Dorota Kaminska1, Pirjo Käkelä2, Elina Nikkola3, Sari Venesmaa2, Imre Ilves2, Karl-Heinz Herzig4,5,6, Marjukka Kolehmainen1, Leila Karhunen1, Johanna Kuusisto7, Helena Gylling1, Päivi Pajukanta3,8, Markku Laakso7, Jussi Pihlajamäki9,10. 1. Institute of Public Health and Clinical Nutrition, University of Eastern Finland, Kuopio Finland. 2. Department of Surgery, University of Eastern Finland and Kuopio University Hospital, Finland. 3. Department of Human Genetics, David Geffen School of Medicine at UCLA, Los Angeles, California, USA. 4. Institute of Biomedicine and Biocenter of Oulu, University of Oulu, Finland. 5. Medical Research Center Oulu & Oulu University Hospital, Finland. 6. Department of Gastroenterology and Metabolism, Poznan University of Medical Sciences, Poland. 7. Institute of Clinical Medicine, Internal Medicine, University of Eastern Finland and Kuopio University Hospital, Finland. 8. Molecular Biology Institute at UCLA, Los Angeles, California, USA. 9. Institute of Public Health and Clinical Nutrition, University of Eastern Finland, Kuopio Finland. jussi.pihlajamaki@uef.fi. 10. Clinical Nutrition and Obesity Center, Kuopio University Hospital, Finland. jussi.pihlajamaki@uef.fi.
Abstract
OBJECTIVE: Multiple obesity susceptibility loci have been identified by genome-wide association studies, yet the mechanisms by which these loci influence obesity remain unclear. Alternative splicing could contribute to obesity by regulating the transcriptomic and proteomic diversity of genes in these loci. METHODS: Based on a database search, 72 of the 136 genes at the 13 obesity loci encoded multiple protein isoforms. Thus, alternative splicing of these genes in adipose tissue samples was analyzed from the Metabolic Syndrome in Men population-based study and from two weight loss intervention studies (surgical and very low calorie diet). RESULTS: Alternative splicing was confirmed in 11 genes with PCR capillary electrophoresis in human subcutaneous adipose tissue. Interestingly, differential splicing of TRA2B, BAG6, and MSH5 was observed between lean individuals with normoglycemia and overweight individuals with type 2 diabetes. Of these genes, we detected fat depot-dependent splicing of TRA2B and BAG6 and weight loss-induced regulation of MSH5 splicing in the intervention studies. Finally, body mass index was a major determinant of TRA2B, BAG6, and MSH5 splicing in the combined data. CONCLUSIONS: This study provides evidence for alternative splicing in obesity loci, suggesting that alternative splicing at least in part mediates the obesity-associated risk in these loci.
OBJECTIVE:Multiple obesity susceptibility loci have been identified by genome-wide association studies, yet the mechanisms by which these loci influence obesity remain unclear. Alternative splicing could contribute to obesity by regulating the transcriptomic and proteomic diversity of genes in these loci. METHODS: Based on a database search, 72 of the 136 genes at the 13 obesity loci encoded multiple protein isoforms. Thus, alternative splicing of these genes in adipose tissue samples was analyzed from the Metabolic Syndrome in Men population-based study and from two weight loss intervention studies (surgical and very low calorie diet). RESULTS: Alternative splicing was confirmed in 11 genes with PCR capillary electrophoresis in human subcutaneous adipose tissue. Interestingly, differential splicing of TRA2B, BAG6, and MSH5 was observed between lean individuals with normoglycemia and overweight individuals with type 2 diabetes. Of these genes, we detected fat depot-dependent splicing of TRA2B and BAG6 and weight loss-induced regulation of MSH5 splicing in the intervention studies. Finally, body mass index was a major determinant of TRA2B, BAG6, and MSH5 splicing in the combined data. CONCLUSIONS: This study provides evidence for alternative splicing in obesity loci, suggesting that alternative splicing at least in part mediates the obesity-associated risk in these loci.
Authors: Jussi Pihlajamäki; Carles Lerin; Paula Itkonen; Tanner Boes; Thomas Floss; Joshua Schroeder; Farrell Dearie; Sarah Crunkhorn; Furkan Burak; Josep C Jimenez-Chillaron; Tiina Kuulasmaa; Pekka Miettinen; Peter J Park; Imad Nasser; Zhenwen Zhao; Zhaiyi Zhang; Yan Xu; Wolfgang Wurst; Hongmei Ren; Andrew J Morris; Stefan Stamm; Allison B Goldfine; Markku Laakso; Mary Elizabeth Patti Journal: Cell Metab Date: 2011-08-03 Impact factor: 27.287
Authors: Jussi Pihlajamäki; Tiina Kuulasmaa; Dorota Kaminska; Marko Simonen; Vesa Kärjä; Sari Grönlund; Pirjo Käkelä; Matti Pääkkönen; Sakari Kainulainen; Kari Punnonen; Johanna Kuusisto; Helena Gylling; Markku Laakso Journal: J Hepatol Date: 2011-10-23 Impact factor: 25.083
Authors: G Sesti; M A Marini; A N Tullio; A Montemurro; P Borboni; A Fusco; D Accili; R Lauro Journal: Biochem Biophys Res Commun Date: 1991-12-31 Impact factor: 3.575
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