Truncation of Pik3r1 causes severe insulin resistance uncoupled from obesity and dyslipidaemia by increased energy expenditure.

ABSTRACT:

Objective

Insulin signalling via phosphoinositide 3-kinase (PI3K) requires PIK3R1-encoded regulatory subunits. C-terminal PIK3R1 mutations cause SHORT syndrome, as well as lipodystrophy and insulin resistance (IR), surprisingly without fatty liver or metabolic dyslipidaemia. We sought to investigate this discordance.

Methods

The human pathogenic Pik3r1 Y657^∗ mutation was knocked into mice by homologous recombination. Growth, body composition, bioenergetic and metabolic profiles were investigated on chow and high-fat diet (HFD). We examined adipose and liver histology, and assessed liver responses to fasting and refeeding transcriptomically.

Results

Like humans with SHORT syndrome, Pik3r1^WT/Y657∗ mice were small with severe IR, and adipose expansi

SUBMITTER: Kwok A 

PROVIDER: S-EPMC7385515 | biostudies-literature | 2020 Oct

REPOSITORIES: biostudies-literature