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

Mol Metab. 2020 Oct:40:101020. doi: 10.1016/j.molmet.2020.101020. Epub 2020 May 19.


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, Pik3r1WT/Y657∗ mice were small with severe IR, and adipose expansion on HFD was markedly reduced. Also as in humans, plasma lipid concentrations were low, and insulin-stimulated hepatic lipogenesis was not increased despite hyperinsulinemia. At odds with lipodystrophy, however, no adipocyte hypertrophy nor adipose inflammation was found. Liver lipogenic gene expression was not significantly altered, and unbiased transcriptomics showed only minor changes, including evidence of reduced endoplasmic reticulum stress in the fed state and diminished Rictor-dependent transcription on fasting. Increased energy expenditure, which was not explained by hyperglycaemia nor intestinal malabsorption, provided an alternative explanation for the uncoupling of IR from dyslipidaemia.

Conclusions: Pik3r1 dysfunction in mice phenocopies the IR and reduced adiposity without lipotoxicity of human SHORT syndrome. Decreased adiposity may not reflect bona fide lipodystrophy, but rather, increased energy expenditure, and we suggest that further study of brown adipose tissue in both humans and mice is warranted.

Keywords: Diabetes; Insulin resistance; Lipids; Lipotoxicity; PI 3-Kinase; Pik3r1; p85.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adipose Tissue, Brown / metabolism
  • Adiposity
  • Animals
  • Class Ia Phosphatidylinositol 3-Kinase / genetics*
  • Class Ia Phosphatidylinositol 3-Kinase / metabolism
  • Diet, High-Fat
  • Dyslipidemias / genetics
  • Energy Metabolism / genetics
  • Fatty Liver / metabolism
  • Growth Disorders / genetics
  • Growth Disorders / metabolism*
  • Hypercalcemia / genetics
  • Hypercalcemia / metabolism*
  • Inflammation / metabolism
  • Insulin / metabolism
  • Insulin Resistance / genetics*
  • Lipogenesis
  • Liver / metabolism
  • Male
  • Metabolic Diseases / genetics
  • Metabolic Diseases / metabolism*
  • Mice
  • Mice, Inbred C57BL
  • Nephrocalcinosis / genetics
  • Nephrocalcinosis / metabolism*
  • Obesity / genetics
  • Phosphatidylinositol 3-Kinases / genetics
  • Phosphatidylinositol 3-Kinases / metabolism


  • Insulin
  • Class Ia Phosphatidylinositol 3-Kinase
  • Pik3r1 protein, mouse

Supplementary concepts

  • SHORT syndrome