Wt1 haploinsufficiency induces browning of epididymal fat and alleviates metabolic dysfunction in mice on high-fat diet

Karin M Kirschner,Tim J Schulz,Chen Li,Anna Foryst-Ludwig,Ulrich Kintscher,Roberto E Flores,Michael Schupp,Holger Scholz,Sabrina Gohlke

doi:10.1007/s00125-021-05621-1

Abstract

Aims/hypothesisDespite a similar fat storing function, visceral (intra-abdominal) white adipose tissue (WAT) is detrimental, whereas subcutaneous WAT is considered to protect against metabolic disease. Recent findings indicate that thermogenic genes, expressed in brown adipose tissue (BAT), can be induced primarily in subcutaneous WAT. Here, we investigate the hypothesis that the Wilms tumour gene product (WT1), which is expressed in intra-abdominal WAT but not in subcutaneous WAT and BAT, suppresses a thermogenic program in white fat cells.MethodsHeterozygous Wt1 knockout mice and their wild-type littermates were examined in terms of thermogenic and adipocyte-selective gene expression. Glucose tolerance and hepatic lipid accumulation in these mice were assessed under normal chow and high-fat diet conditions. Pre-adipocytes isolated from the stromal vascular fraction of BAT were transduced with Wt1-expressing retrovirus, induced to differentiate and analysed for the expression of thermogenic and adipocyte-selective genes.ResultsExpression of the thermogenic genes Cpt1b and Tmem26 was enhanced and transcript levels of Ucp1 were on average more than tenfold higher in epididymal WAT of heterozygous Wt1 knockout mice compared with wild-type mice. Wt1 heterozygosity reduced epididymal WAT mass, improved whole-body glucose tolerance and alleviated severe hepatic steatosis upon diet-induced obesity in mice. Retroviral expression of WT1 in brown pre-adipocytes, which lack endogenous WT1, reduced mRNA levels of Ucp1, Ppargc1a, Cidea, Prdm16 and Cpt1b upon in vitro differentiation by 60–90%. WT1 knockdown in epididymal pre-adipocytes significantly lowered Aldh1a1 and Zfp423 transcripts, two key suppressors of the thermogenic program. Conversely, Aldh1a1 and Zfp423 mRNA levels were increased approximately five- and threefold, respectively, by retroviral expression of WT1 in brown pre-adipocytes.Conclusion/interpretationWT1 functions as a white adipocyte determination factor in epididymal WAT by suppressing thermogenic genes. Reducing Wt1 expression in this and other intra-abdominal fat depots may represent a novel treatment strategy in metabolic disease.Graphical abstract

Highlights

Obesity has emerged as a global health problem that increases the prevalence of many life-shortening disorders including type 2 diabetes, cardiovascular disease, chronic kidney disease and cancer [1, 2]
The classical brown adipose tissue (BAT) fuels energy expenditure by non-shivering thermogenesis [5, 6]. This involves uncoupling protein-1 (UCP1), which dissociates H+ fluxes into the mitochondrial matrix from ATP synthesis, allowing energy to dissipate as heat [7]
WT1 suppresses thermogenic genes in differentiating brown precursor cells WT1 protein was detected in epididymal white adipose tissue (WAT) but neither in inguinal WAT nor in interscapular BAT (Fig. 1a) [15, 28]

Summary

Introduction

Obesity has emerged as a global health problem that increases the prevalence of many life-shortening disorders including type 2 diabetes, cardiovascular disease, chronic kidney disease and cancer [1, 2]. Lipid accumulation in visceral (intra-abdominal) white adipose tissue (WAT) coincides with increased mortality, even in individuals with normal BMI, whereas subcutaneous obesity is less detrimental [3, 4]. At least two types of brown adipocytes exist besides the energy-storing white fat cells. The classical brown adipose tissue (BAT) fuels energy expenditure by non-shivering thermogenesis [5, 6]. This involves uncoupling protein-1 (UCP1), which dissociates H+ fluxes into the mitochondrial matrix from ATP synthesis, allowing energy to dissipate as heat [7]. A population of brown adipocytes exist in WAT, the so-called beige or brite (brown-in-white) adipocytes, which normally express much lower levels of UCP1 than classical brown fat cells [8,9,10]. The appearance of visceral fat-like features in Prdm16-deficient subcutaneous adipocytes is indicated by their reduced thermogenic and enforced proinflammatory gene expression pattern [13]

Methods

Results

Conclusion