Abstract
Obesity and type 2 diabetes are the most common metabolic diseases globally. They are associated with inflammation, oxidative stress, autophagy, and insulin resistance. Sitagliptin, a dipeptidyl-peptidase 4 inhibitor, has been reported to show multiple biological activities beyond the antidiabetic property. This study was aimed at investigating the effect of sitagliptin on hepatic steatosis, insulin resistance, inflammation, and autophagy and exploring the underlying molecular mechanism. In the current study, ob/ob mice, a mouse model of genetic obesity and diabetes, were administered via gavage with sitagliptin 50 mg/kg daily for 4 weeks. Changes in glycolipid metabolism, inflammatory responses, and autophagy in the liver were evaluated. Body weight gain, lipid metabolic disorder, and hepatic steatosis as well as systemic and hepatic insulin sensitivity in ob/ob mice were significantly attenuated after sitagliptin treatment. Furthermore, sitagliptin decreased inflammatory responses by regulating macrophage M1/M2 polarization and inhibiting the activities of NF-κB and JNK. Moreover, sitagliptin increased the levels of phosphorylation of AMPK and decreased those of mTOR. This study indicates that sitagliptin significantly ameliorates the development of hepatic steatosis and insulin resistance in ob/ob mice by inhibiting inflammatory responses and activating autophagy via AMPK/mTOR signaling pathway.
Highlights
The prevalence of diabetes and obesity has increased tremendously worldwide, mainly because of increased energy intake and decreased energy expenditure
The results revealed that sitagliptin could attenuate obesity-induced hepatic insulin resistance and steatosis, suppress inflammation by regulating macrophage M1/M2 polarization imbalance, and promote liver autophagy via AMPK/mammalian target of rapamycin (mTOR) signaling pathway
Sitagliptin-treated group showed a slight but significant reduction in body weight and not significant decrease in fasting plasma glucose at week 4 compared with the ob/ ob group
Summary
The prevalence of diabetes and obesity has increased tremendously worldwide, mainly because of increased energy intake and decreased energy expenditure. Low-grade, metabolic inflammation is a key component in the pathogenesis of obesity and associated disorders such as insulin resistance and type 2 diabetes (T2D) [1]. Genetic ablation of Jun N-terminal kinase (JNK) or IκB kinase (IKKβ) protected mice from high-fat diet- (HFD-) induced inflammation and insulin resistance [6, 7], demonstrating that these inflammatory signaling pathways in macrophages are crucial regulators in metabolic dysfunction. Several studies have proposed that during obesity, the hepatic inflammation was induced, associated with a significant increase in International Journal of Endocrinology liver macrophages [8, 9]. Chemical ablation of hepatic macrophages protects mice from HFD-induced insulin resistance and hepatic steatosis, revealing the importance of these cells in the development of metabolic disorders [9, 10]. Inflammatory activation of liver macrophages contributes importantly to the pathogenesis of obesity-induced insulin resistance and hepatic steatosis
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