New genetic loci link adipose and insulin biology to body fat distribution.

Body fat distribution is a heritable trait and a well-established predictor of adverse metabolic outcomes, independent of overall adiposity. To increase our understanding of the genetic basis of body fat distribution and its molecular links to cardiometabolic traits, here we conduct genome-wide association meta-analyses of traits related to waist and hip circumferences in up to 224,459 individuals. We identify 49 loci (33 new) associated with waist-to-hip ratio adjusted for body mass index (BMI), and an additional 19 loci newly associated with related waist and hip circumference measures (P < 5 × 10(-8)). In total, 20 of the 49 waist-to-hip ratio adjusted for BMI loci show significant sexual dimorphism, 19 of which display a stronger effect in women. The identified loci were enriched for genes expressed in adipose tissue and for putative regulatory elements in adipocytes. Pathway analyses implicated adipogenesis, angiogenesis, transcriptional regulation and insulin resistance as processes affecting fat distribution, providing insight into potential pathophysiological mechanisms

Deletion of Protein Tyrosine Phosphatase 1B (PTP1B) Enhances Endothelial Cyclooxygenase 2 Expression and Protects Mice from Type 1 Diabetes-Induced Endothelial Dysfunction.

Protein tyrosine phosphatase 1B (PTP1B) dephosphorylates receptors tyrosine kinase and acts as a molecular brake on insulin signaling pathway. Conditions of metabolic dysfunction increase PTP1B, when deletion of PTP1B protects against metabolic disorders by increasing insulin signaling. Although vascular insulin signaling contributes to the control of glucose disposal, little is known regarding the direct role of PTP1B in the control of endothelial function. We hypothesized that metabolic dysfunctions increase PTP1B expression in endothelial cells and that PTP1B deletion prevents endothelial dysfunction in situation of diminished insulin secretion. Type I diabetes (T1DM) was induced in wild-type (WT) and PTP1B-deficient mice (KO) with streptozotocin (STZ) injection. After 28 days of T1DM, KO mice exhibited a similar reduction in body weight and plasma insulin levels and a comparable increase in glycemia (WT: 384 ± 20 vs. Ko: 432 ± 29 mg/dL), cholesterol and triglycerides, as WT mice. T1DM increased PTP1B expression and impaired endothelial NO-dependent relaxation, in mouse aorta. PTP1B deletion did not affect baseline endothelial function, but preserved endothelium-dependent relaxation, in T1DM mice. NO synthase inhibition with L-NAME abolished endothelial relaxation in control and T1DM WT mice, whereas L-NAME and the cyclooxygenases inhibitor indomethacin were required to abolish endothelium relaxation in T1DM KO mice. PTP1B deletion increased COX-2 expression and PGI2 levels, in mouse aorta and plasma respectively, in T1DM mice. In parallel, simulation of diabetic conditions increased PTP1B expression and knockdown of PTP1B increased COX-2 but not COX-1 expression, in primary human aortic endothelial cells. Taken together these data indicate that deletion of PTP1B protected endothelial function by compensating the reduction in NO bioavailability by increasing COX-2-mediated release of the vasodilator prostanoid PGI2, in T1DM mice

Deletion of Protein Tyrosine Phosphatase 1B (PTP1B) Enhances Endothelial Cyclooxygenase 2 Expression and Protects Mice from Type 1 Diabetes-Induced Endothelial Dysfunction.

Protein tyrosine phosphatase 1B (PTP1B) dephosphorylates receptors tyrosine kinase and acts as a molecular brake on insulin signaling pathway. Conditions of metabolic dysfunction increase PTP1B, when deletion of PTP1B protects against metabolic disorders by increasing insulin signaling. Although vascular insulin signaling contributes to the control of glucose disposal, little is known regarding the direct role of PTP1B in the control of endothelial function. We hypothesized that metabolic dysfunctions increase PTP1B expression in endothelial cells and that PTP1B deletion prevents endothelial dysfunction in situation of diminished insulin secretion. Type I diabetes (T1DM) was induced in wild-type (WT) and PTP1B-deficient mice (KO) with streptozotocin (STZ) injection. After 28 days of T1DM, KO mice exhibited a similar reduction in body weight and plasma insulin levels and a comparable increase in glycemia (WT: 384 ± 20 vs. Ko: 432 ± 29 mg/dL), cholesterol and triglycerides, as WT mice. T1DM increased PTP1B expression and impaired endothelial NO-dependent relaxation, in mouse aorta. PTP1B deletion did not affect baseline endothelial function, but preserved endothelium-dependent relaxation, in T1DM mice. NO synthase inhibition with L-NAME abolished endothelial relaxation in control and T1DM WT mice, whereas L-NAME and the cyclooxygenases inhibitor indomethacin were required to abolish endothelium relaxation in T1DM KO mice. PTP1B deletion increased COX-2 expression and PGI2 levels, in mouse aorta and plasma respectively, in T1DM mice. In parallel, simulation of diabetic conditions increased PTP1B expression and knockdown of PTP1B increased COX-2 but not COX-1 expression, in primary human aortic endothelial cells. Taken together these data indicate that deletion of PTP1B protected endothelial function by compensating the reduction in NO bioavailability by increasing COX-2-mediated release of the vasodilator prostanoid PGI2, in T1DM mice

PTP1B deletion prevents STZ-induced endothelial dysfunction.

<p>Concentration response curves to acetylcholine (ACh, <b>A</b>, <b>B</b>)) and sodium nitroprusside (SNP, <b>C, D</b>) conducted in wild-type (WT) and PTP1B KO mice (KO) treated with citrate-buffer (control) or streptozotocin (STZ). Data are mean±SEM, n = 6 per group, **p<0.001 <i>vs</i>. Control.</p

Acute or chronic COX-2 inhibition reduces endothelial sensitivity to ACh in PTP1B KO mice treated with STZ.

<p>Concentration response curves to acetylcholine (ACh) conducted in the presence or not of the unspecific cyclooxygenases inhibitor indomethacin (Indo,10μM) or in mice chronically treated with the selective COX-2 inhibitor, celecoxib (25mg/kg/day). Data are mean±SEM, n = 6 per group, *p<0.05, **p<0.001 <i>vs</i>. Vehicle within the same group.</p

1H-NMR metabolomics response to a realistic diet contamination with the mycotoxin deoxynivalenol: Effect of probiotics supplementation

International audienceLow-level contamination of food and feed by mycotoxin deoxynivalenol (DON) is unavoidable. We investigated the effects of subclinical challenge with DON, and dietary supplementation with probiotic yeast Saccharomyces cerevisiae boulardii I1079 as preventive strategy. Thirty-six piglets were randomly assigned to four different diets: control diet, diet contaminated with DON (3 mg/kg), diet supplemented with yeast (4x10 9 CFU/kg), or DON-contaminated diet supplemented with yeast, for four weeks. Plasma samples were collected for biochemistry, and tissue samples for histology. 1 H-NMR untargeted metabolomics of plasma and liver were also explored. DON induced no significant modification of biochemistry parameters. However, higher lesional scores were observed and metabolomics highlighted alteration of the metabolism of amino acids and 2-oxocarboxylic acids. Administration of yeast impacted aminoacyl-tRNA synthesis and metabolism of amino acids and glycerophospholipids. Yeast supplementation to DON-exposed piglets prevented histological alterations, while partial least square discriminant analysis underlined similarity of their plasma metabolic profile to control group. In contrast to plasma, the effect on liver metabolome remained marginal, indicating that the toxicity of the mycotoxin was not abolished. These data indicate that 1 H-NMR metabolomics profile is a good biomarker for subclinical exposure to DON, and supplementation with S. cerevisiae boulardii increases piglet resilience to this mycotoxin