Central glucocorticoid administration promotes weight gain and increased 11ß-hydroxysteroid dehydrogenase type 1 expression in white adipose tissue.

Glucocorticoids (GCs) are involved in multiple metabolic processes, including the regulation of insulin sensitivity and adipogenesis. Their action partly depends on their intracellular activation by 11ß-hydroxysteroid dehydrogenase type 1 (11ß-HSD1). We previously demonstrated that central GC administration promotes hyperphagia, body weight gain, hyperinsulinemia and marked insulin resistance at the level of skeletal muscles. Similar dysfunctions have been reported to occur upon specific overexpression of 11ß-HSD1 in adipose tissue. The aim of the present study was therefore to determine whether the effects of central GC infusion may enhance local GC activation in white adipose tissue. Male Wistar and Sprague Dawley (SD) rats were intracerebroventricularly infused with GCs for 2 to 3 days. Body weight, food intake and metabolic parameters were measured, and expression of enzymes regulating 11ß-HSD1, as well as that of genes regulated by GCs, were quantified. Central GC administration induced a significant increase in body weight gain and in 11ß-HSD1 and resistin expression in adipose tissue. A decrease 11ß-HSD1 expression was noticed in the liver of SD rats, as a partial compensatory mechanism. Such effects of GCs are centrally elicited. This model of icv dexamethasone infusion thus appears to be a valuable acute model, that helps delineating the initial metabolic defects occurring in obesity. An impaired downregulation of intracellular GC activation in adipose tissue may be important for the development of insulin resistance.

Mechanisms of the anti-obesity effects of oxytocin in diet-induced obese rats.

Apart from its role during labor and lactation, oxytocin is involved in several other functions. Interestingly, oxytocin- and oxytocin receptor-deficient mice develop late-onset obesity with normal food intake, suggesting that the hormone might exert a series of beneficial metabolic effects. This was recently confirmed by data showing that central oxytocin infusion causes weight loss in diet-induced obese mice. The aim of the present study was to unravel the mechanisms underlying such beneficial effects of oxytocin. Chronic central oxytocin infusion was carried out in high fat diet-induced obese rats. Its impact on body weight, lipid metabolism and insulin sensitivity was determined. We observed a dose-dependent decrease in body weight gain, increased adipose tissue lipolysis and fatty acid ß-oxidation, as well as reduced glucose intolerance and insulin resistance. The additional observation that plasma oxytocin levels increased upon central infusion suggested that the hormone might affect adipose tissue metabolism by direct action. This was demonstrated using in vitro, ex vivo, as well as in vivo experiments. With regard to its mechanism of action in adipose tissue, oxytocin increased the expression of stearoyl-coenzyme A desaturase 1, as well as the tissue content of the phospholipid precursor, N-oleoyl-phosphatidylethanolamine, the biosynthetic precursor of the oleic acid-derived PPAR-alpha activator, oleoylethanolamide. Because PPAR-alpha regulates fatty acid ß-oxidation, we hypothesized that this transcription factor might mediate the oxytocin effects. This was substantiated by the observation that, in contrast to its effects in wild-type mice, oxytocin infusion failed to induce weight loss and fat oxidation in PPAR-alpha-deficient animals. Altogether, these results suggest that oxytocin administration could represent a promising therapeutic approach for the treatment of human obesity and type 2 diabetes.

Peripheral ghrelin enhances sweet taste food consumption and preference, regardless of its caloric content.

AIMS: Ghrelin is one of the most potent orexigens known to date. While the prevailing view is that ghrelin participates in the homeostatic control of feeding, the question arose as to whether consummatory responses evoked by this compound could be related to search for reward. We therefore attempted to delineate the involvement of ghrelin in the modulation of non-caloric but highly rewarding consumption. METHODS: We tested the effect of intraperitoneally injected ghrelin on the acceptance and preference for a 0.3% saccharin solution using single bottle tests and free-choice preference test procedures in C57BL6/J mice, as well as in mice lacking the ghrelin receptor (GHSR1a -/-) and their wild-type (WT) littermates. RESULTS: In the single bottle tests, peripheral ghrelin consistently increased the consumption of saccharin, independently of availability of caloric food. In the free-choice preference test procedures, ghrelin increased the preference for saccharin in WT mice, while it did had not effect in GHSR1a -/-animals, indicating that the ghrelin receptor pathway is necessary to mediate this parameter. CONCLUSIONS: Peripheral ghrelin enhances intake and preference for a sweet food, regardless of whether the food has caloric content. This effect, mediated through the ghrelin receptor pathway, may serve as additional enhancers of energy intake.

A negative feedback regulatory loop associates the tyrosine kinase receptor ERBB2 and the transcription factor GATA4 in breast cancer cells.

Overexpression of the ERBB2 gene, linked to genomic and transcriptional amplifications, is a poor prognosis indicator in 25% to 30% of breast cancers. In contrast to some well-documented genomic amplifications, molecular mechanisms leading to ERBB2 transcriptional overexpression remain poorly characterized. Gene expression analyses of breast cancer have characterized distinct transcriptional signatures allowing a molecular classification of breast carcinoma. Coexpression of the ERBB2 and GATA4 genes was originally observed in tumors. Both genes are essential for cardiovascular development and GATA4 has been proposed to control the transcription of critical genes for the differentiation and the function of myocardium. We determined that ERBB2-targeted small interfering RNA repressed both ERBB2 and GATA4 genes, whereas GATA4-targeted small interfering RNA repressed GATA4 and activated ERBB2 transcription. Transfected GATA4-expressing construct repressed ERBB2 promoter. Phylogenetic foot printing revealed multiple putative GATA4 binding sites conserved in mammals within the ERBB2 promoter region. Chromatin immunoprecipitation showed that GATA4 binds specifically to several ERBB2 gene noncoding regions. Electrophoretic mobility shift assay revealed GATA4 binding to a well-conserved consensus motif. Site-directed mutagenesis confirmed the role of this new regulatory element for the activity of the ERBB2 gene enhancer. In agreement with a repressor role of GATA4 on ERBB2 gene expression balanced by ERBB2 activation of the GATA4 gene, a negative correlation between the relative levels of ERBB2 and GATA4 mRNA was observed in breast cancer cell lines and breast tumor samples. We propose that the negative feedback loop linking ERBB2 and GATA4 plays a role in the transcriptional dysregulation of ERBB2 gene expression in breast cancer.