OBJECTIVEThe 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 METHODSIn 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).RESULTSWhen 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.CONCLUSIONSOur 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.

Brown adipose tissue (BAT) can be identified by 18 F-fluorodeoxyglucose (FDG)-positron emission tomography (PET) combined with X-ray computed tomography (CT) in adult humans. The objective of this study was to clarify the relationship between BAT and adiposity in healthy adult humans, particularly to test the idea that decreased BAT activity may be associated with body fat accumulation with age. One hundred and sixty-two healthy volunteers aged 20-73 years (103 males and 59 females) underwent FDG-PET/CT after 2-h cold exposure at 19 °C with light clothing. Cold-activated BAT was detected in 41% of the subjects (BAT-positive). Compared with the BAT-negative group, the BAT-positive group was younger (P < 0.01) and showed a lower BMI (P < 0.01), body fat content (P < 0.01), and abdominal fat (P < 0.01). The incidence of cold-activated BAT decreased with age (P < 0.01), being more than 50% in the twenties, but less than 10% in the fifties and sixties. The adiposity-related parameters showed some sex differences, but increased with age in the BAT-negative group (P < 0.01), while they remained unchanged from the twenties to forties in the BAT-positive group, in both sexes. These results suggest that decreased BAT activity may be associated with accumulation of body fat with age.

A link between circadian rhythm and metabolism has long been discussed. Circadian rhythm is controlled by positive and negative transcriptional and translational feedback loops composed of several clock genes. Among clock genes, the brain and muscle Arnt-like protein-1 (BMAL1) and circadian locomotor output cycles kaput (CLOCK) play important roles in the regulation of the positive rhythmic transcription. In addition to control of circadian rhythm, we have previously shown that BMAL1 regulates adipogenesis. In metabolic syndrome patients, the function of BMAL1 is dysregulated in visceral adipose tissue. In addition, analysis of SNPs has revealed that BMAL1 is associated with susceptibility to hypertension and type II diabetes. Furthermore, the significant roles of BMAL1 in pancreatic β cells proliferation and maturation were recently reported. These results suggest that BMAL1 regulates energy homeostasis. Therefore, in this study, we examined whether loss of BMAL1 function is capable of inducing metabolic syndrome. Deficient of the Bmal1 gene in mice resulted in elevation of the respiratory quotient value, indicating that BMAL1 is involved in the utilization of fat as an energy source. Indeed, lack of Bmal1 reduced the capacity of fat storage in adipose tissue, resulting in an increase in the levels of circulating fatty acids, including triglycerides, free fatty acids, and cholesterol. Elevation of the circulating fatty acids level induced the formation of ectopic fat in the liver and skeletal muscle in Bmal1 -/- mice. Interestingly, ectopic fat formation was not observed in tissue-specific (liver or skeletal muscle) Bmal1 -/- mice even under high fat diet feeding condition. Therefore, we were led to conclude that BMAL1 is a crucial factor in the regulation of energy homeostasis, and disorders of the functions of BMAL1 lead to the development of metabolic syndrome.

. Indispensable role of mitochondrial UCP1 for antiobesity effect of ␤ 3-adrenergic stimulation. Am J Physiol Endocrinol Metab 290: E1014 -E1021, 2006. First published December 20, 2005 doi:10.1152/ajpendo.00105.2005.-Mitochondrial uncoupling protein-1 (UCP1) has been thought to be a key molecule for thermogenesis during cold exposure and spontaneous hyperphagia and thereby in the autonomic regulation of energy expenditure and adiposity. However, UCP1 knockout (KO) mice were reported to be cold intolerant but unexpectedly did not get obese even after hyperphagia, implying that UCP1 may not be involved in the regulation of adiposity. Treatment of obese animals with ␤ 3-adrenergic agonists is known to increase lipid mobilization, induce UCP1, and, finally, reduce body fat content. To obtain direct evidence for the role of UCP1 in the anti-obesity effect of ␤ 3-adrenergic stimulation, in the present study, UCP1-KO and wild-type (WT) mice were fed on cafeteria diets for 8 wk and then given a ␤ 3-adrenergic agonist, CL-316,243 (CL), or saline for 2 wk. A single injection of CL increased whole body oxygen consumption and brown fat temperature in WT mice but not in KO mice, and it elicited almost the same plasma free fatty acid response in WT and KO mice. WT and KO mice increased similarly their body and white fat pad weights on cafeteria diets compared with those on laboratory chow. Daily treatment with CL resulted in a marked reduction of white fat pad weight and the size of adipocytes in WT mice, but not in KO mice. Compared with WT mice, KO mice expressed increased levels of UCP2 in brown fat but decreased levels in white fat and comparable levels of UCP3. It was concluded that the anti-obesity effect of ␤ 3-adrenergic stimulation is largely attributable to UCP1, but less to UCP2 and UCP3, and thereby to UCP1-dependent degradation of fatty acids released from white adipose tissue.uncoupling protein-1; adiposity; CL-316,243; energy expenditure; hyperphagia UNCOUPLING PROTEIN (UCP) IS A MOLECULE, as its name suggests, that uncouples mitochondrial oxidative phosphorylation by bypassing the electrochemical gradient across the inner membrane from the F1-ATPase and thereby dissipates energy as heat. Among several isoforms of the UCP family so far reported in mammals, UCP1 is the only one whose physiological importance has been firmly established; that is, UCP1 is present exclusively in brown adipose tissue (BAT), an organ specified for nonshivering thermogenesis during cold acclimation, arousal from hibernation, and recovery from anesthetic hypothermia (2). UCP1 has also been proposed to be involved in diet-induced thermogenesis, as well as cold-induced nonshivering thermogenesis, and play a significant role in the control of energy expenditure and whole body energy balance. This is supported by the observations, for example, that spontaneous overfeeding of highly palatable diets and/or high-fat diets gives rise to increased energy expenditure (oxygen consumption) in association with BAT hyperplasia and increased UCP1 c...

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.