We previously reported that systemic inhibition of insulin receptor (IR) and IGF-1 receptor (IGF1R) by administration of OSI-906 (linstinib), a dual IR/IGF1R inhibitor, for a week induced glucose intolerance, hepatic steatosis, and lipoatrophy in mice. In this study, we investigated the effects of a DPP-4 inhibitor linagliptin on hepatic steatosis in OSI-906-terated mice (OSI mice). Eight-week-old C57BL/6 mice were administrated 45 mg/kg of OSI-906 or vehicle with or without 3 mg/kg of linagliptin for 7 days. Linagliptin did not influence on hyperinsulinemia elicited by OSI-906. On the other hand, linagliptin reduced plasma triglyceride levels in OSI mice. Linagliptin also improved OSI-906-induced hepatic steatosis without changes in visceral fat atrophy. Hepatic gluconeogenic gene expressions, such as G6Pase, PEPCK and PGC-1α, were elevated by the administration of OSI-906, and linagliptin had no significant effect on those gene expressions. OSI-906-induced hepatic steatosis showed no significant changes in gene expressions of fatty acid synthesis or inflammation, such as SREBP-1c, TNF-α and IL-6. We also performed hepatic quantitative proteomic and phosphoproteomic analysis in OSI-906- or linagliptin-treated mice. Linagliptin significantly upregulated 3 proteins and significantly downregulated 7 proteins in the liver of OSI mice (fold change >1.5, p<0.05). The phosphorylation of 102 proteins and 191 proteins were up- and down-regulated by linagliptin in OSI mice. Proteomic analysis indicated Mup20, Cyp2b10, Perilipin-2, and Sirt2 were modulated in the process of amelioration of hepatic steatosis by linagliptin. Taken together, linagliptin improved hepatic steatosis induced by IR and IGF1R inhibition via a previously unknown mechanism, except for gluconeogenesis, lipogenesis, or inflammation, suggesting the potential action of DPP-4 inhibitors for the treatment of hepatic steatosis under insulin resistant conditions.
T. Okuyama: None. J. Shirakawa: None. Y. Terauchi: Advisory Panel; Self; AstraZeneca, Daiichi Sankyo Company, Limited, Eli Lilly and Company, Merck Sharp & Dohme Corp., Mitsubishi Tanabe Pharma Corporation, Novo Nordisk A/S, Sanofi. Research Support; Self; Daiichi Sankyo Company, Limited, Eli Lilly and Company, Merck Sharp & Dohme Corp., Novartis Pharmaceuticals Corporation, Novo Nordisk A/S, Ono Pharmaceutical Co., Ltd., Sanofi, Shionogi & Co., Ltd., Sumitomo Dainippon Pharma Co., Ltd. Speaker's Bureau; Self; Astellas Pharma Inc., AstraZeneca, Bayer Yakuhin, Ltd., Daiichi Sankyo Company, Limited, Eli Lilly and Company, Merck Sharp & Dohme Corp., Mitsubishi Tanabe Pharma Corporation, Novartis Pharmaceuticals Corporation, Novo Nordisk A/S, Ono Pharmaceutical Co., Ltd., Sanofi, Sanwa Kagaku Kenkyusho, Shionogi & Co., Ltd., Sumitomo Dainippon Pharma Co., Ltd.