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During fasting, induction of hepatic gluconeogenesis is crucial to ensure proper energy homeostasis (1). Such induction is dysregulated in type 2 diabetes, resulting in the development of fasting hyperglycemia (2). [...]

White adipocytes are unique in that they contain large unilocular lipid droplets that occupy most of the cytoplasm. To identify genes involved in the maintenance of mature adipocytes, we expressed dominant-negative PPAR[gamma] in 3T3-L1 cells and performed a microarray screen. The fat-specific protein of 27 kDa (FSP27) was strongly downregulated in this context. FSP27 expression correlated with induction of differentiation in cultured preadipocytes, and the protein localized to lipid droplets in murine white adipocytes in vivo. Ablation of FSP27 in mice resulted in the formation of multilocular lipid droplets in these cells. Furthermore, FSP27-deficient mice were protected from diet-induced obesity and insulin resistance and displayed an increased metabolic rate due to increased mitochondrial biogenesis in white adipose tissue (WAT). Depletion of FSP27 by siRNA in murine cultured white adipocytes resulted in the formation of numerous small lipid droplets, increased lipolysis, and decreased triacylglycerol storage, while expression of FSP27 in COS cells promoted the formation of large lipid droplets. Our results suggest that FSP27 contributes to efficient energy storage in WAT by promoting the formation of unilocular lipid droplets, thereby restricting lipolysis. In addition, we found that the nature of lipid accumulation in WAT appears to be associated with maintenance of energy balance and insulin sensitivity., Introduction Obesity is associated with various complications such as insulin resistance, type 2 diabetes, dyslipidemia, and atherosclerosis (1), (2). It results from an imbalance between energy intake and energy expenditure [...]

Insulin receptor substrate (IRS)-1 and IRS-2 have dominant roles in the action of insulin (1), but other substrates of the insulin receptor kinase, such as Gabl, c-Cbl, SH2-B and APS, are also of physiological relevance (2-5). Although the protein downstream of tyrosine kinases-1 (Dok1) is known to function as a multisite adapter molecule in insulin signaling (6-8), its role in energy homeostasis has remained unclear. Here we show that Dok1 regulates adiposity. Expression of Dok1 in white adipose tissue was markedly increased in mice fed a high-fat diet, whereas adipocytes lacking this adapter were smaller and showed a reduced hypertrophic response to this dietary manipulation. Dok1-deficient mice were leaner and showed improved glucose tolerance and insulin sensitivity compared with wild-type mice. Embryonic fibroblasts from Dok1-deficient mice were impaired in adipogenic differentiation, and this defect was accompanied by an increased activity of the protein kinase ERK and a consequent increase in the phosphorylation of peroxisome proliferator-activated receptor (PPAR)-[gamma] on Ser112. Mutation of this negative regulatory site for the transactivation activity of PPAR-[gamma] blocked development of the lean phenotype caused by Dok1 ablation. These results indicate that Dok1 promotes adipocyte hypertrophy by counteracting the inhibitory effect of ERK on PPAR-[gamma] and may thus confer predisposition to diet-induced obesity., We and others have shown that tyrosine-phosphorylated Dok1 binds and recruits p120 Ras GTPase-activating protein (rasGAP) as well as the adapter protein Nck, thereby regulating mitogenic signaling mediated by Ras [...]

Testis induction is associated with gonadal Sry, and Sox9 expression in mammals. This study investigated whether Sry expression directly induces male-specific Sox9 activation during early phases of testis differentiation. We have established an XX sex-reversal mouse line carrying the Sry transgene driven by a weak basal promoter of the Hsp70.3 gene (Hsp-Sry), whereby the transgene was activated in the gonads along the entire anteroposterior axis from earlier stages. The effects of misexpression and overexpression of Sry, on the spatiotemporal pattern of Sox9 expression were examined using both XX and XY gonads of Hsp-Sry transgenic embryos. It was shown that ectopic expression of Sty transcripts in the entire gonadal area from earlier stages promotes neither any advance in the timing nor any appreciable ectopic activation of endogenous Sox9 expression. Immediately after the onset of Sox9 activation, however, both the level of Sox9 expression and the number of SOX9-positive cells were significantly enhanced in Hsp-Sry/XY gonads, as compared with those in wild-type/XY and Hsp-Sry/XX gonads. These findings suggest that, although Sry is capable of up-regulating Sox9 expression dose-dependently, Sry mRNA expression alone is not likely to provide positional or timing information needed for male-specific Sox9 activation in developing XY gonads. Keywords: Sry; Sox9; Anteroposterior axis; Sex differentiation; Genital ridge; Testis; Gonad; Gene dosage; Transgenic mice

The transcription factor, signal transducer and activator of transcription-3 (STAT-3) contributes to various physiological processes. Here we show that mice with liver-specific deficiency in STAT-3, achieved using the Cre-loxP system, show insulin resistance associated with increased hepatic expression of gluconeogenic genes. Restoration of hepatic STAT-3 expression in these mice, using adenovirus-mediated gene transfer, corrected the metabolic abnormalities and the alterations in hepatic expression of gluconeogenic genes. Overexpression of STAT-3 in cultured hepatocytes inhibited gluconeogenic gene expression independently of peroxisome proliferator-activated receptor-[gamma] coactivator-1[alpha] (PGC-1[alpha]), an upstream regulator of gluconeogenic genes. Liver-specific expression of a constitutively active form of STAT-3, achieved by infection with an adenovirus vector, markedly reduced blood glucose, plasma insulin concentrations and hepatic gluconeogenic gene expression in diabetic mice. Hepatic STAT-3 signaling is thus essential for normal glucose homeostasis and may provide new therapeutic targets for diabetes mellitus., Author(s): Hiroshi Inoue [1]; Wataru Ogawa [1]; Michitaka Ozaki [2, 3]; Sanae Haga [2]; Michihiro Matsumoto [1]; Kensuke Furukawa [1]; Naoko Hashimoto [1]; Yoshiaki Kido [1]; Toshiyuki Mori [1]; Hiroshi [...]

The immunoglobulin kappa gene 3' enhancer (E3') suppresses V(sub kappa)-J(sub kappa) recombination and restricts it to the pre-B developmental stage of B cells. The B/T specificity of V(sub kappa)-J(sub kappa) recombination is controled by the PU.1 binding domain in E3'. A mutation in the PU.1 domain causes recombination in both B and T cells. Deletion of E3' causes rearrangement of the kappa gene in the early pro-B stage of B cells.