884 resultados para insulin receptor substrate 1
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Background: There is a current lack of consensus on defining metabolically healthy obesity (MHO). Limited data on dietary and lifestyle factors and MHO exist. The aim of this study is to compare the prevalence, dietary factors and lifestyle behaviours of metabolically healthy and unhealthy obese and non-obese subjects according to different metabolic health criteria. Method: Cross-sectional sample of 1,008 men and 1,039 women aged 45-74 years participated in the study. Participants were classified as obese (BMI ≥30kg/m2) and non-obese (BMI <30kg/m2). Metabolic health status was defined using five existing MH definitions based on a range of cardiometabolic abnormalities. Dietary composition and quality, food pyramid servings, physical activity, alcohol and smoking behaviours were examined. Results: The prevalence of MHO varied considerably between definitions (2.2% to 11.9%), was higher among females and generally increased with age. Agreement between MHO classifications was poor. Among the obese, prevalence of MH was 6.8% to 36.6%. Among the non-obese, prevalence of metabolically unhealthy subjects was 21.8% to 87%. Calorie intake, dietary macronutrient composition, physical activity, alcohol and smoking behaviours were similar between the metabolically healthy and unhealthy regardless of BMI. Greater compliance with food pyramid recommendations and higher dietary quality were positively associated with metabolic health in obese (OR 1.45-1.53 unadjusted model) and non-obese subjects (OR 1.37-1.39 unadjusted model), respectively. Physical activity was associated with MHO defined by insulin resistance (OR 1.87, 95% CI 1.19-2.92, p = 0.006).
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Osteoporosis is a complex skeletal disorder characterized by compromised bone strength. Variation in bone mineral density (BMD) is a contributing factor. The aim of this research as to select informative single nucleotide polymorphisms (SNPs) in potential candidate genes from loci suggestively linked to BMD variation for fine mapping. The gene regulated by oestrogen in breast cancer 1 (GREB1), located at 2p25.1, was selected. GREB1 transcription is initiated early in the oestrogen receptor alpha regulated pathway. There was significant association between GREB1_03 and BMD variation at the lumbar spine and femoral neck (FN) in the discovery cohort. Significant association was observed between GREB1_04 and FN BMD in the replication cohort. The development and differentiation enhancing factor 2, the integrin cytoplasmic domain associated protein 1 and A-disintegrin and metalloprotease 17 were selected due to their respective roles in cell mobility and adhesion. There was no linkage or association observed between the Chr2 cluster SNPs and BMD. Two factors in bone remodelling are the attraction of bone cell precursors and endocrine regulation of the process, primarily through the action of parathyroid hormone (PTH). The C-C chemokine receptor type 3 (CCR3) encodes a CC chemokine receptor expressed in osteoclast precursors. The PTH receptor type 1 (PTHR1) encodes a G-protein coupled receptor for PTH. Association was observed between CCR3 haplotypes and BMD variation at the FN. There was no linkage or association observed between PTHR1 SNPs and BMD variation. Population genetic studies with complex phenotypes endeavour to elucidate the traits genetic architecture. This study presents evidence of association between GREB1 and BMD variation and as such, introduces GREB1 as a novel gene target for osteoporosis genetics studies. It affirms that common genomic variants in PTHR1 are not associated with BMD variation in Caucasians and supports the evidence that CCR3 may be contributing to BMD variation
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Using C57BL/6J mice fed whey protein isolate (WPI) enriched high fat (HFD) or low-fat diets (LFD), this study tested the hypothesis that WPI directly impacts on adiposity by influencing lipid metabolism. WPI suppressed HFD-induced body fat and increased lean mass at 8 weeks of dietary challenge despite elevated plasma triacylglycerol (TAG) levels, suggesting reduced TAG storage. WPI reduced HFD-associated hypothalamic leptin and insulin receptor (IR) mRNA expression, and prevented HFD-associated reductions in adipose tissue IR and glucose transporter 4 expression. These effects were largely absent at 21 weeks of HFD feeding, however WPI increased lean mass and cause a trend towards decreased fat mass, with notable increased Lactobacillus and decreased Clostridium gut bacterial species. Increasing the protein to carbohydrate ratio enhanced the above effects, and shifted the gut microbiota composition away from the HFD group. Seven weeks of WPI intake with a LFD decreased insulin signalling gene expression in the adipose tissue in association with an increased fat accumulation. WPI reduced intestinal weight and length, suggesting a potential functional relationship between WPI, gastro-intestinal morphology and insulin related signalling in the adipose. Extending the study to 15 weeks, did not affect adipose fat weight, but decreased energy intake, weight gain and intestinal length. The functionality of protein sensing lysophosphatidic acid receptor 5 (LPA5) in 3T3-L1 pre-adipocytes was assessed. Over-expression of the receptor in 3T3-L1 pre-adipocytes provided a growth advantage to the cells and suppressed cellular differentiation into mature fat cells. In conclusion, the data demonstrates WPI impacts on adiposity by influencing lipid metabolism in a temporal manner, resulting possibly due to changes in lean mass, hypothalamic and adipose gene expression, gut microbiota and gastrointestinal morphology. The data also showed LPA5 is a novel candidate in regulating of preadipocyte growth and differentiation, and may mediate dietary protein effects on adipose tissue.
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Mesenchymal stem cells (MSCs) and endothelial progenitor cells (EPCs) represent promising cell sources for angiogenic therapies. There are, however, conflicting reports regarding the ability of MSCs to support network formation of endothelial cells. The goal of this study was to assess the ability of human bone marrow-derived MSCs to support network formation of endothelial outgrowth cells (EOCs) derived from umbilical cord blood EPCs. We hypothesized that upon in vitro coculture, MSCs and EOCs promote a microenvironment conducive for EOC network formation without the addition of angiogenic growth supplements. EOC networks formed by coculture with MSCs underwent regression and cell loss by day 10 with a near 4-fold and 2-fold reduction in branch points and mean segment length, respectively, in comparison with networks formed by coculture vascular smooth muscle cell (SMC) cocultures. EOC network regression in MSC cocultures was not caused by lack of vascular endothelial growth factor (VEGF)-A or changes in TGF-β1 or Ang-2 supernatant concentrations in comparison with SMC cocultures. Removal of CD45+ cells from MSCs improved EOC network formation through a 2-fold increase in total segment length and number of branch points in comparison to unsorted MSCs by day 6. These improvements, however, were not sustained by day 10. CD45 expression in MSC cocultures correlated with EOC network regression with a 5-fold increase between day 6 and day 10 of culture. The addition of supplemental growth factors VEGF, fibroblastic growth factor-2, EGF, hydrocortisone, insulin growth factor-1, ascorbic acid, and heparin to MSC cocultures promoted stable EOC network formation over 2 weeks in vitro, without affecting CD45 expression, as evidenced by a lack of significant differences in total segment length (p=0.96). These findings demonstrate the ability of MSCs to support EOC network formation correlates with removal of CD45+ cells and improves upon the addition of soluble growth factors.
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In dog thyroid cells, insulin or IGF-1 induces cell growth and is required for the mitogenic action of TSH through cyclic AMP, of EGF, and of phorbol esters. HGF per se stimulates cell proliferation and is thus the only full mitogenic agent. TSH and cAMP enhance, whereas EGF phorbol esters and HGF repress differentiation expression. In this study, we have investigated for each factor and regulatory cascade of the intermediate step of immediate early gene induction, that is, c-myc, c-jun, jun D, jun B, c-fos, fos B, fra-1, fra-2, and egr1; fra-1 and fra-2 expressions were very low. TSH or forskolin increased the levels of c-myc, jun B, jun D, c-fos, and fos B while decreasing those of c-jun and egr1. Phorbol myristate ester stimulated the expression of all the genes. EGF and HGF stimulated the expression of all the genes except jun D and for EGF fos B. All these effects were obtained in the presence and in the absence of insulin, which shows that insulin is not necessary for the effects of the mitogens on immediate early gene expression. The definition of the repertoire of early immediate genes inductible by the various growth cascades provides a framework for the analysis of gene expression in tumors. (1) Insulin was able to induce all the protooncogenes investigated except fos B. This suggests that fos B could be the factor missing for insulin to induce mitogenesis. (2) No characteristic pattern of immediate early gene expression has been observed for insulin, which induces cell hypertrophy and is permissive for the action of the other growth factors. These effects are therefore not accounted for by a specific immediate early gene expression. On the other hand, insulin clearly enhances the effects of TSH, phorbol ester, and EGF on c-myc, junB, and c-fos expression. This suggests that the effect of insulin on mitogenesis might result from quantitative differences in the transcription complexes formed. (3) c-myc, c-fos, and jun B mRNA induction by all stimulating agents, whether inducing cell hypertrophy, or growth and dedifferentiation, or growth and differentiation, suggests that, although these expressions are not sufficient, they may be necessary for the various growth responses of thyroid cells. (4) The inhibition of c-jun and egr1 mRNA expression, and the marked induction of jun D mRNA appear to be specific features of the TSH cAMP pathway. They might be related to its differentiating action. (5) fos B, which is induced by TSH, forskolin, phorbol ester, and HGF but not by insulin, could be involved in the mitogenic action of the former factors.
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Background: Inflammation and genetic instability are enabling characteristics of prostate carcinoma (PCa). Inactivation of the tumour suppressor gene phosphatase and tensin homolog (PTEN) is prevalent in early PCa. The relationship of PTEN deficiency to inflammatory signalling remains to be characterised.
Objective: To determine how loss of PTEN functionality modulates expression and efficacy of clinically relevant, proinflammatory chemokines in PCa.
Design, setting and participants: Experiments were performed in established cell-based PCa models, supported by pathologic analysis of chemokine expression in prostate tissue harvested from PTEN heterozygous (Pten(+/-)) mice harbouring inactivation of one PTEN allele.
Interventions: Small interfering RNA (siRNA)- or small hairpin RNA (shRNA)-directed strategies were used to repress PTEN expression and resultant interleukin-8 (CXCL8) signalling, determined under normal and hypoxic culture conditions.
Outcome measurements and statistical analysis: Changes in chemokine expression in PCa cells and tissue were analysed by real-time polymerase chain reaction (PCR), immunoblotting, enzyme-linked immunosorbent assay (ELISA), and immunohistochemistry; effects of chemokine signalling on cell function were assessed by cell cycle analysis, apoptosis, and survival assays.
Results and limitations: Transient (siRNA) or prolonged (shRNA) PTEN repression increased expression of CXCL8 and its receptors, chemokine (C-X-C motif) receptor (CXCR) 1 and CXCR2, in PCa cells. Hypoxia-induced increases in CXCL8, CXCR1, and CXCR2 expression were greater in magnitude and duration in PTEN-depleted cells. Autocrine CXCL8 signalling was more efficacious in PTEN-depleted cells, inducing hypoxia-inducible factor-1 (HIF-1) and nuclear factor kappa-light-chain-enhancer of activated B cells (NF-?B) transcription and regulating genes involved in survival and angiogenesis. Increased expression of the orthologous chemokine KC was observed in regions displaying atypical cytologic features in Pten(+/-) murine prostate tissue relative to normal epithelium in wild-type PTEN (Pten(WT)) glands. Attenuation of CXCL8 signalling decreased viability of PCa cells harbouring partial or complete PTEN loss through promotion of G1 cell cycle arrest and apoptosis. The current absence of clinical validation is a limitation of the study.
Conclusions: PTEN loss induces a selective upregulation of CXCL8 signalling that sustains the growth and survival of PTEN-deficient prostate epithelium.
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Lipoxins, which are endogenously produced lipid mediators, promote the resolution of inflammation, and may inhibit fibrosis, suggesting a possible role in modulating renal disease. Here, lipoxin A4 (LXA4) attenuated TGF-ß1-induced expression of fibronectin, N-cadherin, thrombospondin, and the notch ligand jagged-1 in cultured human proximal tubular epithelial (HK-2) cells through a mechanism involving upregulation of the microRNA let-7c. Conversely, TGF-ß1 suppressed expression of let-7c. In cells pretreated with LXA4, upregulation of let-7c persisted despite subsequent stimulation with TGF-ß1. In the unilateral ureteral obstruction model of renal fibrosis, let-7c upregulation was induced by administering an LXA4 analog. Bioinformatic analysis suggested that targets of let-7c include several members of the TGF-ß1 signaling pathway, including the TGF-ß receptor type 1. Consistent with this, LXA4-induced upregulation of let-7c inhibited both the expression of TGF-ß receptor type 1 and the response to TGF-ß1. Overexpression of let-7c mimicked the antifibrotic effects of LXA4 in renal epithelia; conversely, anti-miR directed against let-7c attenuated the effects of LXA4. Finally, we observed that several let-7c target genes were upregulated in fibrotic human renal biopsies compared with controls. In conclusion, these results suggest that LXA4-mediated upregulation of let-7c suppresses TGF-ß1-induced fibrosis and that expression of let-7c targets is dysregulated in human renal fibrosis.
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Streptococcus pyogenes is the causative agent of numerous diseases ranging from benign infections (pharyngitis and impetigo) to severe infections associated with high mortality (necrotizing fasciitis and bacterial sepsis). As with other bacterial infections, there is considerable interest in characterizing the contribution of interleukin-17A (IL-17A) responses to protective immunity. We here show significant il17a up-regulation by quantitative real-time PCR in secondary lymphoid organs, correlating with increased protein levels in the serum within a short time of S. pyogenes infection. However, our data offer an important caveat to studies of IL-17A responsiveness following antigen inoculation, because enhanced levels of IL-17A were also detected in the serum of sham-infected mice, indicating that inoculation trauma alone can stimulate the production of this cytokine. This highlights the potency and speed of innate IL-17A immune responses after inoculation and the importance of proper and appropriate controls in comparative analysis of immune responses observed during microbial infection.
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MOLECULES that perform logic operations are prerequisites for molecular information processing and computation. We and others have previously reported receptor molecules that can be considered to perform simple logic operations by coupling ionic bonding or more complex molecular-recognition processes with photonic (fluorescence) signals: in these systems, chemical binding (the 'input') results in a change in fluorescence intensity (the 'output') from the receptor. Here we describe a receptor (molecule (1) in Fig. 1) that operates as a logic device with two input channels: the fluorescence signal depends on whether the molecule binds hydrogen ions, sodium ions or both. The input/output characteristics of this molecular device correspond to those of an AND gate.
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CONTEXT: Minority communities are disproportionately affected by diabetes, and minority women are at an increased risk for glucose intolerance (dysglycemia) during pregnancy.
OBJECTIVES: In pregnant American Indian women, the objectives of the study were to use current criteria to estimate the prevalence of first-trimester (Tr1) dysglycemia and second-trimester (Tr2) incidence of gestational diabetes mellitus (GDM) and to explore new candidate measures and identify associated clinical factors.
DESIGN: This was a prospective cohort study. In Tr1 we performed a 75-g, 2-hour oral glucose tolerance test (OGTT) and glycated hemoglobin (HbA1c) to determine the following: fasting insulin; homeostasis model assessment of insulin resistance; serum 1,5-anhydroglucitol; noninvasive skin autofluorescence (SCOUT). We defined dysglycemia by American Diabetes Association and Endocrine Society criteria and as HbA1c of 5.7% or greater. In Tr2 in an available subset, we performed a repeat OGTT and SCOUT.
PARTICIPANTS: Pregnant American Indian women (n = 244 at Tr1; n = 114 at Tr2) participated in the study.
OUTCOMES: The prevalence of dysglycemia at Tr1 and incidence of GDM at Tr2 were measured.
RESULTS: At Tr1, one woman had overt diabetes; 36 (15%) had impaired glucose tolerance (American Diabetes Association criteria and/or abnormal HbA1c) and 59 (24%) had GDM-Tr1 (Endocrine Society criteria). Overall, 74 (30%) had some form of dysglycemia. Associated factors were body mass index, hypertension, waist/hip circumferences, SCOUT score, fasting insulin, and homeostasis model assessment of insulin resistance. At Tr2, 114 of the Tr1 cohort underwent a repeat OGTT and SCOUT, and 26 (23%) had GDM. GDM-Tr2 was associated with increased SCOUT scores (P = .029) and Tr1 body mass index, waist/hip circumferences, diastolic blood pressure, fasting insulin, and triglyceride levels. Overall, dysglycemia at Tr1 and/or Tr2 affected 38% of the women.
CONCLUSIONS: Dysglycemia at some point during pregnancy was common among American Indian women. It was associated with features of insulin resistance and may confer long-term health risks for mother and child.
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Increasingly invasive bladder cancer cells lines displayed insensitivity toward a panel of dietary-derived ligands for members of the nuclear receptor superfamily. Insensitivity was defined through altered gene regulatory actions and cell proliferation and reflected both reduced receptor expression and elevated nuclear receptor corepressor 1 (NCOR1) expression. Stable overexpression of NCOR1 in sensitive cells (RT4) resulted in a panel of clones that recapitulated the resistant phenotype in terms of gene regulatory actions and proliferative responses toward ligand. Similarly, silencing RNA approaches to NCOR1 in resistant cells (EJ28) enhanced ligand gene regulatory and proliferation responses, including those mediated by peroxisome proliferator-activated receptor (PPAR) gamma and vitamin D receptor (VDR) receptors. Elevated NCOR1 levels generate an epigenetic lesion to target in resistant cells using the histone deacetylase inhibitor vorinostat, in combination with nuclear receptor ligands. Such treatments revealed strong-additive interactions toward the PPARgamma, VDR and Farnesoid X-activated receptors. Genome-wide microarray and microfluidic quantitative real-time, reverse transcription-polymerase chain reaction approaches, following the targeting of NCOR1 activity and expression, revealed the selective capacity of this corepressor to govern common transcriptional events of underlying networks. Combined these findings suggest that NCOR1 is a selective regulator of nuclear receptors, notably PPARgamma and VDR, and contributes to their loss of sensitivity. Combinations of epigenetic therapies that target NCOR1 may prove effective, even when receptor expression is reduced.
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Preclinical evidence suggests that metformin could delay cancer progression. Previous epidemiological studies however have been limited by small sample sizes and certain time-related biases. This study aimed to investigate whether colorectal cancer patients with type 2 diabetes who were exposed to metformin had reduced cancer-specific mortality. We conducted a retrospective cohort study of 1,197 colorectal cancer patients newly diagnosed from 1998 to 2009 (identified from English cancer registries) with type 2 diabetes (based upon Clinical Practice Research Datalink, CPRD, prescription and diagnosis records). In this cohort 382 colorectal cancer-specific deaths occurred up to 2012 from the Office of National Statistics (ONS) mortality data. Metformin use was identified from CPRD prescription records. Using time-dependent Cox regression models, unadjusted and adjusted hazard ratios (HR) and 95% CIs were calculated for the association between post-diagnostic exposure to metformin and colorectal cancer-specific mortality. Overall, there was no evidence of an association between metformin use and cancer-specific death before or after adjustment for potential confounders (adjusted HR 1.06, 95% CI 0.80, 1.40). In addition, after adjustment for confounders, there was also no evidence of associations between other diabetic medications and cancer-specific mortality including sulfonylureas (HR 1.14, 95% CI 0.86, 1.51), insulin use (HR 1.35, 95% CI 0.95, 1.93) or other anti-diabetic medications including thiazolidinediones (HR 0.73, 95% CI 0.46, 1.14). Similar associations were observed by duration of use and for all-cause mortality. This population-based study, the largest to date, does not support a protective association between metformin and survival in colorectal cancer patients.
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The inflammatory response to pulpal injury or infection has major clinical significance. Neurogenic inflammation describes the local release of neuropeptides, notably substance P (SP), from afferent neurones, and may play a role in the pathogenesis of pulpal disease. The fibroblast is the most numerous cell type in the dental pulp and recent work has suggested that it is involved in the inflammatory response. Objectives: The aims of the study were to determine whether pulp fibroblasts could produce SP, and to investigate the expression of the SP receptor, NK-1, by these cells. Methods: Primary pulp fibroblast cell populations were isolated by enzymatic digestion from non-carious teeth extracted for orthodontic reasons. Whole pulp tissue was obtained from freshly extracted sound (n=35) and carious (n=39) teeth. Expression of SP and NK-1 mRNA was determined by RT-PCR. The effects of interleukin-1β (IL-1β) and transforming growth factor-β1 (TGF-β1) on SP and NK-1 expression were also determined. The presence of NK-1 on fibroblast cell membranes was established by western blotting. The effects of the cytokines on each parameter were analysed by ANOVA. Radioimmunoassay (RIA) was carried out to quantify SP expression by pulp fibroblasts and in whole pulp tissue. Results: SP was expressed by pulpal fibroblasts both at the mRNA level and the protein level. In addition, NK-1 was detected in fibroblast cultures at the mRNA level and appeared as a double band on western blots of membrane extracts. IL-1β and TGF-β1 significantly stimulated the expression of SP and NK-1. SP levels were significantly greater (p<0.05) in carious compared to sound teeth. Conclusion: Pulp fibroblasts are capable of synthesising and secreting SP, as well as expressing the SP receptor, NK-1. These findings suggest that pulp fibroblasts play a role in neurogenic inflammation in pulpal disease. (Supported by the European Society of Endodontology.)
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La cellule utilise des nœuds d’interactions protéiques relativement stables, conservés et souvent constitués d’adaptateurs moléculaires pour gérer des signaux reçus (synthèse, sécrétion, traffic, métabolisme, division), des problèmes de sécurité et de niveaux d’énergie. Nos résultats montrent que la cellule utilise aussi des nœuds relativement petits et dynamiques où des informations propres concernant des voies métaboliques apparemment indépendantes sont évaluées. Ces informations y sont intégrées localement et une décision y est prise pour action immédiate. Cette idée est supportée par notre étude sur le récepteur de l’insuline (RI). Ce récepteur transmembranaire à activité tyrosine kinase reconnaît un signal externe (insuline circulante) et engage la signalisation de l’insuline, les réponses métaboliques et le contrôle du glucose circulant. Le RI est aussi impliqué dans l’internalisation de l’insuline et sa dégradation dans les endosomes (clairance). Il régule donc indirectement la sécrétion de l’insuline par les cellules du pancréas endocrine. La signification pathophysiologique de l’endocytose du RI ainsi que les bases moléculaires d’une telle coordination sont peu connues. Nous avons construit un réseau d’interactions du RI (IRGEN) à partir d’un protéome de fractions Golgi-endosomales (G/E) hépatiques. Nous démontrons une forte hétérogénéité fonctionnelle autour du RI avec la présence des protéines ATIC, PTPLAD1, AMPKα et ANXA2. ANXA2 est une protéine impliquée dans la biogénèse et le transport endosomal. Nos résultats identifient un site de SUMOylation régulé par l’insuline dans sa région N-terminale. ATIC est une enzyme de la voie de synthèse des purines de novo dont le substrat AICAR est un activateur de l’AMPKα. Des analyses biochimiques in vitro et in vivo nous montrent que ATIC favorise la tyrosine phosphorylation du RI par opposition fonctionnelle à PTPLAD1. Une délétion partielle d’ATIC stimule l’activation de l’AMPK dont la sous-unité AMPKα2 apparaît déterminante pour le trafic du RI. Nous démontrons que ATIC, PTPLAD1, AMPKα, AICAR et ANXA2 contrôlent l’endocytose du RI à travers le cytosquelette d’actine et le réseau de microtubules. Nous ressortons un nœud de signalisation (ATIC, PTPLAD1, AMPKα) capable de détecter les niveaux d’activation du RI, d’énergie cellulaires (rapports AMP/ATP) et aussi d’agir sur la signalisation et l’endocytose du RI. Cette proximité moléculaire expliquerait le débat sur le mécanisme primaire du diabète de type 2 (DT2), notamment entre la sensibilité à l’insuline et sa clairance. Nous avons calculé un enrichissement de 61% de variants communs du DT2 parmi les protéines fonctionnellement proches du RI incluant RI, ATIC, AMPKα, KIF5A et GLUT2. Cet enrichissement suggère que l’hétérogénéité génétique révélée par les consortiums sur études génomiques (GWAS) converge vers des mécanismes peu étudiés de biologie cellulaire.
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Transcriptional coregulators control the activity of many transcription factors and are thought to have wide-ranging effects on gene expression patterns. We show here that muscle-specific loss of nuclear receptor corepressor 1 (NCoR1) in mice leads to enhanced exercise endurance due to an increase of both muscle mass and of mitochondrial number and activity. The activation of selected transcription factors that control muscle function, such as MEF2, PPARβ/δ, and ERRs, underpins these phenotypic alterations. NCoR1 levels are decreased in conditions that require fat oxidation, resetting transcriptional programs to boost oxidative metabolism. Knockdown of gei-8, the sole C. elegans NCoR homolog, also robustly increased muscle mitochondria and respiration, suggesting conservation of NCoR1 function. Collectively, our data suggest that NCoR1 plays an adaptive role in muscle physiology and that interference with NCoR1 action could be used to improve muscle function.