resistance, dyslipidemia, metabolic syndrome, and hypertension, while cardiovascular endpoints included atherosclerosis, atherosclerotic cardiovascular disease, endothelial dysfunction, heart failure, and cardiovascular mortality. The key characteristics and findings of the included studies are summarized in Table\u0026nbsp;01, providing an integrated overview of diet-induced inflammatory mechanisms and their association with cardio-metabolic and cardiovascular risk.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec11\" class=\"Section2\"\u003e \u003ch2\u003e3.3. In-silico pathway enrichment analysis\u003c/h2\u003e \u003cp\u003ePathway enrichment analysis using Shiny GO v0.8 revealed significant enrichment of CRP, IL-6, TNF-α, and IL-1β in inflammation-related pathways, including cytokine\u0026ndash;cytokine receptor interaction, NF-κB signalling, JAK\u0026ndash;STAT signalling, NLRP3 inflammasome activation, and lipid-associated atherosclerosis pathways. These pathways are implicated in immune activation, endothelial dysfunction, oxidative stress, and metabolic dysregulation, providing mechanistic support for the observed association between pro-inflammatory diets, cardio-metabolic risk, and cardiovascular disease, as shown in Figs.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e01\u003c/span\u003e and \u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e02\u003c/span\u003e.\u003c/p\u003e "},{"header":"4. Discussion","content":"\u003cp\u003eThis review provides a comprehensive synthesis of evidence demonstrating that high-fat and pro-inflammatory dietary patterns are major drivers of chronic low-grade inflammation, which serves as a central mechanistic link between cardiometabolic dysfunction and cardiovascular disease. Across population-based, clinical, and mechanistic studies, poor diet quality characterized by high intake of saturated fats, refined carbohydrates, and ultra-processed foods was consistently associated with elevated inflammatory biomarkers and adverse metabolic profiles, reinforcing the role of diet-induced inflammation in cardiovascular risk.\u003c/p\u003e \u003cdiv id=\"Sec13\" class=\"Section2\"\u003e \u003ch2\u003e4.1. Full section-by-section narrative\u003c/h2\u003e \u003cp\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec14\" class=\"Section2\"\u003e \u003ch2\u003e4.2. Diet-induced inflammation as a mechanistic link\u003c/h2\u003e \u003cp\u003eThe collective findings summarized in Table\u0026nbsp;1 highlight inflammation as a primary biological consequence of high-fat and pro-inflammatory diets. Elevated circulating levels of C-reactive protein, interleukin-6, tumour necrosis factor-α, and interleukin-1β were consistently observed across diverse populations, indicating systemic immune activation. These inflammatory responses appear to originate largely from adipose tissue dysfunction, where excess lipid accumulation promotes adipocyte hypertrophy, immune cell infiltration, and increased secretion of pro-inflammatory cytokines.\u003c/p\u003e \u003cp\u003eImportantly, inflammatory activation was frequently reported to precede or accompany cardio-metabolic abnormalities, including obesity, insulin resistance, dyslipidaemia, metabolic syndrome, and hypertension. This temporal and mechanistic relationship supports inflammation as a key mediator linking dietary exposure to metabolic dysregulation, rather than a secondary consequence of established disease, consistent with findings reported by Shivappa and H\u0026eacute;bert in Preventive Medicine (2014).\u003c/p\u003e \u003cp\u003eConversely, studies evaluating plant-based or less inflammatory dietary patterns reported lower inflammatory biomarker levels and more favourable metabolic profiles, further supporting diet quality as a modifiable determinant of inflammation-driven cardio-metabolic risk.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec15\" class=\"Section2\"\u003e \u003ch2\u003e4.3. Molecular pathways and inflammatory signalling mechanisms\u003c/h2\u003e \u003cp\u003eAt the molecular level, the reviewed studies identify several interconnected pathways through which high-fat diets promote inflammation and cardio-metabolic dysfunction. Activation of innate immune signalling pathways, particularly Toll-like receptor 4 by saturated fatty acids and gut-derived lipopolysaccharides, initiates downstream cascades involving nuclear factor-κB, mitogen-activated protein kinase, and the NOD-like receptor protein 3 inflammasome. These pathways collectively drive transcriptional upregulation of pro-inflammatory cytokines and sustain chronic inflammatory signalling.\u003c/p\u003e \u003cp\u003eOxidative stress emerged as an important complementary mechanism, with increased reactive oxygen species production and impaired antioxidant defences contributing to endothelial dysfunction and vascular inflammation. Dysregulation of endothelial nitric oxide synthase, increased expression of vascular adhesion molecules, and activation of the renin\u0026ndash;angiotensin\u0026ndash;aldosterone system further link metabolic inflammation to hypertension, arterial stiffness, and atherosclerotic progression.\u003c/p\u003e \u003cp\u003eIn addition, immune-metabolic crosstalk involving adipokines, eicosanoid signalling, and cannabinoid receptor pathways underscores the complexity of interactions between lipid metabolism and inflammation. Collectively, these molecular mechanisms provide a biologically plausible explanation for epidemiological findings showing that pro-inflammatory dietary patterns are associated with increased risk of cardio-metabolic disorders and cardiovascular disease, as reported in large cohort analyses published in \u003cem\u003ePreventive Medicine\u003c/em\u003e (Wirth et al., \u003cspan citationid=\"CR40\" class=\"CitationRef\"\u003e2016\u003c/span\u003e).\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec16\" class=\"Section2\"\u003e \u003ch2\u003e4.4. Sex-related biological considerations\u003c/h2\u003e \u003cp\u003eAlthough most included studies involved both male and female participants, explicit sex-stratified analyses were limited. Nevertheless, emerging evidence suggests that biological sex may modify inflammatory and metabolic responses to high-fat and pro-inflammatory diets. Differences in sex hormone signalling, adipose tissue distribution, immune responsiveness, and gut microbiota composition may influence susceptibility to diet-induced inflammation and cardiometabolic dysfunction.\u003c/p\u003e \u003cp\u003eFemale-specific conditions, such as polycystic ovary syndrome, demonstrated heightened inflammatory sensitivity and metabolic impairment in response to unhealthy dietary patterns, potentially increasing long-term cardiovascular risk. In contrast, males often exhibit greater visceral adiposity and macrophage infiltration, which may amplify inflammatory responses and insulin resistance. These observations support the interpretation of sex as a biological modifier of diet-induced cardio-metabolic risk rather than an independent determinant, highlighting the need for more consistent sex-stratified reporting in future research.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec17\" class=\"Section2\"\u003e \u003ch2\u003e4.5. Cardio-metabolic outcomes and cardiovascular risk\u003c/h2\u003e \u003cp\u003eThe convergence of inflammatory signalling, oxidative stress, and metabolic dysregulation culminates in a spectrum of cardiometabolic outcomes that substantially increase cardiovascular risk. High-fat and pro-inflammatory diets were consistently associated with obesity, insulin resistance, type 2 diabetes mellitus, dyslipidaemia, metabolic syndrome, and hypertension, conditions that collectively constitute cardiometabolic risk.\u003c/p\u003e \u003cp\u003eEndothelial dysfunction, impaired flow-mediated dilation, arterial stiffness, and chronic vascular inflammation were frequently reported as intermediate phenotypes linking metabolic abnormalities to cardiovascular pathology. Chronic exposure to inflammatory mediators facilitates lipid deposition within arterial walls, accelerates atherosclerotic plaque formation, and promotes plaque instability, thereby increasing the risk of atherosclerotic cardiovascular disease, heart failure, and cardiovascular mortality.\u003c/p\u003e \u003cp\u003eLongitudinal studies employing dietary inflammatory indices further demonstrated dose-response relationships between higher dietary inflammatory potential and increased incidence of cardiovascular events and mortality, reinforcing the clinical relevance of dietary inflammation in cardiovascular disease progression.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec18\" class=\"Section2\"\u003e \u003ch2\u003e4.6. Clinical and public health implications\u003c/h2\u003e \u003cp\u003eFrom a clinical perspective, the findings of this review underscore the importance of targeting diet-induced inflammation as a preventive and therapeutic strategy for cardio-metabolic and cardiovascular disease. Inflammatory biomarkers such as C-reactive protein, interleukin-6, and tumour necrosis factor-α may serve as accessible indicators for early risk stratification and monitoring of cardio-metabolic health.\u003c/p\u003e \u003cp\u003eDietary interventions emphasizing anti-inflammatory patterns, including plant-based, Mediterranean, or nutrient-dense diets, have the potential to attenuate inflammatory signalling, improve metabolic profiles, and reduce cardiovascular risk. Incorporating dietary inflammatory assessment tools into clinical practice may enhance personalized nutrition strategies and support early prevention. Recognition of sex-related biological differences may further refine risk assessment and intervention strategies, supporting more tailored approaches to cardio-metabolic and cardiovascular disease prevention.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec19\" class=\"Section2\"\u003e \u003ch2\u003e4.7. In-silico pathway enrichment analysis\u003c/h2\u003e \u003cp\u003eThe convergence of lipid-driven and innate immune inflammatory pathways provides a mechanistic basis for how high-fat diets translate into increased cardio-metabolic risk and overt cardiovascular disease. Excess dietary fat and lipid overload generate metabolic stress signals that activate the NOD-like receptor family pyrin domain containing 3 (NLRP3) inflammasome via oxidative stress, mitochondrial dysfunction, and the accumulation of lipid crystals in metabolic tissues, leading to caspase-1-mediated release of IL-1β and IL-18. These cytokines, together with IL-6, TNF-α, and C-reactive protein (CRP), act systemically and within vascular and metabolic tissues to impair insulin sensitivity, promote endothelial dysfunction, and perpetuate low-grade chronic inflammation. Concurrently, elevated LDL and oxidized LDL activate endothelial receptors such as LOX-1, TLR4, and RAGE, amplifying NF-κB and JAK/STAT-dependent inflammatory gene expression, leukocyte recruitment, foam cell formation, and atherosclerotic plaque development and instability. Clinically, this integrated inflammatory milieu helps explain epidemiological observations linking pro-inflammatory dietary patterns with higher incidence of metabolic syndrome, hypertension, type 2 diabetes, and atherosclerotic cardiovascular disease (ASCVD), as well as increased cardiovascular mortality; for example, \u003cem\u003ePreventive Medicine\u003c/em\u003e has documented how dietary patterns with high inflammatory potential are associated with elevated cardiovascular risk and adverse outcomes linked to chronic inflammation and metabolic dysregulation (Shivappa et al., \u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e2018\u003c/span\u003e). In this context, inflammatory mediators such as IL-1β, IL-6, TNF-α, and CRP serve as actionable biomarkers and therapeutic targets, supporting dietary modulation (e.g., reducing saturated fats and pro-inflammatory foods) and anti-inflammatory strategies as integral components of cardio-metabolic and cardiovascular disease prevention.\u003c/p\u003e \u003cp\u003e \u003cb\u003eIntegrated interpretation\u003c/b\u003e \u003c/p\u003e \u003cp\u003eOverall, this review consolidates evidence that high-fat and pro-inflammatory dietary patterns act as potent triggers of chronic low-grade inflammation, which mediates the progression from metabolic dysfunction to cardiovascular disease. At the molecular level, diet-induced activation of innate immune pathways, oxidative stress, and endothelial dysfunction converge to impair metabolic and vascular homeostasis. These processes manifest clinically as cardio-metabolic disorders that substantially elevate cardiovascular risk.\u003c/p\u003e \u003cp\u003eBy integrating molecular, metabolic, and clinical evidence within a nutrition-focused framework, this review highlights inflammation as a unifying pathological process linking diet quality to cardio-metabolic and cardiovascular outcomes. These findings reinforce the critical role of dietary modulation as a cornerstone of cardiovascular disease prevention and management (Smith et al., \u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e2022\u003c/span\u003e).\u003c/p\u003e \u003c/div\u003e"},{"header":"5. Conclusion and Future Perspectives","content":"\u003cp\u003eCurrent evidence supports the concept that pro-inflammatory dietary patterns fundamentally reprogram cardio-metabolic physiology through sustained activation of innate immune and inflammatory signalling pathways. Excess dietary fat and poor diet quality initiate a cascade involving TLR4-dependent immune activation, NF-κB and MAPK signalling, inflammasome assembly, and oxidative stress, collectively impairing insulin sensitivity, adipose tissue function, and vascular homeostasis. These physiological disturbances converge to accelerate the development of cardiometabolic disorders and cardiovascular disease.\u003c/p\u003e \u003cp\u003eImportantly, emerging data indicate that inflammatory responses to dietary exposure are not uniform, with biological sex acting as a critical modifier of immune\u0026ndash;metabolic signalling, adiposity, and cardiovascular vulnerability. Incorporating sex as a biological variable will be essential for refining mechanistic understanding and improving translational relevance.\u003c/p\u003e \u003cp\u003eFrom a physiological perspective, diet-induced inflammation represents a modifiable node within the integrated network linking metabolism, immunity, and cardiovascular function. Future research should prioritize mechanistic human studies, integrative multi-omics approaches, and longitudinal designs to clarify causal pathways and adaptive versus maladaptive inflammatory responses. Such insights will support the development of personalized nutritional and therapeutic strategies aimed at restoring immune-metabolic balance and reducing inflammation-driven cardiovascular disease.\u003c/p\u003e"},{"header":"6. Limitation of Resources available","content":"\u003cp\u003eDespite providing a comprehensive synthesis of current evidence, this review has several limitations that should be acknowledged. First, substantial heterogeneity existed across the included studies with respect to dietary assessment methods, inflammatory biomarkers measured, study populations, and cardio-metabolic and cardiovascular endpoints. This variability limited direct comparison across studies and precluded quantitative meta-analysis.\u003c/p\u003e \u003cp\u003eAlthough most studies included both male and female participants, sex-stratified analyses were inconsistently reported. As a result, conclusions regarding sex-related differences in diet-induced inflammation and cardio-metabolic risk remain largely inferential rather than definitive. Third, most included studies were observational in nature, which limits causal inference between dietary patterns, inflammatory processes, and cardiovascular outcomes.\u003c/p\u003e \u003cp\u003eAdditionally, differences in follow-up duration, population characteristics, confounding adjustment, and dietary measurement error may have influenced reported associations. Finally, restriction to peer-reviewed English-language publications may have introduced publication bias and limited representation of diverse dietary patterns across global populations.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003col\u003e\n \u003cli\u003eHFD\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;\u0026nbsp;High Fat Diet\u0026nbsp;\u003c/li\u003e\n \u003cli\u003eWHO\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;\u0026nbsp;World Health Organisation\u003c/li\u003e\n \u003cli\u003eCMR \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;\u0026nbsp;Cardio Metabolic Risk\u003c/li\u003e\n \u003cli\u003eCVD \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;\u0026nbsp;Cardiovascular Dysfunction\u003c/li\u003e\n \u003cli\u003eTG\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;Triglycerides\u003c/li\u003e\n \u003cli\u003eHDL\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;\u0026nbsp;High Density Lipoproteins\u003c/li\u003e\n \u003cli\u003eLDL\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;Low Density Lipoproteins\u003c/li\u003e\n \u003cli\u003eM/F\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;Male / Female\u003c/li\u003e\n \u003cli\u003ePI Diet \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;Pro-inflammatory Diet\u003c/li\u003e\n \u003cli\u003eHFD\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;\u0026nbsp;High Fat Diet\u003c/li\u003e\n \u003cli\u003eCRP\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;\u0026nbsp;C- Reactive Protein\u003c/li\u003e\n \u003cli\u003eIL\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;\u0026nbsp;Interleukin\u0026nbsp;\u003c/li\u003e\n \u003cli\u003eTNF- \u0026alpha; Tumour\u0026nbsp;Necrosis\u0026nbsp;Factor\u003c/li\u003e\n \u003cli\u003eNF-\u0026kappa;B Nuclear Factor kappa-light-chain-enhancer of activated B cells\u003c/li\u003e\n \u003cli\u003eASCVD Atherosclerotic cardiovascular disease\u003c/li\u003e\n \u003cli\u003eWOS\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;Web Of Science\u003c/li\u003e\n \u003cli\u003eNA\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;\u0026nbsp;Not Applicable\u003c/li\u003e\n \u003cli\u003eFMD Flow-mediated dilation\u003c/li\u003e\n \u003cli\u003eTLR4 \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;Toll-Like Receptor 4\u003c/li\u003e\n \u003cli\u003eMAPK\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;Mitogen-Activated Protein Kinase\u003c/li\u003e\n \u003cli\u003eNLRP3\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;\u0026nbsp;NOD-Like Receptor Family, Pyrin Domain-Containing 3\u0026nbsp;\u003c/li\u003e\n \u003cli\u003eDII\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;\u0026nbsp;Dietary Inflammatory Index\u003c/li\u003e\n \u003cli\u003e\u0026nbsp;LPS\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;\u0026nbsp;Lipopolysaccharide\u003c/li\u003e\n \u003cli\u003eCB1R \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;Cannabinoid Receptor 1\u003c/li\u003e\n \u003cli\u003e\u0026nbsp;CB2R\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;Cannabinoid Receptor 2\u003c/li\u003e\n \u003cli\u003eSOD\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;\u0026nbsp;Superoxide Dismutase\u003c/li\u003e\n \u003cli\u003eCAT\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;\u0026nbsp;Catalase\u003c/li\u003e\n \u003cli\u003eROS\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;\u0026nbsp;Reactive Oxygen Species\u003c/li\u003e\n \u003cli\u003eMCP\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;\u0026nbsp;Monocyte Chemoattractant Protein\u003c/li\u003e\n \u003cli\u003eCAD\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;\u0026nbsp;Coronary Artery Disease\u0026nbsp;\u003c/li\u003e\n \u003cli\u003eMI \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; Myocardial Infarction\u003c/li\u003e\n\u003c/ol\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eFuture directions\u003c/strong\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eFuture research should prioritize well-designed longitudinal and interventional studies to establish causal relationships between high-fat and pro-inflammatory dietary patterns, inflammatory signalling pathways, and cardio-metabolic and cardiovascular outcomes. Greater emphasis on standardized dietary assessment tools, including dietary inflammatory indices, and harmonized biomarker panels would enhance comparability across studies. Importantly, future investigations should incorporate consistent sex-stratified analyses to clarify sex-related biological mechanisms influencing inflammatory and metabolic responses to dietary exposure. Integration of multi-omics approaches such as genomics, epigenomics, metabolomics, and gut microbiome profiling may further elucidate molecular pathways linking diet-induced inflammation to cardio-metabolic dysfunction.\u003c/p\u003e\n\u003cp\u003eFrom a clinical perspective, future studies should explore the utility of inflammatory biomarkers and dietary inflammatory scores in risk stratification, personalized nutrition, and prevention strategies aimed at reducing cardio-metabolic dysfunction and cardiovascular disease burden.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding Statement\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWe acknowledge that the work was financially supported by \u0026ldquo;Savitribai Jyotirao Phule Fellowship for Single Girl Child\u0026rdquo; under \u0026ldquo;University Grants Commission\u0026rdquo; of grant number: UGCES-22-OB-TAM-F-SJSGC-8474.\u003c/p\u003e\u003ch2\u003eAuthor Contribution\u003c/h2\u003e\u003cp\u003eV.M - Framing concepts, original draftK.M - Formal analysis, Validation, Correction\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eAnsari P, Khan JT, Chowdhury S, Reberio AD, Kumar S, Seidel V, Abdel-Wahab YH, Flatt PR. 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Nutr Metab Cardiovasc Dis. 2024;34(4):1046-1053.\u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"Diet-induced inflammation, Cardio-metabolic physiology, Immune-metabolic signalling, Innate immune pathways, Endothelial dysfunction, Adipose tissue inflammation, Oxidative stress, Sex differences, Cardiovascular physiology","lastPublishedDoi":"10.21203/rs.3.rs-8782385/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-8782385/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eDietary patterns enriched in saturated fats and refined carbohydrates exert profound effects on metabolic and cardiovascular physiology by promoting chronic low-grade inflammation. Accumulating evidence indicates that diet-induced inflammatory signalling acts as a central integrator linking adipose tissue dysfunction, insulin resistance, endothelial impairment, and cardiovascular pathology. In this review, we synthesize current physiological insights into how pro-inflammatory diets activate innate immune pathways, including Toll-like receptor 4, nuclear factor-κB, mitogen-activated protein kinases, and the NLRP3 inflammasome thereby disrupting metabolic and vascular homeostasis. We highlight the coordinated roles of inflammatory cytokines, oxidative stress, lipid signalling, and immune\u0026ndash;metabolic crosstalk in the pathogenesis of obesity, metabolic syndrome, hypertension, and atherosclerotic cardiovascular disease. Emerging evidence suggests that biological sex modifies inflammatory and metabolic responses to dietary excess through differences in adipose distribution, sex hormone signalling, immune regulation, and interactions with the gut microbiota. Together, these findings position diet-induced inflammation as a fundamental physiological mechanism linking nutrition to cardio-metabolic dysfunction and cardiovascular risk. Understanding these pathways provides a framework for developing targeted, physiology-informed dietary and therapeutic strategies aimed at reducing inflammation-driven cardiovascular disease.\u003c/p\u003e","manuscriptTitle":"Diet-Driven Inflammatory Signalling in Cardio-Metabolic Physiology: Molecular Pathways, Sex Differences, and Cardiovascular Consequences","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2026-02-16 15:12:45","doi":"10.21203/rs.3.rs-8782385/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"af48ec7b-65af-42c3-8eb1-e7aa956ebe54","owner":[],"postedDate":"February 16th, 2026","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2026-03-27T19:39:14+00:00","versionOfRecord":[],"versionCreatedAt":"2026-02-16 15:12:45","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-8782385","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-8782385","identity":"rs-8782385","version":["v1"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}