Dynamic Regulation of Genes Involved in Mitochondrial DNA Replication and Transcription during Mouse Brown Fat Cell Differentiation and Recruitment

Maria Murholm,Bjørn Quistorff,Lillian H L Hansen,Klaus Qvortrup,Karen Dixen,Lise Madsen,Giorgio Barbatelli,Ez-Zoubir Amri,Jacob B Hansen,Patricia T Bozza

doi:10.1371/journal.pone.0008458

Abstract

BackgroundBrown adipocytes are specialised in dissipating energy through adaptive thermogenesis, whereas white adipocytes are specialised in energy storage. These essentially opposite functions are possible for two reasons relating to mitochondria, namely expression of uncoupling protein 1 (UCP1) and a remarkably higher mitochondrial abundance in brown adipocytes.Methodology/Principal FindingsHere we report a comprehensive characterisation of gene expression linked to mitochondrial DNA replication, transcription and function during white and brown fat cell differentiation in vitro as well as in white and brown fat, brown adipose tissue fractions and in selected adipose tissues during cold exposure. We find a massive induction of the majority of such genes during brown adipocyte differentiation and recruitment, e.g. of the mitochondrial transcription factors A (Tfam) and B2 (Tfb2m), whereas only a subset of the same genes were induced during white adipose conversion. In addition, PR domain containing 16 (PRDM16) was found to be expressed at substantially higher levels in brown compared to white pre-adipocytes and adipocytes. We demonstrate that forced expression of Tfam but not Tfb2m in brown adipocyte precursor cells promotes mitochondrial DNA replication, and that silencing of PRDM16 expression during brown fat cell differentiation blunts mitochondrial biogenesis and expression of brown fat cell markers.Conclusions/SignificanceUsing both in vitro and in vivo model systems of white and brown fat cell differentiation, we report a detailed characterisation of gene expression linked to mitochondrial biogenesis and function. We find significant differences in differentiating white and brown adipocytes, which might explain the notable increase in mitochondrial content observed during brown adipose conversion. In addition, our data support a key role of PRDM16 in triggering brown adipocyte differentiation, including mitochondrial biogenesis and expression of UCP1.

Highlights

White and brown fat cells share a number of characteristics, including similarities in cell morphology, secretion of adipokines, enzymes of lipid metabolism and patterns of gene expression [1,2]
We demonstrate that the majority of factors involved in mitochondrial transcription and replication are up-regulated during brown adipose conversion, whereas many of the same genes remain unchanged or are induced to a lesser extent during white adipocyte differentiation
We aimed at characterising various aspects of mitochondrial biogenesis and function during fat cell differentiation, with emphasis on differences between white and brown adipocytes

Summary

Introduction

White and brown fat cells share a number of characteristics, including similarities in cell morphology, secretion of adipokines, enzymes of lipid metabolism and patterns of gene expression [1,2] Despite these similarities, white and brown adipose tissues (WAT and BAT, respectively) carry out essentially opposite functions, with WAT being the major energy reserve through triglyceride accumulation, and BAT having the ability to dissipate energy through adaptive thermogenesis. Brown-like adipocytes appearing in some WAT depots following extended periods of exposure to a b-adrenergic agonist do not share progenitors with skeletal muscle [4]. These observations suggest that two types of brown fat cells could exist in mammals. These essentially opposite functions are possible for two reasons relating to mitochondria, namely expression of uncoupling protein 1 (UCP1) and a remarkably higher mitochondrial abundance in brown adipocytes

Methods

Results

Conclusion