Several histone deacetylase (HDAC) inhibitors have been shown to play beneficial roles in treating obesity and its related metabolic syndromes. However, the underlying mechanisms are still not understood well. In this study, we examined the potential roles of SAHA, a potent inhibitor of HDACs, on energy expenditure and explored the molecular mechanism involved. Our data showed that SAHA induces less lipid accumulation and smaller lipid droplets in cultured adipocytes. In vivo studies showing SAHA reduces body weight gain and increases core temperature in lean and obese mice. Furthermore, SAHA accelerates blood glucose disposal, improves insulin sensitivity and attenuates fatty liver in obese animals. Transcriptome sequencing found that a group of zinc finger proteins (Zfps) was up-regulated by SAHA. Functional studies showed that the knockdown of Zfp691 or Zfp719 largely abolishes SAHA-induced Ucp1 expression in adipocytes. ChIP assay showed that SAHA stimulates histone H3 acetylation at Zfp719 promoter. Luciferase reporter analysis revealed that Zfp719 activates Ucp1 promoter. As a consequence, forced expression of Zfp719 increases Ucp1 expression and promotes lipid catabolism in adipocytes. Taken together, our data indicate that by stimulating axis of ZFPs-UCP1, SAHA induces white fat browning and energy consumption, which makes it a potential drug for treating obesity and related metabolic dysfunctions.
Jinyu Ma, Yuejun Wang, Jie Ding, Shouping Zhang, Yinuo Yang, and Cheng Sun
Hong Ma, Jin Yuan, Jinyu Ma, Jie Ding, Weiwei Lin, Xinlei Wang, Mingliang Zhang, Yi Sun, Runze Wu, Chun Liu, Cheng Sun, and Yunjuan Gu
Bone morphogenetic protein 7 (BMP7), a member of the transforming growth factor-β (TGF-β) family, plays pivotal roles in energy expenditure. However, whether and how BMP7 regulates hepatic insulin sensitivity is still poorly understood. Here, we show that hepatic BMP7 expression is reduced in high-fat diet (HFD)-induced diabetic mice and palmitate (PA)-induced insulin-resistant HepG2 and AML12 cells. BMP7 improves insulin signaling pathway in insulin resistant hepatocytes. On the contrary, knockdown of BMP7 further impairs insulin signal transduction in PA-treated cells. Increased expression of BMP7 by adenovirus expressing BMP7 improves hyperglycemia, insulin sensitivity and insulin signal transduction. Furthermore, BMP7 inhibits mitogen-activated protein kinases (MAPKs) in both the liver of obese mice and PA-treated cells. In addition, inhibition of MAPKs recapitulates the effects of BMP7 on insulin signal transduction in cultured hepatocytes treated with PA. Activation of p38 MAPK abolishes the BMP7-mediated upregulation of insulin signal transduction both in vitro and in vivo. Together, our results show that hepatic BMP7 has a novel function in regulating insulin sensitivity through inhibition of MAPKs, thus providing new insights into treating insulin resistance-related disorders such as type 2 diabetes.