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

Albert Kwok,Ilona Zvetkova,Sam Virtue,Ineke Luijten,Isabel Huang-Doran,Patsy Tomlinson,David A Bulger,James West,Steven Murfitt,Julian Griffin,Rafeah Alam,Daniel Hart,Rachel Knox,Peter Voshol,Antonio Vidal-Puig,Jørgen Jensen,Stephen O'Rahilly,Robert K Semple

doi:10.1016/j.molmet.2020.101020

Abstract

ObjectiveInsulin 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. MethodsThe 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. ResultsLike 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. ConclusionsPik3r1 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.

Highlights

Adipose tissue is essential for metabolic health in the face of sustained positive energy balance
SHORT syndrome is a human monogenic syndrome including lipodystrophy [3e5]. This form of lipodystrophy is highly unusual - though associated with insulin resistant diabetes [3e5], this is uncoupled from fatty liver and dyslipidaemia [6]
We report a novel murine SHORT syndrome model caused by a human pathogenic allele, Y657*, that reproduces uncoupling of metabolic dyslipidaemia from severe Insulin resistance (IR)

Summary

Introduction

Adipose tissue is essential for metabolic health in the face of sustained positive energy balance. Injury and inflammation of any residual adipose tissue ensues, causing systemic inflammation and rerouting substrates to the liver, pancreas and muscle. Insulin resistance (IR), diabetes, aggressive fatty liver disease, and severely elevated plasma lipoprotein concentrations are common consequences of lipodystrophy [2]. SHORT syndrome (short stature, hyperextensibility of joints, ocular depression, Rieger anomaly of the iris, and teething delay) is a human monogenic syndrome including lipodystrophy [3e5]. This form of lipodystrophy is highly unusual - though associated with insulin resistant diabetes [3e5], this is uncoupled from fatty liver and dyslipidaemia [6]. SHORT syndrome does not feature the suppressed plasma adiponectin concentration commonly seen in IR and other

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