Transcriptional Cofactor TBLR1 Controls Lipid Mobilization in White Adipose Tissue

• DOI: 10.1016/j.cmet.2013.02.010
• Publication Date: 2013-03-14T17:09:15Z
• Authors: Maria Rohm; Anke Sommerfeld; Daniela Strzoda; Allan Jones; Tjeerd P. Sijmonsma; Gottfried Rudofsky; Christian Wolfrum; Carsten Sticht; Norbert Gretz; Maximilian Zeyda; Lukas Leitner; Peter P. Nawroth; Thomas M. Stulnig; Mauricio Berriel ...; Alexandros Vegiop...; Stephan Herzig
• Keywords: 0301 basic medicine; Physiology; Adipose Tissue, White; Lipolysis; Mice, Obese; Receptors, Cytoplasmic and Nuclear; Fatty Acids, Nonesterified; Diet, High-Fat; Mice; 03 medical and health sciences; 3T3-L1 Cells; Cyclic AMP; Animals; Humans; Obesity; RNA, Messenger; RNA, Small Interfering; Molecular Biology; Mice, Knockout; 2. Zero hunger; Lipid Mobilization; Cell Biology; Receptors, Adrenergic; 3. Good health; Mice, Inbred C57BL; RNA Interference; Insulin Resistance

Lipid mobilization (lipolysis) in white adipose tissue (WAT) critically controls lipid turnover and adiposity in humans. While the acute regulation of lipolysis has been studied in detail, the transcriptional determinants of WAT lipolytic activity remain still largely unexplored. Here we show that the genetic inactivation of transcriptional cofactor transducin beta-like-related 1(TBLR1) blunts the lipolytic response of white adipocytes through the impairment of cAMP-dependent signal transduction. Indeed, mice lacking TBLR1 in adipocytes are defective in fasting-induced lipid mobilization and, when placed on a high-fat-diet, show aggravated adiposity, glucose intolerance, and insulin resistance. TBLR1 levels are found to increase under lipolytic conditions in WAT of both human patients and mice, correlating with serum free fatty acids (FFAs). As a critical regulator of WAT cAMP signaling and lipid mobilization, proper activity of TBLR1 in adipocytes might thus represent a critical molecular checkpoint for the prevention of metabolic dysfunction in subjects with obesity-related disorders.