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

•SHORT syndrome features insulin resistance and reduced adiposity without dyslipidaemia and fatty liver.•A mouse model with a pathogenic human PI 3-Kinase mutation recapitulates this uncoupling.•Surprisingly, no adipose injury nor increased liver de novo lipogenesis is seen.•Energy expenditure is increased, causing resistance to diet-induced obesity.•This increases evidence for some beneficial metabolic effects of PI 3-Kinase inhibition.