Deletion of Trim28 in committed adipocytes promotes obesity but preserves glucose tolerance

Simon T Bond,Anna C Calkin,Christine Yang,Adrian Tran,Yingying Liu,Emily J King,Natalie A Mellett,Peter J Meikle,Michael Inouye,Sarah C Moody,Darren C Henstridge,Brian G Drew,Artika P Nath,Thomas Q De Aguiar Vallim,Elizabeth J Tarling

doi:10.1038/s41467-020-20434-3

Abstract

The effective storage of lipids in white adipose tissue (WAT) critically impacts whole body energy homeostasis. Many genes have been implicated in WAT lipid metabolism, including tripartite motif containing 28 (Trim28), a gene proposed to primarily influence adiposity via epigenetic mechanisms in embryonic development. However, in the current study we demonstrate that mice with deletion of Trim28 specifically in committed adipocytes, also develop obesity similar to global Trim28 deletion models, highlighting a post-developmental role for Trim28. These effects were exacerbated in female mice, contributing to the growing notion that Trim28 is a sex-specific regulator of obesity. Mechanistically, this phenotype involves alterations in lipolysis and triglyceride metabolism, explained in part by loss of Klf14 expression, a gene previously demonstrated to modulate adipocyte size and body composition in a sex-specific manner. Thus, these findings provide evidence that Trim28 is a bona fide, sex specific regulator of post-developmental adiposity and WAT function.

Highlights

The effective storage of lipids in white adipose tissue (WAT) critically impacts whole body energy homeostasis
In the current study, we demonstrated that Trim[28] deletion in adipose tissue resulted in increased adiposity, in female mice, which was not associated with decrements in glucose homeostasis
These findings are consistent with previous studies demonstrating that global Trim[28] haploinsufficient mice are obese and metabolically healthy[8,9]. We demonstrated that this adipose-specific phenotype can be recapitulated in vitro, and that the in vivo phenotype is robust and does not present in a bistable fashion as does the global haploinsufficient model, challenging the previous paradigm that tripartite motif containing 28 (Trim28)-induced obesity primarily stems from alterations in developmental cellular lineages

Summary

Introduction

The effective storage of lipids in white adipose tissue (WAT) critically impacts whole body energy homeostasis. These effects were exacerbated in female mice, contributing to the growing notion that Trim[28] is a sex-specific regulator of obesity This phenotype involves alterations in lipolysis and triglyceride metabolism, explained in part by loss of Klf[14] expression, a gene previously demonstrated to modulate adipocyte size and body composition in a sex-specific manner. These findings provide evidence that Trim[28] is a bona fide, sex specific regulator of post-developmental adiposity and WAT function. Trim[28] is associated with autophagy, with Trim[28] being shown to regulate microRNAs that target autophagy-related genes and subsequently regulate autophagosome formation[13,14]

Methods

Results

Conclusion