Brown adipose tissue (BAT) is vital for proper thermogenesis during cold exposure in rodents, but until recently its presence in adult humans and its contribution to human metabolism were thought to be minimal or insignificant. Recent studies using PET with 18 F-fluorodeoxyglucose ( 18 FDG) have shown the presence of BAT in adult humans. However, whether BAT contributes to cold-induced nonshivering thermogenesis in humans has not been proven. Using PET with 11 C-acetate, 18 FDG, and 18 F-fluoro-thiaheptadecanoic acid ( 18 FTHA), a fatty acid tracer, we have quantified BAT oxidative metabolism and glucose and nonesterified fatty acid (NEFA) turnover in 6 healthy men under controlled cold exposure conditions. All subjects displayed substantial NEFA and glucose uptake upon cold exposure. Furthermore, we demonstrated cold-induced activation of oxidative metabolism in BAT, but not in adjoining skeletal muscles and subcutaneous adipose tissue. This activation was associated with an increase in total energy expenditure. We found an inverse relationship between BAT activity and shivering. We also observed an increase in BAT radio density upon cold exposure, indicating reduced BAT triglyceride content. In sum, our study provides evidence that BAT acts as a nonshivering thermogenesis effector in humans.

The gene Ucp2 is a member of a family of genes found in animals and plants, encoding a protein homologous to the brown fat uncoupling protein Ucp1 (refs 1-3). As Ucp2 is widely expressed in mammalian tissues, uncouples respiration and resides within a region of genetic linkage to obesity, a role in energy dissipation has been proposed. We demonstrate here, however, that mice lacking Ucp2 following targeted gene disruption are not obese and have a normal response to cold exposure or high-fat diet. Expression of Ucp2 is robust in spleen, lung and isolated macrophages, suggesting a role for Ucp2 in immunity or inflammatory responsiveness. We investigated the response to infection with Toxoplasma gondii in Ucp2-/- mice, and found that they are completely resistant to infection, in contrast with the lethality observed in wild-type littermates. Parasitic cysts and inflammation sites in brain were significantly reduced in Ucp2-/- mice (63% decrease, P<0.04). Macrophages from Ucp2-/- mice generated more reactive oxygen species than wild-type mice (80% increase, P<0.001) in response to T. gondii, and had a fivefold greater toxoplasmacidal activity in vitro compared with wild-type mice (P<0.001 ), which was absent in the presence of a quencher of reactive oxygen species (ROS). Our results indicate a role for Ucp2 in the limitation of ROS and macrophage-mediated immunity.

The present study identifies outdoor temperature, age, sex, BMI, and diabetes status as determinants of the prevalence, mass, and glucose-uptake activity of (18)F-FDG-detected BAT.

The estrogen-related receptor ␣ (ERR␣) is an orphan member of the superfamily of nuclear hormone receptors expressed in tissues that preferentially metabolize fatty acids. Despite the molecular characterization of ERR␣ and identification of target genes, determination of its physiological function has been hampered by the lack of a natural ligand. To further understand the in vivo function of ERR␣, we generated and analyzed Estrra-null (ERR␣ ؊/؊ ) mutant mice. Here we show that ERR␣ ؊/؊ mice are viable, fertile and display no gross anatomical alterations, with the exception of reduced body weight and peripheral fat deposits. No significant changes in food consumption and energy expenditure or serum biochemistry parameters were observed in the mutant animals. However, the mutant animals are resistant to a high-fat diet-induced obesity. Importantly, DNA microarray analysis of gene expression in adipose tissue demonstrates altered regulation of several enzymes involved in lipid, eicosanoid, and steroid synthesis, suggesting that the loss of ERR␣ might interfere with other nuclear receptor signaling pathways. In addition, the microarray study shows alteration in the expression of genes regulating adipogenesis as well as energy metabolism. In agreement with these findings, metabolic studies showed reduced lipogenesis in adipose tissues. This study suggests that ERR␣ functions as a metabolic regulator and that the ERR␣ ؊/؊ mice provide a novel model for the investigation of metabolic regulation by nuclear receptors.Nuclear receptors are ligand-regulated transcription factors that control key pathways required for normal development and maintenance of homeostasis throughout life (37). Nuclear receptors now comprise a family of 48 genes in mice and humans that encode structurally and functionally related proteins. However, the existence of fewer than 10 receptors had been predicted by classic physiological and biochemical studies (10). Since the discovery of many nuclear receptors had not been anticipated and thus is not linked to recognized natural ligands, these new gene products were referred to as orphan nuclear receptors. During the last decade, extensive study of this gene family revealed that orphan nuclear receptors control essential developmental and metabolic functions in response to natural ligands as diverse as steroid hormones, retinoic acids, leukotrienes, bile acids, cholesterol metabolites, and long-chain fatty acids (reviewed in references 5, 26, and 48). In addition, orphan nuclear receptors have been shown to react to the presence of exogenous ligands such as pesticides (15, 70), phenobarbital (53, 61), and a wide variety of xenobiotic agents and drugs (2,24,39,55,66,68,69). Gene deletion analyses in mice have been particularly useful to uncover biological functions of orphan nuclear receptors. Nuclear orphan receptors have been shown to participate in the development and/or maintenance of the placenta, somitogenesis, brain, heart, hypothalamus-pituitary axis, immune system, and pathways controlling s...

The most common pathology associated with obesity is insulin resistance, which results in the onset of type 2 diabetes mellitus. Several studies have implicated the mammalian target of rapamycin (mTOR) signaling pathway in obesity. Eukaryotic translation initiation factor 4E-binding (eIF4E-binding) proteins (4E-BPs), which repress translation by binding to eIF4E, are downstream effectors of mTOR. We report that the combined disruption of 4E-BP1 and 4E-BP2 in mice increased their sensitivity to diet-induced obesity. Increased adiposity was explained at least in part by accelerated adipogenesis driven by increased expression of CCAAT/enhancerbinding protein δ (C/EBPδ), C/EBPα, and PPARγ coupled with reduced energy expenditure, reduced lipolysis, and greater fatty acid reesterification in the adipose tissue of 4E-BP1 and 4E-BP2 double KO mice. Increased insulin resistance in 4E-BP1 and 4E-BP2 double KO mice was associated with increased ribosomal protein S6 kinase (S6K) activity and impairment of Akt signaling in muscle, liver, and adipose tissue. These data clearly demonstrate the role of 4E-BPs as a metabolic brake in the development of obesity and reinforce the idea that deregulated mTOR signaling is associated with the development of the metabolic syndrome.