Thermogenic Brown Fat in Humans: Implications in Energy Homeostasis, Obesity and Metabolic Disorders

We have been facing a worldwide pandemic of obesity, which is closely associated with not only musculoskeletal disorders but also common diseases such as diabetes mellitus, dyslipidemias, fatty liver, hypertension, and arteriosclerosis. Moreover, obesity predisposes to adverse outcomes in some diseases, as in the example of the increased mortality in patients with COVID-19. Obesity is the state of excessive accumulation of triglyceride in adipose tissues because of a prolonged positive energy balance. In mammals including humans, there are two types of adipose tissue, white and brown adipose tissues (BATs). The two tissues are similar in their major population of adipocyte having intracellular lipid droplets, but are quite different in the physiological functions. White adipose tissue is the primary site of energy storage, while BAT is a specialized tissue for non-shivering thermogenesis to dissipate energy as heat.

Although BAT research has long been limited mostly in small rodents, the rediscovery of metabolically active BAT using fluorodeoxyglucose positron emission tomography and computed tomography in adult humans has dramatically accelerated the translational studies on BAT in health and diseases. It is now established that BAT, through its thermogenic and energy dissipating activities, plays a role in the regulation of body temperature, energy expenditure, and body fatness. Moreover, over the past decade, increasing evidence has demonstrated that BAT cross talks with some peripheral tissues and controls their functions and systemic homeostasis of energy and metabolic substrates, suggesting BAT as a metabolic regulator beyond thermogenesis. In this review, the authors summarize current knowledge on human BAT with reference to its patho-physiological roles in energy homeostasis, obesity and metabolic diseases.

This narrative review synthesizes evidence from human and animal studies on the physiology, regulation, and clinical implications of brown adipose tissue (BAT). Key topics include: (1) BAT as a major site of non-shivering thermogenesis (NST), contributing to cold-induced thermogenesis (CIT) and diet-induced thermogenesis (DIT), with human evidence from FDG-PET/CT and 15O-PET studies, as well as whole-room calorimetry. (2) Cellular and molecular mechanisms of BAT activation: sympathetic nervous system signaling via β-adrenergic receptors, UCP1-mediated mitochondrial uncoupling, recruitment of beige adipocytes in white adipose tissue, and neuroendocrine inputs including TRP channel activation, gut hormones (secretin, cholecystokinin, GLP-1), bile acids, and vagal pathways. (3) BAT’s role in energy balance and adiposity: genetic associations (UCP1, β3AR polymorphisms), inverse correlations between BAT prevalence/activity and adiposity, and age effects. (4) Interventions to activate/recruit BAT: cold acclimation, dietary TRP agonists (capsaicin/capsinoids, menthol, isothiocyanates), and β3-agonists (mirabegron), with variable cardiometabolic outcomes. (5) BAT as a regulator of systemic metabolism beyond thermogenesis: improved glucose tolerance and insulin sensitivity, enhanced triglyceride clearance and HDL turnover, potential anti-atherosclerotic effects, and associations with reduced prevalence of cardiometabolic diseases in large patient cohorts. (6) BAT secretome (batokines): polypeptides (e.g., IL-6, FGF21, NRG4, myostatin), exosomal microRNAs, lipid mediators (12,13-diHOME, maresin 2), and metabolites (succinate handling) that mediate inter-organ communication. (7) Age-related decline in BAT amount and function: reduced progenitor competence, mitochondrial dysfunction, altered sympathetic signaling, and inflammatory macrophage milieu. (8) Sex differences in BAT across lifespan: higher prevalence/activity and browning propensity reported in females in many settings, with complex roles of estrogens and androgens. The review concludes with methodological considerations and the need for improved, non-invasive BAT assessment beyond FDG-PET/CT.

This is a narrative review article; no single primary study protocol was conducted by the authors. The review compiles and interprets results from prior experimental and clinical studies that used: (1) Imaging modalities to detect and quantify human BAT: FDG-PET/CT as a surrogate for activity/amount following acute cold exposure; alternative PET tracers (15O-O2 and 15O-H2O) to directly measure oxygen consumption and blood flow as indicators of thermogenesis; and emerging non-invasive tools (infrared thermal imaging, near-infrared time-resolved spectroscopy). (2) Whole-body energy expenditure assessment: indirect calorimetry in whole-room human calorimeters over 24 hours to quantify diet-induced thermogenesis (DIT) and compare BAT-positive versus BAT-negative individuals. (3) Physiological and interventional paradigms: acute and chronic cold exposure/acclimation (e.g., 2–6 hours daily for several weeks) to activate and recruit BAT; administration of dietary TRP agonists (such as capsinoids) and β3-adrenergic agonists (mirabegron) to test pharmacologic/nutritional activation; measurements of sympathetic activity (e.g., norepinephrine levels/turnover) and gut hormone responses after meals (e.g., secretin). (4) Metabolic and clinical outcomes: assessments of glucose homeostasis (glucose disposal, oxidation, insulin sensitivity, HbA1c), lipid metabolism (triglyceride-rich lipoprotein clearance, HDL levels/turnover), and epidemiologic associations between BAT presence and cardiometabolic disease prevalence. Mechanistic insights are drawn from complementary rodent studies on UCP1 function, beige adipocyte biology, batokine signaling, and mitochondrial/metabolic adaptations.

• BAT is a key site for human non-shivering thermogenesis. Cold exposure increases BAT activity (FDG and fatty acid tracer uptake) and correlates positively with cold-induced thermogenesis (CIT). • Beyond cold, BAT contributes to diet-induced thermogenesis (DIT): in 24-h calorimetry, postprandial EE was higher in BAT-positive than BAT-negative individuals (≈9.7% vs 6.5% of energy intake), suggesting roughly a 3% BAT-dependent component. • BAT activity and prevalence decline with age: prevalence exceeds 50% in individuals in their twenties but falls below 10% by the fifties–sixties. BAT-negative individuals display age-related increases in adiposity, whereas BAT-positive individuals show relative stability into midlife. • Cold acclimation (2–6 h/day for weeks) recruits/activates BAT and reduces body fat; changes in BAT activity are negatively correlated with changes in fat mass. • Nutritional and pharmacologic activation: TRP agonists (e.g., capsinoids) increase EE via BAT activation and can reduce body fat. β3-agonist mirabegron acutely increases BAT glucose uptake and EE at high doses and, with chronic clinically used dosing, induces WAT beiging and improves glucose homeostasis and HDL without consistent fat loss. • Systemic metabolic effects extend beyond thermogenesis: individuals with active BAT have lower blood glucose and HbA1c; mild cold exposure improves glucose disposal and insulin sensitivity in BAT-positive humans and patients with type 2 diabetes after acclimation. BAT metabolizes circulating branched-chain amino acids, potentially improving insulin signaling. • Lipid metabolism: BAT activation accelerates clearance of triglyceride-rich lipoproteins, increases HDL levels, and enhances reverse cholesterol transport; in animals, activation protects from atherosclerosis. • Large clinical datasets (e.g., >50,000 patients) show independent associations of BAT presence with lower rates of type 2 diabetes, dyslipidemia, hypertension, coronary artery disease, and congestive heart failure. • BAT secretes batokines (e.g., IL-6, FGF21), exosomal miRNAs, and lipid mediators (12,13-diHOME, maresin 2) that influence liver, muscle, and immune pathways, underpinning systemic benefits. • Aging reduces beige/brown adipocyte progenitor competence, mitochondrial function, and adrenergic responsiveness; inflammatory macrophage infiltration impairs browning. Sex differences favor higher BAT prevalence and browning potential in females in many contexts, with estrogens generally stimulatory and androgens showing context-dependent effects.

The compiled evidence supports BAT as a multifunctional organ in humans that contributes to energy homeostasis, mitigates adiposity, and exerts endocrine and metabolic effects on glucose and lipid handling. BAT activity enhances CIT and DIT, raising total energy expenditure; while daily NST contributions can be modest, sustained activation/recruitment (e.g., via cold acclimation or TRP agonists) can meaningfully affect body fat over time. Importantly, BAT influences systemic metabolism beyond thermogenesis through substrate clearance (glucose, triglycerides, BCAA) and batokine signaling, aligning with observed associations between BAT and improved cardiometabolic profiles and lower disease prevalence. Age-related BAT decline and sex dimorphism highlight physiological modulators and potential therapeutic windows; estrogens and sympathetic signaling appear to augment BAT, whereas inflammation and diminished progenitor competence contribute to decline. Pharmacologic strategies (e.g., β3-agonists) and nutritional approaches (TRP agonists, bile acids) show promise for activating/beiging adipose tissue, improving insulin sensitivity and lipid profiles. However, translation requires careful consideration of dose, safety, and inter-individual variability. The limitations of current BAT assessment (FDG-PET/CT) complicate longitudinal and interventional studies; developing non-invasive, reproducible measures will be critical to clarify causal pathways, quantify thermogenic versus endocrine mechanisms, and stratify responders.

BAT in humans participates in regulating whole-body energy expenditure, body fatness, and systemic glucose and lipid metabolism, with implications for obesity, diabetes, dyslipidemia, fatty liver, and cardiovascular disease risk. Interventions such as cold acclimation, dietary TRP agonists, and β3-adrenergic stimulation can activate or recruit thermogenic adipocytes, improving metabolic parameters and potentially reducing adiposity. BAT also communicates with other organs via batokines, lipokines, and exosomal miRNAs, mediating effects that extend beyond heat production. Future research should: (1) identify genetic and environmental determinants of inter-individual differences in BAT quantity and activity; (2) delineate the physiological importance of UCP1-independent thermogenic pathways in humans; (3) develop and validate safe, non-invasive, and quantitative tools to assess BAT repeatedly in clinical settings; and (4) design practical, scalable regimens that safely activate/beige adipose tissue to prevent and treat cardiometabolic diseases.

As a narrative review, synthesis is limited by heterogeneity and design differences among included studies. Human BAT assessment relies predominantly on FDG-PET/CT, which is costly, involves radiation and cold exposure, and may not reflect thermogenesis under some conditions (e.g., postprandial competition for tracer). Daily NST attributable to BAT can be modest in thermoneutral, clothed conditions. Interventional evidence (e.g., with TRP agonists, bile acids, or β3-agonists) varies in dosing, duration, and endpoints, and mirabegron’s adiposity effects are inconsistent despite glycemic/lipid benefits. Mechanistic insights on batokines and UCP1-independent pathways are largely from animal studies, with uncertain translation to humans. Age and sex confound BAT prevalence/activity, complicating causal inference. There is a need for standardized protocols and improved, non-invasive BAT quantification methods for longitudinal and large-scale human studies.