OR51-3 Fat mass and obesity associated gene (FTO) deficiency induces expression of UCP-1 and mitochondrial uncoupling

Program: Abstracts - Orals, Featured Poster Presentations, and Posters
Session: OR51-Obesity: From Genes to Populations
Tuesday, June 18, 2013: 9:15 AM-10:45 AM
Presentation Start Time: 9:45 AM
Room 303 (Moscone Center)
Daniel Tews*1, Pamela Fischer-Posovszky2, Tobias Fromme3, Martin Klingenspor3, Julia Fischer4, Ulrich Rüther4 and Martin Wabitsch1
1University Medical Center Ulm, 2University Medical Center Ulm, Ulm, Germany, 3Technical University Munich, 4Heinrich-Heine University Duesseldorf
Introduction: The association between gene variants in FTO (fat mass and obesity associated) has been shown in different genome-wide association studies. FTO encodes a 2-oxoglutarate dependent demethylase and is expressed ubiquitously. The phenotype of FTO deficient mouse models points to a participation of this gene in energy metabolism. However, its precise role in adipocyte metabolism has not been elucidated so far. This study aimed at identifying the role of FTO in human adipocyte metabolism.

Methods: By using lentiviral-mediated expression of shRNA, we generated FTO deficient SGBS pre- and adipocytes. Successful knockdown and expression of marker genes involved in adipogenic differentiation and glucose and lipid metabolism were monitored by qPCR. Relative mitochondrial content was determined by measurement of citrate synthase activity. Cellular oxygen consumption rates were analyzed by cell respirometry.

Results: In human SGBS preadipocytes and adipocytes we reached a transduction efficiency of >90%. This led to an inhibition of FTO mRNA expression by 73% and to a total repression of FTO protein expression. FTO deficiency did not affect differentiation into mature adipocytes. Interestingly, expression of uncoupling protein 1 (UCP-1) was approximately 4-fold increased in mitochondria of FTO deficient adipocytes compared to preadipocytes. This led to an increased basal as well as uncoupled mitochondrial respiration in FTO deficient adipocytes. In both gonadal and inguinal adipose tissues of FTO deficient mice, expression of brown adipocyte markers and appearance of multivacuolar adipocytes were detected.

Conclusions: We conclude that FTO deficiency leads to the induction of a brown adipocyte phenotype, thereby enhancing energy expenditure. Further understanding of the signaling pathways connecting FTO with UCP-1 expression might lead to new options for obesity treatment.

Nothing to Disclose: DT, PF, TF, MK, JF, UR, MW

*Please take note of The Endocrine Society's News Embargo Policy at http://www.endo-society.org/endo2013/media.cfm

Sources of Research Support: Federal Ministry of Education and Research;Boehringer Ingelheim University Ulm Biocenter