Abstract
Adipose tissue is an essential regulator of metabolic homeostasis. In contrast with white adipose tissue (WAT), which stores excess energy in the form of triglycerides, brown adipose tissue (BAT) is thermogenic, dissipating energy as heat via the unique expression of the mitochondrial uncoupling protein UCP1. Subsets of UCP1+ adipocytes develop within WAT in response to physiological stimuli, which are referred to as “brite” or “beige” adipocytes. We aim to characterize novel mechanisms regulating the formation of beige/brite adipocytes in mice with the goal of identifying targets for anti-obesity drug development. First, we have identified a BMP7-ROCK signaling axis regulating beige adipocyte formation via control of the G-actin-regulated transcriptional coactivator myocardin-related transcription factor A, MRTFA. WAT from MRTFA–/– mice contains more multilocular adipocytes and expresses enhanced levels of brown-selective proteins, including UCP1. MRTFA–/– mice also show improved metabolic profiles and protection from diet-induced obesity and insulin resistance. Our study hence unravels a central pathway driving the development of physiologically functional beige adipocytes. Second, we show that post-translational modification of PPAR gamma also regulates the recruitment of brite adipocytes to inquinal WAT. Expression of mutant PPAR gamma in which S112 and S273 have been modified to prevent phosphorylation by ERKs and/or CDK5 selectively induces transcription of brown adipose genes including UCP-1. Treatment of mice with roscovitine, a CDK inhibitor potently induces browning of WAT and resistance to diet induced obesity. We have generated a mouse in which UCP-1+ adipocytes express GFP to facilitate FACS isolation of green brite cells from iWAT of mice treated with roscovitine, rosiglitazone and a beta-adrenergic agonist. Analysis of RNA from each population of UCP-1+ cells should allow us to define the phenotype of each cell. Studies are ongoing and relevant information will be presented.
CV
Professor Stephen R Farmer received his PhD in 1976 from National Institute for Medical Research in London. In the following years he worked as Postdoctoral Fellow and Research Associate at MIT under the supervision of Professor Sheldon Penman and Professor Phillip Sharp. In 1980 he accepted an Assistant Professorship of Biochemistry at Boston University School of Medicine and established his independent research laboratory. Since 1993 he is Professor of Biochemistry at Boston University School of Medicine.
His research focus is on nuclear factors that modulate the activity of the two principal regulators of adipogenesis peroxisome proliferator-activated receptor gamma (PPARg) and CCAAT/enhancer binding proteins alpha, beta dn delta (C/EBPs). In particular he is interested in identifying the factors regulating commitment of mesenchymal progenitors to the adipogenic lineage by adopting a variety of approaches to achieve this goal, which includes gene profiling to discover novel regulators as well as investigating the role of selected candidate genes.
This lecture will take place on July 7, 2015 from 17:15 to 18:15 hours in Seminar Room, Ground Floor, MFC I.
Host: Prof. Dr. Hendrik Lehnert
Department of Internal Medicine I
University of Lübeck
