Variation in the Adiponutrin Gene Influences Its Expression and Associates With Obesity

Variation in the Adiponutrin Gene Influences Its Expression and Associates With Obesity Lovisa E. Johansson 1 , Johan Hoffstedt 2 , Hemang Parikh 3 , Emma Carlsson 1 , Martin Wabitsch 4 , Anne-Greth Bondeson 5 , Jan Hedenbro 6 , Hans Tornqvist 1 7 , Leif Groop 3 and Martin Ridderstråle 1 1 Department of Clinical Sciences Malmö, Clinical Obesity, Lund University, University Hospital MAS, Malmö, Sweden 2 Department of Medicine, Karolinska Institute, Huddinge University Hospital, Stockholm, Sweden 3 Department of Clinical Sciences Malmö, Diabetes and Endocrinology, Lund University, University Hospital MAS, Malmö, Sweden 4 Department of Pediatrics, University of Ulm, Ulm, Germany 5 Department of Clinical Sciences Malmö, Emergency Medicine/Medicine/Surgery, Lund University, University Hospital MAS, Malmö, Sweden 6 Department of Clinical Sciences Lund, Lund University, Lund University Hospital, Lund, Sweden 7 Department of Diabetes Biology, Novo Nordisk, Målöv, Denmark Address correspondence and reprint requests to Lovisa E. Johansson, Department of Clinical Sciences Malmö, Clinical Obesity, Lund University, Wallenberg Laboratory, Malmö University Hospital, S-205 02 Malmö, Sweden. E-mail: lovisa.johansson{at}med.lu.se Abstract Adiponutrin is one of three recently identified adipocyte lipases. Surprisingly, these proteins also retain transacylase activity, a hitherto unknown pathway of triacylglycerol synthesis in the adipocytes. This may enable them to participate in both anabolic and catabolic processes. The adiponutrin gene ( ADPN ) is downregulated by fasting and upregulated by refeeding, suggesting a role in lipogenesis. Experiments in human adipocytes confirmed that the gene is upregulated in response to insulin in a glucose-dependent fashion. Obese subjects had increased levels of subcutaneous and visceral abdominal adipose tissue ADPN mRNA. Visceral ADPN mRNA expression was correlated to measures of insulin sensitivity (fasting insulin and homeostasis model assessment). We also studied genetic variation in ADPN and its relation to obesity, lipolysis, and mRNA expression. Two ADPN polymorphisms showed association with obesity. Carriers of the obesity-associated variants showed a lesser increase in the levels of adipose tissue ADPN mRNA and an increased basal lipolysis. Our results suggest that obese subjects that are insulin resistant and/or carriers of the obesity-associated ADPN alleles fail to upregulate the gene and that upregulation of adiponutrin may