C-terminal truncation of Pik3r1 in mice models human lipodystrophic insulin resistance uncoupled from dyslipidemia

Abstract

SummaryHeterodimeric class IA phosphatidylinositol-3-kinases (PI3K) transduce signals from many receptor tyrosine kinases including the insulin receptor. PI3K recruitment to phosphotyrosines is mediated by Pik3r1 gene products including the most intensely studied PI3K regulatory subunit, p85α, which also binds and regulates the PIP3 phosphatase Pten, and the lipogenic transcription factor Xbp1. Mutations in human PIK3R1 cause SHORT syndrome, featuring lipodystrophy and severe insulin resistance which, uniquely, are uncoupled from fatty liver and dyslipidemia. We describe a novel mouse model of SHORT syndrome made by knock in of the Pik3r1 Y657X mutation. Homozygous embryos die at E11.5, while heterozygous mice exhibit pre-and postnatal growth impairment with diminished placental vascularity. Adipose tissue accretion on high fat feeding was reduced, however adipocyte size was unchanged and preadipocyte differentiation ex vivo unimpaired. Despite severe insulin resistance, heterozygous mice were hypolipidemic, and plasma adiponectin, liver weight, cholesterol, glycogen and triglyceride content were unchanged. Mild downregulation of lipogenic Srebp1, Srebp2 and Chrebp transcriptional activity but no suppression of Xbp1 target genes was seen after fasting. These findings give new insights into the developmental role of Pik3r1, and establish a model of lipodystrophic insulin resistance dissociated from dyslipidemia as seen in SHORT syndrome.

Analysis of Methylome, Transcriptome, and Lipid Metabolites to Understand the Molecular Abnormalities in Polycystic Ovary Syndrome

“…The PIK3R1 gene encodes the 85-kD phosphoinositide-3-kinase regulatory region, which was identified as a potential pathogenic variant in PCOS and accompanied by severe insulin resistance, lipodystrophy, and obesity. [36][37][38] NECTIN2 is a nectin cell adhesion molecule 2 associated with lipid-protein, was reported to be a novel marker in carotid atherosclerosis progression; 39 with PCOS are likely to feature signs of atherosclerosis. 40 TSC2, which encodes for the growth protein tuberin, is activated by AMP-activated protein kinase to promote catabolic activities, and its physiological effect is consistent with insulin resistance in PCOS.…”