Peroxisome Proliferator-Activated Receptor γ2 Controls the Rate of Adipose Tissue Lipid Storage and Determines Metabolic Flexibility

Sam Virtue,Kasparas Petkevicius,José Maria Moreno-Navarrete,Benjamin Jenkins,Daniel Hart,Martin Dale,Albert Koulman,José Manuel Fernández-Real,Antonio Vidal-Puig

doi:10.1016/j.celrep.2018.07.063

Abstract

SummaryOne understudied function of white adipose tissue (AT) is its role in postprandial lipid buffering. In this study, we demonstrate that mice lacking the adipose tissue-specific transcription factor peroxisome proliferator-activated receptor γ2 (PPARγ2) exhibit a defect in their rate of adipose tissue lipid storage. Impaired adipose tissue storage rate reduces metabolic flexibility, without compromising fasted glucose tolerance or insulin sensitivity, even following prolonged high-fat feeding. However, acutely overfeeding PPARγ2-KO mice caused a 10-fold increase in insulin levels compared with controls. Although impaired adipose tissue storage rate did not result in insulin resistance in young mice, 1-year-old PPARγ2-KO mice developed skeletal muscle insulin resistance. Our data indicate that failed adipose tissue storage may occur prior to defects in glucose handling and that overfeeding protocols may uncover genes controlling adipose tissue storage rate, as opposed to capacity, and act as a diagnostic test for early-stage human metabolic disease.

Highlights

The epidemic of obesity has led to epidemics of diabetes and cardiovascular disease
The adipose tissue expansion hypothesis suggests that metabolic complications occur when an individual’s adipose tissue storage capacity is exceeded (Virtue and Vidal-Puig, 2010), that preventing adipose tissue expansion will worsen metabolic complications (Danforth, 2000), whereas unlimited adipose tissue expansion would be metabolically protective, a concept demonstrated in mice (Kim et al, 2007)
We demonstrate that, in line with a potential acute metabolic role for peroxisome proliferator-activated receptor g2 (PPARg2) in adipocytes, PPARg2 but not PPARg1 correlates with wholebody and adipose tissue insulin sensitivity in humans

Summary

Introduction

The epidemic of obesity has led to epidemics of diabetes and cardiovascular disease. An important question is how obesity leads to metabolic complications. A proposed mechanism linking obesity to metabolic complications is the concept of adipose tissue (AT) expansion and lipotoxicity. We previously reported (Medina-Gomez et al, 2005) the phenotype of mice lacking peroxisome proliferator-activated receptor g2 (PPARg2). PPARg2 is the adipose tissue-specific isoform of PPARg. Surprisingly, despite defective adipogenesis in vitro, mice lacking PPARg2 had normal adipocyte size on a chow diet (Medina-Gomez et al, 2005), as well as normal glucose and insulin tolerance on chow or chronic high-fat (3 months of feeding) diets. Defects in insulin sensitivity in POKO mice occurred before any divergence in adiposity between genotypes (Medina-Gomez et al, 2007). The early onset of metabolic impairments in POKO mice raised the question as to which aspect of leptin deficiency was driving the phenotypic divergence. Why PPARg2-KO mice on a non-obese background were metabolically healthy was unresolved

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