Obesity-induced DNA hypermethylation of the adiponectin gene mediates insulin resistance
| Autor: | Abdulelah F. Bassas, Kyong Soo Park, Kyung Cheul Shin, A Young Kim, Xuebo Pan, Jae Bum Kim, Reem M. Sallam, Assim A. Alfadda, Yoon Jeong Park, Aimin Xu, Soo Heon Kwak |
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| Rok vydání: | 2015 |
| Předmět: |
DNA (Cytosine-5-)-Methyltransferase 1
Chromatin Immunoprecipitation medicine.medical_specialty Blotting Western General Physics and Astronomy Adipose tissue Biology Real-Time Polymerase Chain Reaction environment and public health DNA methyltransferase Article General Biochemistry Genetics and Molecular Biology Proinflammatory cytokine Mice Insulin resistance 3T3-L1 Cells Internal medicine medicine Animals Humans DNA (Cytosine-5-)-Methyltransferases Obesity RNA Messenger Promoter Regions Genetic Inflammation Multidisciplinary Adiponectin urogenital system nutritional and metabolic diseases General Chemistry DNA Methylation medicine.disease Molecular biology Real-time polymerase chain reaction Endocrinology Adipose Tissue embryonic structures DNA methylation DNMT1 Cytokines Receptors Leptin Insulin Resistance hormones hormone substitutes and hormone antagonists |
| Zdroj: | NATURE COMMUNICATIONS(6) Nature Communications |
| ISSN: | 2041-1723 |
| DOI: | 10.1038/ncomms8585 |
| Popis: | Adiponectin plays a key role in the regulation of the whole-body energy homeostasis by modulating glucose and lipid metabolism. Although obesity-induced reduction of adiponectin expression is primarily ascribed to a transcriptional regulation failure, the underlying mechanisms are largely undefined. Here we show that DNA hypermethylation of a particular region of the adiponectin promoter suppresses adiponectin expression through epigenetic control and, in turn, exacerbates metabolic diseases in obesity. Obesity-induced, pro-inflammatory cytokines promote DNMT1 expression and its enzymatic activity. Activated DNMT1 selectively methylates and stimulates compact chromatin structure in the adiponectin promoter, impeding adiponectin expression. Suppressing DNMT1 activity with a DNMT inhibitor resulted in the amelioration of obesity-induced glucose intolerance and insulin resistance in an adiponectin-dependent manner. These findings suggest a critical role of adiponectin gene epigenetic control by DNMT1 in governing energy homeostasis, implying that modulating DNMT1 activity represents a new strategy for the treatment of obesity-related diseases. The hormone adiponectin is produced by fat cells and has positive metabolic effects. Here, Kim et al. show that DNA methyltransferase 1 (DNMT1) represses adiponectin expression through hypermethylation of its promoter, and that inflammatory cytokines enhance DNMT1 activity in obese mice and humans. |
| Databáze: | OpenAIRE |
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