Metabolic Reprogramming by 3-Iodothyronamine (T1AM): A New Perspective to Reverse Obesity through Co-Regulation of Sirtuin 4 and 6 Expression
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
Authors: Assadi-Porter, Fariba M.; Reiland, Hannah; Sabatini, Martina; Lorenzini, Leonardo; Carnicelli, Vittoria; Rogowski, Micheal; Alpergin, Ebru S. Selen; Tonelli, Marco; Ghelardoni, Sandra; Saba, Alessandro; Zucchi, Riccardo; Chiellini, Grazia
Abstract
Obesity is a complex disease associated with environmental and genetic factors. 3-Iodothyronamine (T1AM) has revealed great potential as an effective weight loss drug. We used metabolomics and associated transcriptional gene and protein expression analysis to investigate the tissue specific metabolic reprogramming effects of subchronic T1AM treatment at two pharmacological daily doses (10 and 25 mg/kg) on targeted metabolic pathways. Multi-analytical results indicated that T1AM at 25 mg/kg can act as a novel master regulator of both glucose and lipid metabolism in mice through sirtuin-mediated pathways. In liver, we observed an increased gene and protein expression of Sirt6 (a master gene regulator of glucose) and Gck (glucose kinase) and a decreased expression of Sirt4 (a negative regulator of fatty acids oxidation (FAO)), whereas in white adipose tissue only Sirt6 was increased. Metabolomics analysis supported physiological changes at both doses with most increases in FAO, glycolysis indicators and the mitochondrial substrate, at the highest dose of T1AM. Together our results suggest that T1AM acts through sirtuin-mediated pathways to metabolically reprogram fatty acid and glucose metabolism possibly through small molecules signaling. Our novel mechanistic findings indicate that T1AM has a great potential as a drug for the treatment of obesity and possibly diabetes.
Identification of a cellularly active SIRT6 allosteric activator
NATURE CHEMICAL BIOLOGY
Authors: Huang, Zhimin; Zhao, Junxing; Deng, Wei; Chen, Yingyi; Shang, Jialin; Song, Kun; Zhang, Lu; Wang, Chengxiang; Lu, Shaoyong; Yang, Xiuyan; He, Bin; Min, Jinrong; Hu, Hao; Tan, Minjia; Xu, Jianrong; Zhang, Qiufen; Zhong, Jie; Sun, Xiaoxiang; Mao, Zhiyong; Lin, Houwen; Xiao, Mingzhe; Chin, Y. Eugene; Jiang, Hualiang; Xu, Ying; Chen, Guoqiang; Zhang, Jian
Abstract
SIRT6, a member of the SIRT deacetylase family, is responsible for deacetylation of histone H3 N-epsilon-acetyl-lysines 9 (H3K9ac) and 56 (H3K56ac). As a tumor suppressor, SIRT6 has frequently been found to have low expression in various cancers. Here, we report the identification of MDL-800, a selective SIRT6 activator. MDL-800 increased the deacetylase activity of SIRT6 by up to 22-fold via binding to an allosteric site; this interaction led to a global decrease in H3K9ac and H3K56ac levels in human hepatocellular carcinoma (HCC) cells. Consequently, MDL-800 inhibited the proliferation of HCC cells via SIRT6-driven cell-cycle arrest and was effective in a tumor xenograft model. Together, these data demonstrate that pharmacological activation of SIRT6 is a potential therapeutic approach for the treatment of HCC. MDL-800 is a first-in-class small-molecule cellular SIRT6 activator that can be used to physiologically and pathologically investigate the roles of SIRT6 deacetylation.
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