Project Details
Projekt
The role of WT1 in adipose tissue development and homeostasis
Subject Area
Anatomy and Physiology
Term
since 2024
Project identifier
Deutsche Forschungsgemeinschaft (DFG) - Project number 539946993
Two types of adipose tissue exist in the body: White adipose tissue (WAT) with the main function of storing energy in the form of triglycerides, and brown adipose tissue (BAT), which fuels energy expenditure by non-shivering thermogenesis. Heat production in brown fat cells involves uncoupling protein-1 (UCP1), a pore-forming molecule in the inner mitochondrial membrane. UCP1 dissociates H+-fluxes from ATP synthesis, which allows energy to dissipate as heat. Stimuli such as chronic cold exposure and β3-adrenergic agonists can induce the appearance so-called “beige” adipocytes with thermogenic capacity in classical WAT. This phenomenon, which is known as “browning” has received strong attention because of its potential application in reducing excessive body weight and tackling metabolic disorder. Our recent findings indicate that Wilms tumor protein WT1 suppresses WAT browning in visceral (intra-abdominal) fat. Thus, heterozygous Wt1 knockout mice show molecular and morphological signs of browning in their visceral WAT including expression of UCP1 and other thermogenic molecules. Consistently, overexpression of WT1 reduces thermogenic mRNAs in differentiating preadipocytes from murine interscapular BAT. The transcription factor WT1 was initially identified as a suppressor of kidney cancer in children. WT1 is necessary for normal development of the genitourinary system and several other tissues. Homozygous disruption of Wt1 in mice causes embryonic lethality. Wt1 is expressed in progenitor cells (preadipocytes) in visceral WAT, but not in differentiated adipocytes. Ubiquitous Wt1 deletion in adult mice causes atrophy of this fat depot and multiple organ failure. Our recent findings indicate that heterozygous Wt1 knockout mice exhibit significantly better whole-body glucose tolerance and lesser hepatic lipid accumulation under high-fat diet than their wild-type littermates. Improved metabolic function is also seen in other genetic mouse models of WAT browning. This leads us to hypothesize that better metabolic health of heterozygous Wt1 knockout mice under high-fat diet is due to expression of Ucp1 and other thermogenic genes in their visceral WAT. The overall purpose of this project is to clarify the function of WT1 in visceral WAT. We will generate mice with conditional WT1 loss in adipose progenitor cells to investigate (i) whether WT1 is necessary for normal formation of visceral WAT, (ii) whether lack of WT1 in visceral WAT affects the physiological response of mice to metabolic stress, and if so (iii) whether the developmental stage of conditional Wt1 deletion is relevant to this effect. Furthermore, by combining CRISPR/Cas9 genome-editing with RNA sequencing and chromatin immunoprecipitation (ChIP) sequencing we will identify downstream target genes of WT1 in preadipocytes. The expected insights can be useful for the development and implementation of novel therapeutic targeting strategies to combat metabolic disease.
DFG Programme
Research Grants
