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PGC1A regulates the IRS1:IRS2 ratio during fasting to influence hepatic metabolism downstream of insulin.

ABSTRACT: Precise modulation of hepatic glucose metabolism is crucial during the fasting and feeding cycle and is controlled by the actions of circulating insulin and glucagon. The insulin-signaling pathway requires insulin receptor substrate 1 (IRS1) and IRS2, which are found to be dysregulated in diabetes and obesity. The peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC1A) is a fasting-induced transcriptional coactivator. In nonalcoholic fatty liver disease and in patients with type 2 diabetes, low hepatic PGC1A levels are associated with insulin resistance. However, how PGC1A activity impacts the hepatic insulin-signaling pathway is still unclear. We used gain- and loss-of-function models in mouse primary hepatocytes and measured hepatocyte insulin response by gene and protein expression and ex vivo glucose production. We found that the PGC1A level determines the relative ratio of IRS1 and IRS2 in hepatocytes, impacting insulin receptor signaling via protein kinase B/AKT (AKT). PGC1A drove the expression of IRS2 downstream of glucagon signaling while simultaneously reducing IRS1 expression. We illustrate that glucagon- or PGC1A-induced IRS2 expression was dependent on cAMP Response Element Binding Protein activity and that this was essential for suppression of hepatocyte gluconeogenesis in response to insulin in vitro. We also show that increased hepatic PGC1A improves glucose homeostasis in vivo, revealing a counterregulatory role for PGC1A in repressing uncontrolled glucose production in response to insulin signaling. These data highlight a mechanism by which PGC1A plays dual roles in the control of gluconeogenesis during the fasting-to-fed transition through regulated balance between IRS1 and IRS2 expression.

SUBMITTER: Besse-Patin A

PROVIDER: S-EPMC6410797 | biostudies-literature | 2019 Mar

REPOSITORIES: biostudies-literature

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PGC1A regulates the IRS1:IRS2 ratio during fasting to influence hepatic metabolism downstream of insulin.

Besse-Patin Aurèle A Jeromson Stewart S Levesque-Damphousse Philipa P Secco Blandine B Laplante Mathieu M Estall Jennifer L JL

Proceedings of the National Academy of Sciences of the United States of America 20190215 10

Precise modulation of hepatic glucose metabolism is crucial during the fasting and feeding cycle and is controlled by the actions of circulating insulin and glucagon. The insulin-signaling pathway requires insulin receptor substrate 1 (IRS1) and IRS2, which are found to be dysregulated in diabetes and obesity. The peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC1A) is a fasting-induced transcriptional coactivator. In nonalcoholic fatty liver disease and in patients with ...[more]

PMID: 30770439

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Project description:BackgroundType 2 diabetes (T2D) is a high-risk factor for incident of cardiovascular diseases. Women at young ages show a reduced incidence of both T2D and cardiovascular diseases compared with men, but these disparities disappear in postmenopausal women versus age-matched men. Thus, ovaries and ovarian hormones, such as estrogen, are expected to protect from T2D and cardiovascular diseases. In this study, we aimed to investigate the role of ovaries and ovarian hormone estrogen in cardiac function and energy metabolism using the cardiac IRS (insulin receptor substrate) 1 and IRS2 double genes knockout mice that mimic cardiac insulin resistance.MethodsControl and heart-specific IRS1/2 double genes knockout mice were treated with placebo or 17β-estradiol (E2) pellets, respectively, through subcutaneous implantation. Female mice were subjected to a bilateral ovariectomy surgery to remove endogenous E2. The cardiac function and energy metabolism were determined using echocardiography and indirect calorimeter, respectively.ResultsAll male heart-specific IRS1/2 double genes knockout mice died of heart failure at 6 to 8 weeks as we previously described (Qi et al), but all female heart-specific IRS1/2 double genes knockout mice survived >1 year. Removal of ovaries in heart-specific IRS1/2 double genes knockout female mice resulted in cardiac dysfunction, and ultimately animal death. However, E2 supplementation prevented the dilated cardiomyopathy, improved cardiac function and energy metabolism, and enhanced lifespan in both male and ovariectomy female mice deficient for cardiac IRS1 and IRS2 genes, largely owing to the activation of Akt (protein kinase B)-Foxo1 (O1 class of forkhead/winged helix transcription factor) signaling cascades.ConclusionsThese results show that estrogen protects mice from cardiac insulin resistance-induced diabetic cardiomyopathy. This may provide a fundamental mechanism for the gender difference for the incidence of both T2D and cardiovascular diseases. This study highlights that estrogen signaling could be a potential target for improving cardiac function and energy metabolism in humans with T2D.

Project description:Insulin receptor substrate (IRS) proteins are cytoplasmic adaptors that transmit the signal from the IR and insulin-like growth factor-1 receptor to effector proteins. Overexpression of IRS proteins has been indicated to be linked to cancer development. In addition to their expression profiles, studies have indicated that polymorphisms of IRS1 and IRS2 are also associated with the susceptibility to numerous cancer types. IRS1 Gly972Arg and IRS2 Gly1057Asp are the common variants of these genes. The present study aimed to determine the association of IRS1 Gly972Arg and IRS2 Gly1057Asp polymorphisms with gastric cancer development. The study included 100 patients with gastric cancer and 100 controls. Single-nucleotide polymorphisms were detected by real-time PCR using Taqman assays. The results suggested that in individuals with the IRS1 Gly/Arg genotype, the odds of having gastric cancer was increased by 7.891-fold (95% CI: 3.251-19.154, P<0.001) and in individuals with the IRS1 Arg/Arg genotype, it was increased by 22.716-fold (95% CI: 6.311-81.761, P<0.001) compared with those with the IRS1 Gly/Gly genotype. Although the IRS2 Gly1057Asp genotype analysis suggested that subjects with the Asp/Asp genotype had a 2,311-fold increased odds of having gastric cancer compared to those with the Gly/Gly genotype, the result was not statistically significant (95% CI: 0.800-6.678, P=0.122). The combined effects of the IRS1 and IRS2 variants on gastric cancer were also determined. The results suggested that individuals with Gly/Arg+Gly/Asp and Gly/Arg+Asp/Asp genotypes had a higher odds of having gastric cancer compared to individuals of the Gly/Gly+Gly/Gly genotype (P=0.001 and P=0.027, respectively). In conclusion, the present results suggested that the IRS1 Gly972Arg and IRS2 Gly1057Asp variations may be associated with an increased susceptibility to develop gastric cancer. Further studies with larger sample sizes are required to support the present results and to explore the use of these variations as a biomarker for gastric cancer.

Project description:Aim and objectiveThe aim of the study was to investigate the relationships between insulin receptor substrate (IRS) 1 (Gly972Arg) and IRS2 (Gly1057Asp) genes with obstructive sleep apnea (OSA) and non-alcoholic fatty liver disease (NAFLD) in Asian Indians.MethodA total of 410 overweight/obese subjects (130 with OSA with NAFLD, 100 with OSA without NAFLD, 95 without OSA and with NAFLD and 85 without OSA and without NAFLD) were recruited. Degree of NAFLD was based on liver ultrasound and of OSA on overnight polysomnography. Genotyping was performed by polymerase chain reaction-restriction fragment length polymorphism and confirmed by gene sequencing.ResultMean values of blood pressure, body fat markers, blood glucose, lipids, liver function, and markers of insulin resistance were significantly increased in OSA and NAFLD subjects (p<0.05). In addition, according to age (years) categories, blood pressure, blood glucose, lipids, obesity markers, and markers of insulin resistance were significantly higher in 45-60 years group as compared to 20-45 years group (p<0.05). In IRS1 gene, the genotype frequency (%) of Arg/Arg was significantly higher in NAFLD and OSA subjects. In addition, Gly/Arg genotype of IRS1 gene was associated with significantly higher body mass index, fat mass, %body fat, triglycerides, cholesterol, alkaline phosphate, aspartate transaminase, fasting insulin and HOMA-IR levels in OSA and NAFLD subjects. No significant difference in genotype frequencies of IRS2 was observed between four groups. Further we found that subjects carrying IRS1 Gly/Arg (OR 4.49, 95% C.I. 1.06-12.52, p = 0.002) genotype possess a much higher risk of OSA and NAFLD compared to IRS2 Gly/Asp (OR 1.01, 95% C.I. 0.8-2.56, p = 0.05). In sub group analysis of IRS1 Gly/Arg have significant differences between the mild, moderate and severe group (P<0.05). In addition, patients with the 'Gly' allele were inclined to develop more severe OSA.ConclusionWe concluded that Asian Indian subject carrying the allele Gly972Arg polymorphism of IRS1 is predisposed to develop OSA and NAFLD.

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PGC1A regulates the IRS1:IRS2 ratio during fasting to influence hepatic metabolism downstream of insulin.

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PGC1A regulates the IRS1:IRS2 ratio during fasting to influence hepatic metabolism downstream of insulin.

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