Improving Insulin Sensitivity With HDAC Inhibitor

Histone deacetylase (HDAC) has emerged as a new molecular target in the control of obesity and type 2 diabetes. HDAC is an enzyme with well-known functions in the regulation of chromatin structure and gene transcription in the nucleus, where HDAC interacts with corepressor proteins such as NcoR and SMRT to form active corepressor complexes. In the corepressor complex, HDAC catalyzes removal of acetyl groups from histone proteins to inhibit gene expression. Recent studies have consistently suggested that HDAC also exhibits activity in the cytosol and mitochondria to regulate acetylation of metabolic enzymes (1). More than 20% of mitochondria proteins are regulated by acetylation (2,3). Regulation of HDAC activity is a new approach to modify glucose and fatty acid metabolism in the treatment of type 2 diabetes. In HDAC, HDAC3 and sirtuin (SIRT)1 are well-known players in regulation of fatty acid and glucose metabolism. In mammals, HDACs are divided into three classes: class I HDACs (1–3,8,10), class II HDACs (4–7,9,11), and class III HDACs (SIRTs 1–7 and NAD-dependent histone deacetylases). Class I HDACs have strong catalytic activities, and they are targets of most HDAC inhibitors, such as trichostatin A (TSA), sodium butyrate, and suberoylanilide hydroxamic acid. HDAC3 regulates metabolism in genetic and pharmacological studies. NcoR is required by HDAC3 in the regulation of transcription factors including peroxisome proliferator–activated receptor (PPAR)g. NcoR knockout in fat tissue led to enhanced PPARg function in adipose tissue, increased insulin sensitivity, and accelerated weight gain in mice (4), all of which resemble the pharmacological activity of thiazolidinediones. HDAC3 is also involved in circadian-mediated lipid metabolism in liver (5), and hepatic HDAC3 knockout leads to lipid accumulation and glycogen depletion in the mouse liver (6). HDAC3 inactivation in muscle and heart leads to mitochondrial biogenesis deficiency, which reduces fatty acid catabolism in diet-induced obese (DIO) mice (7). Class II HADCs have a weak catalytic activity, and their biological activity is dependent on the class I HDACs. Inhibition of the class I activity will induce suppression of class II. Pharmacological studies suggest that inhibition of class I/II HDACs induces AMP-activated protein kinase (AMPK) activity (8) and has beneficial metabolic effects in humans and rodents (8,9). In contrast, suppression of class III HDACs generates detrimental metabolic effects (11). Activation of class III HDACs promotes energy metabolism, as is being reported for SIRT1, SIRT3, or SIRT5 (10–12). These activities have been reported for class III HDACs in response to NAD, resveratrol, or gene knockout. Pharmacological approaches have been used to target class I/II HDACs in regulation of glucose and fatty acid metabolism (Fig. 1). HDAC3 inhibits PPARg and transcription factor nuclear factor-kB (NF-kB) (13,14). Exchange of HDAC3 is a molecular mechanism of PPARg and NF-kB cross-talk (13,15). NF-kB activation in inflammation promotes HDAC3 activation, leading to suppression of PPARg function (15), and HDAC3 inhibition has been shown to restore PPARg function in obesity (8,15). In one study, two pan-HDAC inhibitors, sodium butyrate and TSA, were supplemented to block HDAC3 activity in DIO mice. The treatment generated a set of unexpected metabolic effects including increased energy expenditure, reduction in adipose tissue expansion, resistance to obesity, and prevention of insulin resistance (8). Mechanistically, AMPK activity and PGC-1a expression were both enhanced in liver and muscle. In a subsequent study, sodium butyrate was found to induce fibroblast growth factor (FGF) 21 expression in liver (16), thereby providing an endocrine pathway for the enhanced energy expenditure in the butyrate-treated mice. Other butyrate derivatives with HDAC inhibitor (HDACi) activity have similar metabolic actions in regulation of insulin sensitivity. Sodium phenylbutyrate alleviated lipid-induced insulin resistance, inhibited endoplasmic reticulum stress, and protected b-cells from failure in obese patients (9). Tributyrin improved insulin sensitivity and inhibited inflammation in DIO mice (17). Inhibition of HDAC4, -5, and -7 (class II) by short hairpin RNA–mediated gene knockdown improved glucose metabolism in DIO mice by suppression of hepatic gluconeogenesis (18). This mechanism is related to downregulation of the transcription factor FOXO1. In these studies, pan-HDACi or class II HDACi was used. Class I HDACi was not tested. In this issue of Diabetes, the class I–specific (MS275) and class II–specific (MC1568) HDACi were compared in regulation of energy metabolism and insulin sensitivity in DIO mice by Galmozzi et al. (19). Results showed that class I HDACi enhanced whole-body energy expenditure, improved insulin sensitivity, and stimulated oxidative phosphorylation and mitochondrial function in the muscle and fat of mice. The mechanism was attributed to induction of PPARg coactivator (PGC)-1a. In contrast, class II HDACi did not exhibit these actions, suggesting that class I HDACi are more important in the regulation of energy metabolism and insulin sensitivity. This study provides new insight into the distinction between class I and class II inhibitors in regulation of insulin sensitivity. Despite these interesting new findings, these data should be interpreted with caution. The authors attributed all effects of the class I inhibitor to increased PGC-1a activity (Fig. 1). However, this interpretation is not supported by the phenotypes of PGC-1a overexpression mice. PGC-1a has From the Antioxidant and Gene Regulation Laboratory, Pennington Biomedical Research Center, Louisiana State University System, Baton Rouge, Louisiana. Corresponding author: Jianping Ye, [email protected]. Received 30 September 2012 and accepted 4 October 2012. DOI: 10.2337/db12-1354 2013 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered. See http://creativecommons.org/licenses/by -nc-nd/3.0/ for details. See accompanying original article, p. 732.