Endocrine Abstracts

Abnormal adipogenesis and adipocyte dysfunctions have been suggested to be important mechanisms underlying the development of metabolic syndrome. Obesity is associated with a chronic, low-grade inflammation status. The pathogenic mechanisms at the molecular level in obesity-associated inflammation and insulin resistance are not fully understood and need to be elucidated. The 51 KD FK506-binding protein 51 (FKBP51), encoded by Fkbp5 gene, is one of the of immunophilin family members. Fkbp5 gene is highly expressed in adipose tissues and FKBP51 expression is most abundant in adipose tissue. Previous study indicated that FKBP51 expression progressively increases during 3T3-L1 adipocytes differentiation and play an important regulator of cellular adipogenesis. In addition, FKBP51 expression in human adipose tissue increases following dexamethasone exposure and is associated with insulin resistance. Therefore, we hypothesize that FKBP51 is a mechanism linking obesity-associated inflammation and insulin resistance. The results showed that high-fat diet (HFD) feeding induced adipose Fkbp5 mRNA up-regulation in wild-type (WT) mice. Global Fkbp5-knockout (KO) can ameliorate the obesity, insulin resistance and inflammation induced by HFD feeding in mice. We also demonstrated that Fkbp5 regulated adipocyte differentiation in vitro. For example, Fkbp5 overexpression promoted adipogenic differentiation in 3T3-F442A preadipocytes. Suppression of endogenous FKBP51 expression by transfecting Fkbp5 shRNA suppressed adipogenic differentiation in 3T3-F442A preadipocytes. Besides, bone marrow Fkbp5 deficiency is successful to protecting against HFD-induced obesity, insulin resistance and inflammation in WT mice transplanted with bone marrow from Fkbp5-KO mice. These results suggested that FKBP51 is a novel link between obesity, adipose inflammation and insulin resistance.