3.2. Linagliptin improved OSI-906-induced hepatic steatosis
We previously reported that OSI-906 administration induced lipoatrophy and hepatic steatosis after 7 days of administration in wild-type mice (Tajima et al., 2017). We also reported that DPP-4 inhibition prevented diet-induced adipose tissue inflammation and hepatic steatosis in diabetic mice (Shirakawa et al., 2016). Next, we investigated the impact of DPP-4 inhibition on lipoatrophy or hepatic steatosis in wild-type mice treated with OSI-906 for 7 days. The atrophic changes in visceral fat elicited by OSI-906 were not affected by the treatment with linagliptin (Supplementary Figure 1a and b). In contrast, DPP-4 inhibition with linagliptin improved OSI-906-induced hepatic steatosis (Figure 2a). Thus, we further assessed the effects of linagliptin on the liver in OSI-906 treated mice. The administration of OSI-906 significantly increased the liver weight, and this increase in liver weight was significantly lower in the OSI-906 + Lina group than in the OSI-906 group (Figure 2b). The hepatic triglyceride content and the hepatic glycogen content were significantly increased in the OSI-906 group, whereas these parameters were reversed by the treatment with linagliptin (Figure 2c and d).
We next examined the hepatic gene expression involved in hepatic metabolism on day 7 (Figure 2e). The expressions of gluconeogenic genes, such as G6pase and Pepck , and a potent activator of gluconeogenesis, Pgc-1α, were increased in the liver by the OSI-906 administration, consistent with the impairment of hepatic insulin action caused by the blocking of IR and IGF1R. The treatment with linagliptin did not change these expressions. The expressions ofFas and Scd1 , which are involved in de novo lipogenesis, were not altered in the presence of linagliptin in OSI-906-treated mice. We also investigated the expressions of genes related to inflammation and oxidative stress in the liver because these processes are closely related to the development of hepatic steatosis or NAFLD (Figure 2e). Interestingly, the expressions of inflammatory genes, such asTnf-a , Il-6, Ccl2, and iNos , tended to be reduced by the administration with OSI-906 for 7 days. Linagliptin restored the reductions in the expressions of Tnf-a , Il-6, andCcl2 in the liver. In addition, PAI-1 expression tended to be reduced by linagliptin treatment in both OSI-906-treated and untreated groups.