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.