Summary A human genome-wide linkage scan for obesity identified a linkage peak on chromosome 5q13–15. Positional cloning revealed an association of a rare haplotype to high body-mass index (BMI) in males but not females. The risk locus contains a single gene, “arrestin domain containing 3” (ARRDC3), an uncharacterized α-arrestin. Inactivating Arrdc3 in mice led to a striking resistance to obesity, with greater impact on male mice. Mice with decreased ARRDC3 levels were protected from obesity due to increased energy expenditure through increased activity levels and increased thermogenesis of both brown and white adipose tissues. ARRDC3 interacted directly with β-adrenergic receptors, and loss of ARRDC3 increased the response to β-adrenergic stimulation in isolated adipose tissue. These results demonstrate that ARRDC3 is a gender-sensitive regulator of obesity and energy expenditure and reveal a surprising diversity for arrestin family protein functions.

Mammalian acyl-CoA thioesterases (Acots) catalyze the hydrolysis of fatty acyl-CoAs to form free fatty acids plus CoA, but their metabolic functions remain undefined. Thioesterase superfamily member 1 (Them1; synonyms Acot11, StarD14, and brown fat inducible thioesterase) is a long-chain fatty acyl-CoA thioesterase that is highly expressed in brown adipose tissue and is regulated by both ambient temperature and food consumption. Here we show that Them1 −/− mice were resistant to diet-induced obesity despite greater food consumption. Them1 −/− mice exhibited increased O 2 consumption and heat production, which were accompanied by increased rates of fatty acid oxidation in brown adipose tissue and up-regulation of genes that promote energy expenditure. Them1 −/− mice were also protected against diet-induced inflammation in white adipose tissue, as well as hepatic steatosis, and demonstrated improved glucose homeostasis. The absence of Them1 expression in vivo and in cell culture led to markedly attenuated diet-or chemically induced endoplasmic reticulum stress responses, providing a mechanism by which Them1 deficiency protects against insulin resistance and lipid deposition. Taken together, these data suggest that Them1 functions to decrease energy consumption and conserve calories. In the setting of nutritional excess, the overproduction of free fatty acids by Them1 provokes insulin resistance that is associated with inflammation and endoplasmic reticulum stress.thermogenesis | liver | diabetes

No abstract

ObjectiveNon-shivering thermogenesis in brown adipose tissue (BAT) plays a central role in energy homeostasis. Thioesterase superfamily member 1 (Them1), a BAT-enriched long chain fatty acyl-CoA thioesterase, is upregulated by cold and downregulated by warm ambient temperatures. Them1−/− mice exhibit increased energy expenditure and resistance to diet-induced obesity and diabetes, but the mechanistic contribution of Them1 to the regulation of cold thermogenesis remains unknown.MethodsThem1−/− and Them1+/+ mice were subjected to continuous metabolic monitoring to quantify the effects of ambient temperatures ranging from thermoneutrality (30 °C) to cold (4 °C) on energy expenditure, core body temperature, physical activity and food intake. The effects of Them1 expression on O2 consumption rates, thermogenic gene expression and lipolytic protein activation were determined ex vivo in BAT and in primary brown adipocytes.ResultsThem1 suppressed thermogenesis in mice even in the setting of ongoing cold exposure. Without affecting thermogenic gene transcription, Them1 reduced O2 consumption rates in both isolated BAT and primary brown adipocytes. This was attributable to decreased mitochondrial oxidation of endogenous but not exogenous fatty acids.ConclusionsThese results show that Them1 may act as a break on uncontrolled heat production and limit the extent of energy expenditure. Pharmacologic inhibition of Them1 could provide a targeted strategy for the management of metabolic disorders via activation of brown fat.

Heme oxygenase consists of two structurally related isozymes, heme oxygenase‐1 and and heme oxygenase‐2, each of which cleaves heme to form biliverdin, iron and carbon monoxide. Expression of heme oxygenase‐1 is increased or decreased depending on cellular microenvironments, whereas little is known about the regulation of heme oxygenase‐2 expression. Here we show that hypoxia (1% oxygen) reduces the expression levels of heme oxygenase‐2 mRNA and protein after 48 h of incubation in human cell lines, including Jurkat T‐lymphocytes, YN‐1 and K562 erythroleukemia, HeLa cervical cancer, and HepG2 hepatoma, as judged by northern blot and western blot analyses. In contrast, the expression level of heme oxygenase‐1 mRNA varies under hypoxia, depending on the cell line; it was increased in YN‐1 cells, decreased in HeLa and HepG2 cells, and remained undetectable in Jurkat and K562 cells. Moreover, heme oxygenase‐1 protein was decreased in YN‐1 cells under the conditions used, despite the induction of heme oxygenase‐1 mRNA under hypoxia. The heme oxygenase activity was significantly decreased in YN‐1, K562 and HepG2 cells after 48 h of hypoxia. To explore the mechanism for the hypoxia‐mediated reduction of heme oxygenase‐2 expression, we showed that hypoxia shortened the half‐life of heme oxygenase‐2 mRNA (from 12 h to 6 h) in YN‐1 cells, without affecting the half‐life of heme oxygenase‐1 mRNA (9.5 h). Importantly, the heme contents were increased in YN‐1, HepG2 and HeLa cells after 48 h of incubation under hypoxia. Thus, the reduced expression of heme oxygenase‐2 may represent an important adaptation to hypoxia in certain cell types, which may contribute to the maintenance of the intracellular heme level.

Whereas white adipose tissue depots contribute to the development of metabolic diseases, brown and beige adipose tissue has beneficial metabolic effects. Here we show that CDK6 regulates beige adipocyte formation. We demonstrate that mice lacking the CDK6 protein or its kinase domain (K43M) exhibit significant increases beige cell formation, enhanced energy expenditure, better glucose tolerance, and improved insulin sensitivity, and are more resistant to high-fat diet-induced obesity. Re-expression of CDK6 in Cdk6−/− mature or precursor cells, or ablation of RUNX1 in K43M mature or precursor cells, reverses these phenotypes. Furthermore, RUNX1 positively regulates the expression of Ucp-1 and Pgc1α by binding to proximal promoter regions. Our findings indicate that CDK6 kinase activity negatively regulates the conversion of fat-storing cells into fat-burning cells by suppressing RUNX1, and suggest that CDK6 may be a therapeutic target for the treatment of obesity and related metabolic diseases.

Targeted ablation of the novel flavoheme reductase Ncb5or knock-out (KO) results in progressive loss of pancreatic ␤-cells and white adipose tissue over time. Lipoatrophy persisted in KO animals in which the confounding metabolic effects of diabetes were eliminated by islet transplantation (transplanted knockout (TKO)). Lipid profiles in livers prepared from TKO animals were markedly deficient in triglycerides and diacylglycerides. Despite enhanced expression of stearoyl-Co-A desaturase-1, levels of palmitoleic and oleic acids (⌬9 fatty acid desaturation) were decreased in TKO relative to wild type controls. Treatment of KO hepatocytes with palmitic acid reduced cell viability and increased apoptosis, a response blunted by coincubation with oleic acid. The results presented here support the hypothesis that Ncb5or supplies electrons for fatty acid desaturation, offer new insight into the regulation of a crucial step in fatty acid biosynthesis, and provide a plausible explanation for both the diabetic and the lipoatrophic phenotype in Ncb5or ؊/؊ mice.The most prevalent and life-threatening metabolic disorders, type 2 diabetes and obesity, arise from the complex interplay of a large number of genetic determinants. Characterizing polygenic disorders is challenging, requiring insight into plausible candidate genes and analysis of genomic data on numerous kindred. Mouse models offer an attractive independent source of information on genes important in pancreatic ␤-cell and adipocyte viability and homeostasis.We have been investigating a novel flavoheme reductase that plays an important role in pancreatic ␤-cell viability and maintenance of white adipose tissue. Ncb5or (alternatively called b5ϩb5R and cyb5r4) is a single 58-kDa polypeptide composed of two well characterized domains tethered by a unique 90-residue hinge (1). The 130-residue N-terminal domain bears strong homology to classic microsomal cytochrome b 5 , a sixcoordinate heme protein. At the C terminus, there is a 300-residue domain with strong homology to classic microsomal cytochrome b 5 reductase, a flavoprotein. Ncb5or is of special interest because it is highly conserved in a wide range of animals from mammals to flies and worms and because there is no other example in the animal kingdom of such a two-domain protein.Ncb5or is expressed in a wide variety of organs, tissues, and cell lines and localized in the endoplasmic reticulum (2). Because of its high negative redox potential, Ncb5or would be expected to function primarily as an electron donor.Mice with a global knock-out of Ncb5or have normal embryonic and fetal development and normal viability at birth with no gross anatomic abnormalities (3). However, after the first month of life, Ncb5or Ϫ/Ϫ mice develop diabetes because of the loss of pancreatic ␤-cells. In addition, there is progressive atrophy of white adipose tissue (WAT).3 The diabetic and lipoatrophic phenotype of the Ncb5or Ϫ/Ϫ mouse raises the question of how this novel reductase impacts ␤-cell and adipocyte viability and function."Class...

With China's great efforts to improve public health insurance, clear progress has been achieved toward the ambitious full health insurance coverage strategy for all. The current health insurance schemes in China fall into three categories: urban employee basic health insurance scheme, urban resident scheme, and new rural cooperative medical system. Despite their phasic success, these substantially identity-based, district-varied health insurance schemes have separate operation mechanisms, various administrative institutions, and consequently poor connections. On the other hand, the establishment and implementation of various health insurance schemes provide the preconditioning of more sophisticated social health insurance schemes, the increase in the income of urban and rural people, and the great importance attached by the government. Moreover, the reform of the "Hukou" (household register) system provides economical, official, and institutional bases. Therefore, the establishment of an urban-rural integrated, citizen-based, and nationwide-universal health insurance scheme by the government is critically important to attain equality and national connection. Accordingly, the differences between urban and rural areas should be minimized. In addition, the current schemes, administrative institutions, and networks should be integrated and interconnected. Moreover, more expenditure on health insurance might be essential for the integration despite the settings of global financial crisis. Regardless of the possible challenges in implementation, the proposed new scheme is promising and may be applied in the near future for the benefit of the Chinese people and global health.