LAUSR

Thiazolidinediones (TZDs) enhance insulin sensitivity and have efficacy for treating nonalcoholic steatohepatitis (NASH). However, the use of TZDs, like rosiglitazone and pioglitazone, has been curtailed by significant side effects mediated via the peroxisome proliferator-activated receptor γ (PPARγ). We conducted a screen to identify compounds with insulin-sensitizing effects that did not contain a thiazolidinedione ring and act independently of PPARγ. A lead candidate, MSDC-5514, was selected for further study due to its ability to induce uncoupling protein 1 expression in brown adipocyte precursors and an inability to bind and activate PPARγ even at high concentrations. We gavaged diet-induced obese (DIO) mice with 30 mg/kg/day MSDC-5514 for six days. MSDC-5514 treatment did not affect body weight, but completely normalized glucose tolerance in insulin-resistant DIO mice. DIO mice exhibited elevated plasma insulin, free fatty acid, and triglyceride concentrations compared to lean mice, all of which were corrected by MSDC-5514 treatment. Liver diacylglycerol and triglyceride content, which were markedly increased in DIO mice compared to lean controls, were significantly decreased by MSDC-5514. The resolution of hepatic steatosis may be due to increased fatty acid oxidation since the expression of several genes encoding fatty acid oxidation enzymes was significantly elevated in livers from MSDC-5514 treated mice and directly by treatment of hepatocytes with MSDC-5514 in culture. Markers of liver injury and NASH, including plasma ALT and liver expression of markers of inflammation, stellate cell activation, and fibrosis were also attenuated by MSDC-5514 treatment. Although the molecular target of MSDC-5514 remains unclear, chemical-genetic screens are ongoing to identify the mechanism of action. In conclusion, these data suggest that MSDC-5514 may be a new PPARγ-independent insulin sensitizer with efficacy for treating diabetes and NASH. Disclosure Y. Chen: None. K. Chambers: None. W. McDonald: Stock/Shareholder; Self; Metabolic Solutions Development Company, LLC. B.N. Finck: Board Member; Self; Cirius Therapeutics. K.S. McCommis: None.