C/EBP␤ Reprograms White 3T3-L1 Preadipocytes to a Brown Adipocyte Pattern of Gene Expression *

cAMP-dependent protein kinase induction of PPAR␥ coactivator-1␣ (PGC-1␣) and uncoupling protein 1 (UCP1) expression is an essential step in the commitment of preadipocytes to the brown adipose tissue (BAT) lineage. We studied the molecular mechanisms responsible for differential expression of PGC-1␣ in HIB1B (BAT) and 3T3-L1 white adipose tissue (WAT) precursor cell lines. In HIB1B cells PGC-1␣ and UCP1 expression is cAMP-inducible, but in 3T3-L1 cells, expression is reduced and is cAMP-insensitive. A proximal 264-bp PGC-1␣ reporter construct was cAMP-inducible only in HIB1B cells and was suppressed by site-directed mutagenesis of the proximal cAMP response element (CRE). In electrophoretic mobility shift assays, the transcription factors CREB and C/EBP␤, but not C/EBP␣ and C/EBP␦, bound to the CRE on the PGC-1␣ promoter region in HIB1B and 3T3-L1 cells. Chromatin immunoprecipitation studies demonstrated that C/EBP␤ and CREB bound to the CRE region in HIB1B and 3T3-L1 cell lysates. C/EBP␤ expression was induced by cAMP only in HIB1B cells, and overexpression of C/EBP␤ rescued cAMP-inducible PGC-1␣ and UCP1 expression in 3T3-L1 cells. These data demonstrate that differentiation of preadipocytes toward the BAT rather than the WAT phenotype is controlled in part by the action of C/EBP␤ on the CRE in PGC-1␣ proximal promoter

Extracellular acidification stimulates GPR68 mediated IL-8 production in human pancreatic β cells.

International audienceAcute or chronic metabolic complications such as diabetic ketoacidosis are often associated with extracellular acidification and pancreatic β-cell dysfunction. However, the mechanisms by which human β-cells sense and respond to acidic pH remain elusive. In this study, using the recently developed human β-cell line EndoC-βH2, we demonstrate that β-cells respond to extracellular acidification through GPR68, which is the predominant proton sensing receptor of human β-cells. Using gain- and loss-of-function studies, we provide evidence that the β-cell enriched transcription factor RFX6 is a major regulator of GPR68. Further, we show that acidic pH stimulates the production and secretion of the chemokine IL-8 by β-cells through NF-кB activation. Blocking of GPR68 or NF-кB activity severely attenuated acidification induced IL-8 production. Thus, we provide mechanistic insights into GPR68 mediated β-cell response to acidic microenvironment, which could be a new target to protect β-cell against acidosis induced inflammation

Ascertainment and critical assessment of the views of the general public and healthcare professionals on nutrigenomics in Greece

Aim: The aim of this study was to understand the general public’s and healthcare professionals’ views on nutrigenomics. Patients & methods: We designed a cross-sectional survey of healthcare professionals (n = 87) and the general public (n = 1504) in the three largest cities in Greece (Athens, Thessaloniki and Patras). Results: Our data revealed that only 11.5% of respondents from the general public had been advised to take a genetic test in order to explore the relationship between their genes and their nutritional status. Although 80.5% of healthcare professionals would have been willing to recommend their patients/clients to undergo nutrigenomic analysis to correlate their genetic profile with their diet, only 17.2% of respondents had actually done so. In general, the general public was opposed to direct-access nutrigenomics testing. Conclusion: The application of genomic information in the context of nutritional choice requires the continuing education of healthcare professionals and the dissemination of accurate and reliable information to the general public

Nocturnal Activation of Melatonin Receptor Type 1 Signaling Modulates Diurnal Insulin Sensitivity via Regulation of Pi3k Activity

Recent genetic studies have highlighted the potential involvement of melatonin receptor 1 (MT1) and melatonin receptor 2 (MT2) in the pathogenesis of type 2 diabetes. Here, we report that mice lacking MT1 (MT1 KO) tend to accumulate more fat mass than WT mice and exhibit marked systemic insulin resistance. Additional experiments revealed that the main insulin signaling pathway affected by the loss of MT1 was the activation of phosphatidylinositol-3-kinase (PI3K). Transcripts of both catalytic and regulatory subunits of PI3K were strongly downregulated within MT1 KO mice. Moreover, the suppression of nocturnal melatonin levels within WT mice, by exposing mice to constant light, resulted in impaired PI3K activity and insulin resistance during the day, similar to what was observed in MT1 KO mice. Inversely, administration of melatonin to WT mice exposed to constant light was sufficient and necessary to restore insulin-mediated PI3K activity and insulin sensitivity. Hence, our data demonstrate that the activation of MT1 signaling at night modulates insulin sensitivity during the day via the regulation of the PI3K transcription and activity. Lastly, we provide evidence that decreased expression of MTNR1A (MT1) in the liver of diabetic individuals is associated with poorly controlled diabetes

Cold-induced changes in gene expression in brown adipose tissue, white adipose tissue and liver

Cold exposure imposes a metabolic challenge to mammals that is met by a coordinated response in different tissues to prevent hypothermia. This study reports a transcriptomic analysis in brown adipose tissue (BAT), white adipose (WAT) and liver of mice in response to 24 h cold exposure at 8°C. Expression of 1895 genes were significantly (P<0.05) up- or down-regulated more than two fold by cold exposure in all tissues but only 5 of these genes were shared by all three tissues, and only 19, 14 and 134 genes were common between WAT and BAT, WAT and liver, and BAT and liver, respectively. We confirmed using qRT-PCR, the increased expression of a number of characteristic BAT genes during cold exposure. In both BAT and the liver, the most common direction of change in gene expression was suppression (496 genes in BAT and 590 genes in liver). Gene ontology analysis revealed for the first time significant (P<0.05) down regulation in response to cold, of genes involved in oxidoreductase activity, lipid metabolic processes and protease inhibitor activity, in both BAT and liver, but not WAT. The results reveal an unexpected importance of down regulation of cytochrome P450 gene expression and apolipoprotein, in both BAT and liver, but not WAT, in response to cold exposure. Pathway analysis suggests a model in which down regulation of the nuclear transcription factors HNF4α and PPARα in both BAT and liver may orchestrate the down regulation of genes involved in lipoprotein and steroid metabolism as well as Phase I enzymes belonging to the cytochrome P450 group in response to cold stress in mice. We propose that the response to cold stress involves decreased gene expression in a range of cellular processes in order to maximise pathways involved in heat production

Implication des mutations du récepteur de la mélatonine MT

Des facteurs génétiques et environnementaux participent au développement du diabète de type 2 (DT2). Des études d’association pangénomique récentes ont permis de découvrir de nouveaux variants génétiques associés au DT2, notamment le variant rs10830963 dans l’intron du gène MTNR1B. Ce gène code pour le récepteur MT2 de la mélatonine, un membre de la famille des récepteurs couplés aux protéines G impliqué dans la régulation des rythmes circadiens et saisonniers. Ce résultat surprenant a ouvert un nouveau champ d’investigation dans le domaine du DT2, notamment dans l’étude du rôle du récepteur MT2 et du rythme circadien dans cette maladie émergente. Cet article envisage de retracer le chemin de la découverte des premiers variants du gène MTNR1B, depuis l’établissement d’un lien fonctionnel entre certains variants et le risque de développer un DT2, jusqu’à quelques hypothèses tentant d’expliquer l’importance du dysfonctionnement du système mélatoninergique qui pourrait favoriser le développement du DT2

A low protein diet during early gestation in sheep detrimentally impacts hepatic glucose metabolism in the adult offspring

Differences in maternal diet can account for variation in the metabolic competence of the subsequent individual as an adult. ‘Developmental programming’ may impair fetal organ development leading to a limitation in function as an adult and/or increase the rate of age-related organ decline for example under conditions of obesity. Here, we have tested the interaction between prenatal nutritional ‘thrift’ and postnatal nutritional excess on gluco-regulatory functions in an ovine model. Seventy-four Scottish Blackface ewes were randomly assigned to receive either a control protein diet with adequate energy (18% protein; CP, n 20) or low protein diet (9% protein) fed during early gestation (0–65 d, term ~147 d; LPE, n 37) or late gestation (65–147 d; LPL, n 17). At 65 d a proportion of ewes was euthanised for fetal sampling. At term, remaining ewes lambed naturally, were weaned at 10 weeks and a random sample of offspring studied longitudinally when lean (1.5 years of age) and after 6 months exposure to an obesogenic environment. Body composition was determined by dual-energy absorptiometry and glucose and insulin tolerance tests were conducted with appropriate sampling intervals. At post mortem, muscle and hepatic tissues were sampled for expression and abundance of relevant gluco-regulatory genes. The diets had little effect on maternal weight and body composition through gestation or on fetal weights at 65 d. Term weight was reduced by ~500 g (P = 0.001) in LPL v. other groups but, by weaning, body weight was similar between groups and growth rate to adulthood was not different. Homeostasis model assessment of baseline glucose and insulin concentrations indicated relative insulin resistance in male LPE . Indeed, when challenged with a GTT, the incremental insulin AUC was significantly greater in male LPE when obese but not when lean (unpublished results). Molecular quantification of glucose-insulin pathways in muscle and liver indicated specific down-regulation of the hepatic insulin, but not lipid, pathways in male liver only. Muscle insulin-signalling pathways were unaffected as determined by microarray (Affymetrix, U133 chip; www.arraymining.net). The data suggest that a maternal, low protein, diet during early gestation specifically impacts upon the function of the resulting adult liver, such that the offspring appear more susceptible to large excursions in plasma insulin during gluco-regulatory challenges. The insulin sensitivity of offspring muscle, the largest single source of insulin-stimulated glucose uptake, was largely unaffected. Thus, obesity appears to exacerbate any functional deficits inherent in low protein exposed offspring in sheep, but those offspring born of low birth weight were largely unaffected, illustrating that nutritional quality is far more important than nutritional quantity especially during sensitive developmental phases of growth

GO Lipid Metabolic Process list of genes up regulated and down regulated genes all tissues.

<p>GO Lipid Metabolic Process list of genes up regulated and down regulated genes all tissues.</p