Functional relevance of genes implicated by obesity genome-wide association study signals for human adipocyte biology
| Autor: | Nora Klöting, Peter Kovacs, A. Berthold, F. Bernhard, D Friebe, Wieland Kiess, Kathrin Landgraf, Petra Büttner, Matthias Blüher, Antje Körner |
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| Rok vydání: | 2012 |
| Předmět: |
Male
Cell Adhesion Molecules Neuronal Endocrinology Diabetes and Metabolism Genome-wide association study Biology GPI-Linked Proteins Real-Time Polymerase Chain Reaction Mitochondrial Membrane Transport Proteins Genome 03 medical and health sciences chemistry.chemical_compound 0302 clinical medicine Niemann-Pick C1 Protein Adipocyte Adipocytes Internal Medicine Humans Obesity Gene Adaptor Proteins Signal Transducing 030304 developmental biology Genetic association Genetics 0303 health sciences Membrane Glycoproteins Brain-Derived Neurotrophic Factor Intracellular Signaling Peptides and Proteins Membrane Proteins Adipose Tissue chemistry Membrane protein Adipogenesis Proto-Oncogene Proteins c-maf Female Carrier Proteins 030217 neurology & neurosurgery Genome-Wide Association Study |
| Zdroj: | Diabetologia; Vol 56 |
| ISSN: | 1432-0428 0012-186X |
| DOI: | 10.1007/s00125-012-2773-0 |
| Popis: | Genome-wide association studies (GWAS) have identified numerous single-nucleotide polymorphisms associated with obesity, consequently implying a role in adipocyte biology for many closely residing genes. We investigated the functional relevance of such genes in human adipocytes.We selected eight genes (BDNF, MAF, MTCH2, NEGR1, NPC1, PTER, SH2B1 and TMEM18) from obesity GWAS and analysed their effect in human adipogenesis using small interfering (si)RNA-mediated knockdown, their regulation by metabolic agents in adipocytes and pre-adipocytes, and gene expression in paired samples of human fat biopsies (68 non-obese, 165 obese) by quantitative real-time PCR.We show a two- to threefold upregulation of MAF, MTCH2 and NEGR1 and a two- to fourfold downregulation of BDNF and PTER during adipogenesis. Knockdown of BDNF (mean ± SEM; 83.8 ± 4.7% of control; p = 0.0002), MTCH2 (72.7 ± 9.5%; p = 0.0006), NEGR1 (70.2 ± 5.7%; p 0.0001) and TMEM18 (70.8 ± 6.1%; p 0.0001) significantly inhibited adipocyte maturation, while knockdown of the other proteins had no effect. Insulin slightly induced MAF (1.65-fold; p = 0.0009) and MTCH2 (1.72-fold; p 0.0001), while it suppressed BDNF (59.6%; p = 0.0009), NEGR1 (58.0%; p = 0.0085) and TMEM18 (69.3%; p = 0.0377) in adipocytes. The synthetic glucocorticoid dexamethasone suppressed MAF (45.7%; p = 0.0022), BDNF (66.6%; p = 0.0012) and TMEM18 (63.5%; p = 0.0181), but induced NEGR1 (3.2-fold; p = 0.0117) expression. Furthermore, MTCH2, NEGR1 and TMEM18 were differentially expressed in subcutaneous and visceral adipose tissue. TMEM18 expression was decreased in the adipose tissue of obese patients, and negatively correlated with anthropometric variables and adipocyte size.Our results imply a regulatory role for TMEM18, BDNF, MTCH2 and NEGR1 in adipocyte differentiation and biology. In addition, we show a variation of MAF expression during adipogenesis, while NPC1, PTER and SH2B1 were not regulated. |
| Databáze: | OpenAIRE |
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