期刊
DIABETES & VASCULAR DISEASE RESEARCH
卷 14, 期 6, 页码 516-524出版社
SAGE PUBLICATIONS LTD
DOI: 10.1177/1479164117728012
关键词
p16(INK4a); CDKN2A; adipogenesis; perivascular adipose tissue; bone marrow
资金
- European Genomic Institute for Diabetes (E.G.I.D.) [ANR-10-LABX-46]
- Fondation pour la Recherche Medicale [DCV20070409276]
- EFSD/GlaxoSmithKline
- Cost Action [BM0602]
- Conseil regional Nord Pas-de-Calais
- FEDER
- Netherlands Organization for Scientific Research (NWO-Veni) [91612056]
- European FP7 Marie Curie grant (FP7-PEOPLE-CIG grant) [322070]
- European Atherosclerosis Society
- Dutch Heart Foundation [NHS-2013T143]
- INSERM [00540009]
The genomic CDKN2A/B locus, encoding p16(INK4a) among others, is linked to an increased risk for cardiovascular disease and type 2 diabetes. Obesity is a risk factor for both cardiovascular disease and type 2 diabetes. p16(INK4a) is a cell cycle regulator and tumour suppressor. Whether it plays a role in adipose tissue formation is unknown. p16(INK4a) knock-down in 3T3/L1 preadipocytes or p16(INK4a) deficiency in mouse embryonic fibroblasts enhanced adipogenesis, suggesting a role for p16(INK4a) in adipose tissue formation. p16(INK4a)-deficient mice developed more epicardial adipose tissue in response to the adipogenic peroxisome proliferator activated receptor gamma agonist rosiglitazone. Additionally, adipose tissue around the aorta from p16(INK4a)-deficient mice displayed enhanced rosiglitazone-induced gene expression of adipogenic markers and stem cell antigen, a marker of bone marrow-derived precursor cells. Mice transplanted with p16(INK4a)-deficient bone marrow had more epicardial adipose tissue compared to controls when fed a high-fat diet. In humans, p16(INK4a) gene expression was enriched in epicardial adipose tissue compared to other adipose tissue depots. Moreover, epicardial adipose tissue from obese humans displayed increased expression of stem cell antigen compared to lean controls, supporting a bone marrow origin of epicardial adipose tissue. These results show that p16(INK4a) modulates epicardial adipose tissue development, providing a potential mechanistic link between the genetic association of the CDKN2A/B locus and cardiovascular disease risk.
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