The Obesity-Susceptibility Gene TMEM18 Promotes Adipogenesis through Activation of PPARG
Kathrin Landgraf,
Nora Klöting,
Martin Gericke,
Nitzan Maixner,
Esther Guiu-Jurado,
Markus Scholz,
A. Veronica Witte,
Frauke Beyer,
Julian T. Schwartze,
Martin Lacher,
Arno Villringer,
Peter Kovacs,
Assaf Rudich,
Matthias Blüher,
Wieland Kiess,
Antje Körner
Affiliations
Kathrin Landgraf
Center for Pediatric Research Leipzig (CPL), Hospital for Children & Adolescents, University of Leipzig, Leipzig 04103, Germany; Corresponding author
Nora Klöting
Helmholtz Institute for Metabolic, Obesity and Vascular Research (HI-MAG) of the Helmholtz Zentrum München at the University of Leipzig and University Hospital Leipzig, Leipzig 04103, Germany; Medical Department III-Endocrinology, Nephrology, Rheumatology, University of Leipzig, Leipzig 04103, Germany
Martin Gericke
Institute of Anatomy, University of Leipzig, Leipzig 04103, Germany
Nitzan Maixner
Department of Clinical Biochemistry and Pharmacology, Ben-Gurion University of the Negev, Beer-Sheva 8410501, Israel
Esther Guiu-Jurado
Medical Department III-Endocrinology, Nephrology, Rheumatology, University of Leipzig, Leipzig 04103, Germany
Markus Scholz
Institute for Medical Informatics, Statistics and Epidemiology, University of Leipzig, Leipzig 04103, Germany; LIFE Research Center for Civilization Diseases, University of Leipzig, Leipzig 04103, Germany
A. Veronica Witte
Department of Neurology, Max Planck Institute for Human Cognitive and Brain Sciences, Leipzig 04103, Germany
Frauke Beyer
Department of Neurology, Max Planck Institute for Human Cognitive and Brain Sciences, Leipzig 04103, Germany
Julian T. Schwartze
Center for Pediatric Research Leipzig (CPL), Hospital for Children & Adolescents, University of Leipzig, Leipzig 04103, Germany
Martin Lacher
Department of Pediatric Surgery, University of Leipzig, Leipzig 04103, Germany
Arno Villringer
Department of Neurology, Max Planck Institute for Human Cognitive and Brain Sciences, Leipzig 04103, Germany
Peter Kovacs
Medical Department III-Endocrinology, Nephrology, Rheumatology, University of Leipzig, Leipzig 04103, Germany
Assaf Rudich
Department of Clinical Biochemistry and Pharmacology, Ben-Gurion University of the Negev, Beer-Sheva 8410501, Israel
Matthias Blüher
Helmholtz Institute for Metabolic, Obesity and Vascular Research (HI-MAG) of the Helmholtz Zentrum München at the University of Leipzig and University Hospital Leipzig, Leipzig 04103, Germany; Medical Department III-Endocrinology, Nephrology, Rheumatology, University of Leipzig, Leipzig 04103, Germany
Wieland Kiess
Center for Pediatric Research Leipzig (CPL), Hospital for Children & Adolescents, University of Leipzig, Leipzig 04103, Germany
Antje Körner
Center for Pediatric Research Leipzig (CPL), Hospital for Children & Adolescents, University of Leipzig, Leipzig 04103, Germany; Corresponding author
Summary: TMEM18 is the strongest candidate for childhood obesity identified from GWASs, yet as for most GWAS-derived obesity-susceptibility genes, the functional mechanism remains elusive. We here investigate the relevance of TMEM18 for adipose tissue development and obesity. We demonstrate that adipocyte TMEM18 expression is downregulated in children with obesity. Functionally, downregulation of TMEM18 impairs adipocyte formation in zebrafish and in human preadipocytes, indicating that TMEM18 is important for adipocyte differentiation in vivo and in vitro. On the molecular level, TMEM18 activates PPARG, particularly upregulating PPARG1 promoter activity, and this activation is repressed by inflammatory stimuli. The relationship between TMEM18 and PPARG1 is also evident in adipocytes of children and is clinically associated with obesity and adipocyte hypertrophy, inflammation, and insulin resistance. Our findings indicate a role of TMEM18 as an upstream regulator of PPARG signaling driving healthy adipogenesis, which is dysregulated with adipose tissue dysfunction and obesity.
