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

The global obesity pandemic is strongly linked to various diseases, including diabetes, dyslipidemia, fatty liver disease, hypertension, and arteriosclerosis. Obesity results from a prolonged positive energy balance leading to excessive triglyceride accumulation in adipose tissue. Mammals, including humans, have two types of adipose tissue: white adipose tissue (WAT) for energy storage and brown adipose tissue (BAT) for non-shivering thermogenesis (NST). While BAT research was initially limited to small rodents, the rediscovery of metabolically active BAT in adult humans using FDG-PET/CT has significantly advanced translational studies on its role in health and disease. This review focuses on human BAT's role in energy homeostasis, obesity, and related metabolic diseases, considering the impact of aging and sex differences.

The rediscovery of metabolically active BAT in adult humans using fluorodeoxyglucose (FDG)-positron emission tomography (PET) and computed tomography (CT) has spurred extensive research. Studies have established BAT's role in regulating body temperature, energy expenditure (EE), and body fatness through its thermogenic and energy-dissipating activities. Furthermore, a growing body of evidence indicates BAT's function as a metabolic regulator beyond thermogenesis, secreting paracrine and endocrine factors that influence other tissues and systemic metabolic homeostasis. Several studies have linked BAT activity to metabolic disorders and cardiovascular diseases.

This is a review article that synthesizes existing research on human brown adipose tissue (BAT). The authors compiled information from various clinical studies and experimental animal models, analyzing data from FDG-PET/CT scans, calorimetry studies, and gene expression analyses. The review integrates findings on BAT's role in non-shivering thermogenesis (NST), its contribution to energy expenditure (EE) from both cold-induced thermogenesis (CIT) and diet-induced thermogenesis (DIT), the mechanisms of BAT activation, BAT's influence on energy balance and body fat, strategies for activating or recruiting BAT, BAT's systemic metabolic regulation, BAT-derived endocrine factors (BATkines), age-related changes in BAT function, and sex differences in BAT.

BAT contributes significantly to both CIT and DIT in humans. Cold exposure activates BAT, increasing FDG uptake and fatty acid oxidation, correlating with increased CIT. Although some studies showed conflicting results regarding postprandial BAT activation using FDG-PET/CT (possibly due to increased insulin-stimulated FDG uptake in skeletal muscle), other studies using 15O2-PET and blood flow measurements confirmed increased oxygen consumption and blood flow in BAT after meal intake. BAT contributes approximately 3% to DIT in humans. The sympathetic nervous system (SNS)-β-adrenergic receptor (βAR) axis plays a crucial role in BAT activation, triggered by cold exposure and potentially by oropharyngeal taste sensation after food intake. Gastrointestinal hormones (secretin, cholecystokinin, glucagon-like peptide 1) and bile acids also contribute to postprandial BAT activation. BAT's long-term impact on EE and body fatness is evidenced by the lower UCP1 levels in obese animals and humans, and lower BAT prevalence in patients with higher BMI. Cold exposure effectively recruits human BAT, reducing body fat. Food ingredients such as menthol and capsaicin can activate BAT thermogenesis through TRP channels. Mirabegron, a β3AR agonist, shows promise in inducing WAT browning and improving glucose homeostasis, although its effect on body fat is less pronounced. BAT significantly impacts systemic metabolism independently of its effect on EE and body fatness. BAT is associated with improved glucose tolerance, insulin sensitivity, and lipid metabolism; it actively metabolizes BCAAs. BAT also plays a role in tumor suppression by reducing blood glucose. BAT secretes various BATkines, including IL-6 and FGF21, which modulate systemic metabolism. MicroRNAs and lipid molecules (12,13-diHOME, maresin 2) are also implicated as BATkines. BAT activity declines with age due to decreased beige adipocyte progenitor cell proliferation and differentiation, impaired SNS-βAR signaling, and increased pro-inflammatory mediators. Sex differences exist in BAT, with women generally exhibiting higher BAT activity and WAT browning potential, possibly influenced by estrogen and androgen levels.

The findings strongly support BAT's pivotal role in energy homeostasis, obesity, and related metabolic disorders. The inverse correlation between BAT activity and adiposity highlights its potential as a therapeutic target for obesity and metabolic syndrome. The ability to recruit and activate BAT through cold exposure, food ingredients, or pharmacological agents offers promising avenues for therapeutic interventions. The impact of BAT on systemic metabolism, beyond thermogenesis, underscores its importance in regulating glucose and lipid metabolism, and its potential role in preventing cardiovascular diseases. Further research is needed to clarify the complex interplay between BAT, its secretory products, and systemic metabolic processes.

BAT plays a crucial role in energy balance, systemic metabolism, and cardiovascular health. Its decline with age contributes to the increased prevalence of obesity and metabolic diseases. Strategies to activate or recruit BAT represent promising therapeutic targets. However, further research is needed to improve methods for assessing BAT activity and to fully elucidate the mechanisms underlying its effects on systemic metabolism and its individual variability.

The primary limitation is reliance on FDG-PET/CT for BAT assessment, which is expensive, involves radiation exposure, and may not perfectly reflect thermogenic activity. Many studies are observational, limiting causal inferences. The review primarily focuses on findings from human studies, but animal models significantly contribute to our understanding, sometimes with inconclusive translation to human physiology.