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Mice Carrying a Dominant-Negative Human PI3K Mutation Are Protected From Obesity and Hepatic Steatosis but Not Diabetes.

ABSTRACT: Phosphatidylinositol 3-kinase (PI3K) plays a central role in insulin signaling, glucose metabolism, cell growth, cell development, and apoptosis. A heterozygous missense mutation (R649W) in the p85? regulatory subunit gene of PI3K (PIK3R1) has been identified in patients with SHORT (Short stature, Hyperextensibility/Hernia, Ocular depression, Rieger anomaly, and Teething delay) syndrome, a disorder characterized by postnatal growth retardation, insulin resistance, and partial lipodystrophy. Knock-in mice with the same heterozygous mutation mirror the human phenotype. In this study, we show that Pik3r1 R649W knock-in mice fed a high-fat diet (HFD) have reduced weight gain and adipose accumulation. This is accompanied by reduced expression of several genes involved in lipid metabolism. Interestingly, despite the lower level of adiposity, the HFD knock-in mice are more hyperglycemic and more insulin-resistant than HFD-fed control mice. Likewise, when crossed with genetically obese ob/ob mice, the ob/ob mice carrying the heterozygous R649W mutation were protected from obesity and hepatic steatosis but developed a severe diabetic state. Together, our data demonstrate a central role of PI3K in development of obesity and fatty liver disease, separating these effects from the role of PI3K in insulin resistance and the resultant hyperglycemia.

SUBMITTER: Solheim MH

PROVIDER: S-EPMC6014554 | biostudies-literature | 2018 Jul

REPOSITORIES: biostudies-literature

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Mice Carrying a Dominant-Negative Human PI3K Mutation Are Protected From Obesity and Hepatic Steatosis but Not Diabetes.

Solheim Marie H MH Winnay Jonathon N JN Batista Thiago M TM Molven Anders A Njølstad Pål R PR Kahn C Ronald CR

Diabetes 20180503 7

Phosphatidylinositol 3-kinase (PI3K) plays a central role in insulin signaling, glucose metabolism, cell growth, cell development, and apoptosis. A heterozygous missense mutation (R649W) in the p85α regulatory subunit gene of PI3K (<i>PIK3R1</i>) has been identified in patients with SHORT (Short stature, Hyperextensibility/Hernia, Ocular depression, Rieger anomaly, and Teething delay) syndrome, a disorder characterized by postnatal growth retardation, insulin resistance, and partial lipodystroph ...[more]

PMID: 29724723

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Project description:OBJECTIVE:The nuclear receptor TAK1/TR4/NR2C2 is expressed in several tissues that are important in the control of energy homeostasis. In this study, we investigate whether TAK1 functions as a regulator of lipid and energy homeostasis and has a role in metabolic syndrome. RESEARCH DESIGN AND METHODS:We generated TAK1-deficient (TAK1?(/)?) mice to study the function of TAK1 in the development of metabolic syndrome in aged mice and mice fed a high-fat diet (HFD). (Immuno)histochemical, biochemical, and gene expression profile analyses were performed to determine the effect of the loss of TAK1 expression on lipid homeostasis in liver and adipose tissues. In addition, insulin sensitivity, energy expenditure, and adipose-associated inflammation were compared in wild-type (WT) and TAK1?(/)? mice fed a HFD. RESULTS:TAK1-deficient (TAK1?(/)?) mice are resistant to the development of age- and HFD-induced metabolic syndrome. Histo- and biochemical analyses showed significantly lower hepatic triglyceride levels and reduced lipid accumulation in adipose tissue in TAK1?(/)? mice compared with WT mice. Gene expression profiling analysis revealed that the expression of several genes encoding proteins involved in lipid uptake and triglyceride synthesis and storage, including Cidea, Cidec, Mogat1, and CD36, was greatly decreased in the liver and primary hepatocytes of TAK1?(/)? mice. Restoration of TAK1 expression in TAK1?(/)? hepatocytes induced expression of several lipogenic genes. Moreover, TAK1?(/)? mice exhibited reduced infiltration of inflammatory cells and expression of inflammatory genes in white adipose tissue, and were resistant to the development of glucose intolerance and insulin resistance. TAK1?(/)? mice consume more oxygen and produce more carbon dioxide than WT mice, suggesting increased energy expenditure. CONCLUSIONS:Our data reveal that TAK1 plays a critical role in the regulation of energy and lipid homeostasis, and promotes the development of metabolic syndrome. TAK1 may provide a new therapeutic target in the management of obesity, diabetes, and liver steatosis.

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Dataset Information

Mice Carrying a Dominant-Negative Human PI3K Mutation Are Protected From Obesity and Hepatic Steatosis but Not Diabetes.

Publications

Mice Carrying a Dominant-Negative Human PI3K Mutation Are Protected From Obesity and Hepatic Steatosis but Not Diabetes.

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