OBJECTIVE The significant roles of brown adipose tissue (BAT) in the regulation of energy expenditure and adiposity are established in small rodents but have been controversial in humans. The objective is to examine the prevalence of metabolically active BAT in healthy adult humans and to clarify the effects of cold exposure and adiposity. RESEARCH DESIGN AND METHODS In vivo 2-[18F]fluoro-2-deoxyglucose (FDG) uptake into adipose tissue was measured in 56 healthy volunteers (31 male and 25 female subjects) aged 23–65 years by positron emission tomography (PET) combined with X-ray computed tomography (CT). RESULTS When exposed to cold (19°C) for 2 h, 17 of 32 younger subjects (aged 23–35 years) and 2 of 24 elderly subjects (aged 38–65 years) showed a substantial FDG uptake into adipose tissue of the supraclavicular and paraspinal regions, whereas they showed no detectable uptake when kept warm (27°C). Histological examinations confirmed the presence of brown adipocytes in these regions. The cold-activated FDG uptake was increased in winter compared with summer (P < 0.001) and was inversely related to BMI (P < 0.001) and total (P < 0.01) and visceral (P < 0.001) fat areas estimated from CT image at the umbilical level. CONCLUSIONS Our findings, being against the conventional view, indicate the high incidence of metabolically active BAT in adult humans and suggest a role in the control of body temperature and adiposity.
The increase of whole-body energy expenditure seen after a single meal ingestion, referred to as diet-induced thermogenesis (DIT), substantially varies depending on the meal's macronutrient composition. Brown adipose tissue (BAT), a site of non-shivering thermogenesis, was reported to be involved in DIT. To examine the effects of meal composition on BAT-associated DIT in humans, healthy male participants underwent fluorodeoxyglucose-positron emission tomography to assess BAT activity, and respiratory gas analysis for 2 h after ingestion of a carbohydrate-, protein-, or fat-rich meal (C-meal, P-meal, and F-meal, respectively). The calculated DIT at 2 h was 6.44 ± 2.01%, 3.49 ± 2.00%, and 2.32 ± 0.90% of the ingested energy after the P-meal, C-meal, and F-meal, respectively. The DIT after C-meal ingestion correlated positively with BAT activity (P = 0.011), and was approximately twice greater in the group with high-BAT activity than in the group with low-BAT activity (4.35 ± 1.74% vs. 2.12 ± 1.76%, P < 0.035). Conversely, the DIT after F-meal or P-meal ingestion did not correlate with BAT activity, with no difference between the two groups. Thus, BAT has a significant role in DIT after ingestion of a carbohydrate-rich meal, but hardly after ingestion either protein- or fat-rich meal.
Brown and beige adipocytes utilize a variety of substrates for cold-induced thermogenesis, contributing to the clearance of metabolites in circulation and, consequently, metabolic health. Food-derived compounds that exhibit agonistic activity at temperature-sensitive transient receptor potential channels may serve as cold mimics to elicit thermogenesis and substrate utilization in brown adipose tissue (BAT). In addition to fatty acids and glucose, branched-chain amino acids (BCAAs), which are essential amino acids obtained from foods, are actively catabolized in BAT through mitochondrial BCAA carrier (MBC). The relative contribution of BCAAs to fueling the tricarboxylic acid cycle as a substrate (i.e., anaplerosis) is estimated to be relatively small, yet BCAA catabolism in BAT exerts a critical role in systemic insulin sensitivity. The nature of this apparent tension remained unclear until the recent discovery that active BCAA catabolism in BAT through MBC is critical for the synthesis of metabolites such as glutathione, which is delivered to the liver to improve hepatic insulin sensitivity through redox homeostasis. Novel mechanistic insights into the control of BAT function and systemic metabolism reveal the therapeutic potential of food-derived compounds for improving metabolic flexibility and insulin sensitivity.
To date, 11 thermosensitive transient receptor potential (thermo-TRP) channels have been identified. Recent studies have characterized the mechanism of thermosensing by thermo-TRPs and the physiological role of thermo-TRPs in energy metabolism. In this review, we highlight the role of various thermo-TRPs in energy metabolism and hormone secretion. In the pancreas, TRPM2 and other TRPs regulate insulin secretion. TRPV2 expressed in brown adipocytes contributes to differentiation and/or thermogenesis. Sensory nerves that express TRPV1 promote increased energy expenditure by activating sympathetic nerves and adrenaline secretion. Here, we first show that capsaicin-induced adrenaline secretion is completely impaired in TRPV1 knockout mice. The thermogenic effects of TRPV1 agonists are attributable to brown adipose tissue (BAT) activation in mice and humans. Moreover, TRPA1- and TRPM8-expressing sensory nerves also contribute to potentiation of BAT thermogenesis and energy expenditure in mice. Together, thermo-TRPs are promising targets for combating obesity and metabolic disorders.
Obesity and diabetes have become a major epidemic problem. Preventing obesity has proven a challenge because this would require increased physical activity and/or reduced energy intake; both of which are difficult to enforce. Brown adipose tissue (BAT) is a major metabolic organ that contributes to the regulation of energy metabolism in small rodents. In humans, since its rediscovery in 2009, BAT has emerged as a potential target to fight obesity and related metabolic diseases such as type 2 diabetes. The BAT of humans is activated by acute cold exposure and mediates cold-induced thermogenesis. The metabolic activity of BAT demonstrates huge individual variation and is negatively associated with body fat accumulation and glucose intolerance. The decreased BAT can be reactivated and recruited by repeated cold exposure, which has the effects of increasing thermogenesis and decreasing body fat. Such effects of cold exposure can be mimicked by oral ingestion of some food ingredients with agonistic activity at temperature-sensitive transient receptor potential channels. To develop strategies to boost BAT thermogenesis for obesity prevention, more insight is needed into the physiological significance of human BAT and mechanisms by which BAT function is regulated by aging, as well as endogenous and environmental factors. This review will summarize the current knowledge on the activation of human BAT thermogenesis and its roles in obesity-related disorders.
Sympathetic activation of brown adipose tissue (BAT) thermogenesis can ameliorate obesity and related metabolic abnormalities. However, crucial subtypes of the β-adrenergic receptor (AR), as well as effects of its genetic variants on functions of BAT, remains unclear in humans. We conducted association analyses of genes encoding β-ARs and BAT activity in human adults.
Melanin-concentrating hormone (MCH) neuron-ablated mice exhibit increased energy expenditure and reduced fat weight. Increased brown adipose tissue (BAT) activity and locomotor activity-independent energy expenditure contributed to body weight reduction in MCH neuron-ablated mice. MCH neurons send inhibitory input to the medullary raphe nucleus to modulate BAT activity.Hypothalamic melanin-concentrating hormone (MCH) peptide robustly affects energy homeostasis. However, it is unclear whether and how MCH-producing neurons, which contain and release a variety of neuropeptides/transmitters, regulate energy expenditure in the central nervous system and peripheral tissues. We thus examined the regulation of energy expenditure by MCH neurons, focusing on interscapular brown adipose tissue (BAT) activity. MCH neuron-ablated mice exhibited reduced body weight, increased oxygen consumption, and increased BAT activity, which improved locomotor activity-independent energy expenditure. Trans-neuronal retrograde tracing with the recombinant pseudorabies virus revealed that MCH neurons innervate BAT via the sympathetic premotor region in the medullary raphe nucleus (MRN). MRN neurons were activated by MCH neuron ablation. Therefore, endogenous MCH neuron activity negatively modulates energy expenditure via BAT inhibition. MRN neurons might receive inhibitory input from MCH neurons to suppress BAT activity.
Since the recent rediscovery of brown adipose tissue (BAT) in adult humans, this thermogenic tissue has been attracting increasing interest. The inverse relationship between BAT activity and body fatness suggests that BAT, because of its energy dissipating activity, is protective against body fat accumulation. Cold exposure activates and recruits BAT, resulting in increased energy expenditure and decreased body fatness. The stimulatory effects of cold exposure are mediated through transient receptor potential (TRP) channels and the sympathetic nervous system (SNS). Most TRP members also function as chemesthetic receptors for various food ingredients, and indeed, agonists of TRP vanilloid 1 such as capsaicin and its analog capsinoids mimic the effects of cold exposure to decrease body fatness through the activation and recruitment of BAT. The antiobesity effect of other food ingredients including tea catechins may be attributable, at least in part, to the activation of the TRP–SNS–BAT axis. BAT is also involved in the facultative thermogenesis induced by meal intake, referred to as diet-induced thermogenesis (DIT), which is a significant component of the total energy expenditure in our daily lives. Emerging evidence suggests a crucial role for the SNS in BAT-associated DIT, particularly during the early phase, but several gut-derived humoral factors may also participate in meal-induced BAT activation. One intriguing factor is bile acids, which activate BAT directly through Takeda G-protein receptor 5 (TGR5) in brown adipocytes. Given the apparent beneficial effects of some TRP agonists and bile acids on whole-body substrate and energy metabolism, the TRP/TGR5–BAT axis represents a promising target for combating obesity and related metabolic disorders in humans.
