| First Author | Kang HJ | Year | 2021 |
| Journal | Exp Mol Med | Volume | 53 |
| Issue | 9 | Pages | 1390-1401 |
| PubMed ID | 34552205 | Mgi Jnum | J:331530 |
| Mgi Id | MGI:6784940 | Doi | 10.1038/s12276-021-00672-1 |
| Citation | Kang HJ, et al. (2021) Pyruvate dehydrogenase kinase 1 and 2 deficiency reduces high-fat diet-induced hypertrophic obesity and inhibits the differentiation of preadipocytes into mature adipocytes. Exp Mol Med 53(9):1390-1401 |
| abstractText | Obesity is now recognized as a disease. This study revealed a novel role for pyruvate dehydrogenase kinase (PDK) in diet-induced hypertrophic obesity. Mice with global or adipose tissue-specific PDK2 deficiency were protected against diet-induced obesity. The weight of adipose tissues and the size of adipocytes were reduced. Adipocyte-specific PDK2 deficiency slightly increased insulin sensitivity in HFD-fed mice. In studies with 3T3-L1 preadipocytes, PDK2 and PDK1 expression was strongly increased during adipogenesis. Evidence was found for epigenetic induction of both PDK1 and PDK2. Gain- and loss-of-function studies with 3T3-L1 cells revealed a critical role for PDK1/2 in adipocyte differentiation and lipid accumulation. PDK1/2 induction during differentiation was also accompanied by increased expression of hypoxia-inducible factor-1alpha (HIF1alpha) and enhanced lactate production, both of which were absent in the context of PDK1/2 deficiency. Exogenous lactate supplementation increased the stability of HIF1alpha and promoted adipogenesis. PDK1/2 overexpression-mediated adipogenesis was abolished by HIF1alpha inhibition, suggesting a role for the PDK-lactate-HIF1alpha axis during adipogenesis. In human adipose tissue, the expression of PDK1/2 was positively correlated with that of the adipogenic marker PPARgamma and inversely correlated with obesity. Similarly, PDK1/2 expression in mouse adipose tissue was decreased by chronic high-fat diet feeding. We conclude that PDK1 and 2 are novel regulators of adipogenesis that play critical roles in obesity. |
