Dipeptidyl peptidase-4 (DPP4) inhibitor sitagliptin alleviates liver inflammation of diabetic mice by acting as a ROS scavenger and inhibiting the NFκB pathway.

As a common chronic metabolic disease, the development of diabetes mellitus (DM) may also be accompanied by liver damage and inflammatory disorders. Sitagliptin is an inhibitor of dipeptidyl peptidase-4 (DPP4, also known as CD26), which is clinically used for DM treatment. However, the mechanism of sitagliptin's efficiency in liver diseases is largely unknown. In this study, mice suffering from streptozotocin (STZ) exhibit elevated liver DPP4 expression and activity, as well as inflammatory and chronic liver injury phenotype, whereas specifically inhibiting the activity of DPP4 in mouse liver tissues and hepatocytes by sitagliptin contributes to decreased cytokines, oxidative stress, cell apoptosis, and inflammation in STZ-induced diabetic mice. Moreover, sitagliptin reduced TNFα or LPS-induced cellular reactive oxygen species (ROS) level, cell apoptosis, and protein expression in the NFκB signaling pathway in HepG2 cells or primary mouse hepatocytes. Altogether, our study confirms that sitagliptin may protect liver tissue by alleviating ROS production and NFκB signaling activation, providing a putative mechanism for preventing the development of diabetic liver disease.

Activation of brown adipocytes by placental growth factor.

Gestational diabetes mellitus (GDM) is a type of diabetes and occurs during pregnancy. Brown adipose tissue (BAT) improves glucose homeostasis and mitigates insulin resistance, however, its activity is reduced in GDM. Placenta growth factor (PlGF) is an angiogenic factor produced by placental trophoblasts. Nevertheless, whether and how PlGF could affect BAT function in GDM are not defined. To investigate this question, 91 non-diabetic pregnant participants and 73 GDM patients were recruited to Gynaecology and Obstetrics Centre in Lu He hospital. Serum levels of PlGF were quantified by ELISA. Skin temperature was measured by far infrared thermography in the supraclavicular region where classical BATs were located. The direct effect of PlGF on BAT function was explored using the established human preadipocyte differentiation system. Thereby, we demonstrated that serum levels of PlGF were lower in GDM patients compared with controls, which was accompanied by decreased skin temperature in the supraclavicular region. By qPCR and western blot, mRNA and protein expression of UCP1 and OXPHOS were elevated in differentiated adipocytes treated with PlGF. PlGF stimulated mitochondrion transcription and increased copy number of mitochondrial. When subjected for respirometry, PlGF-treated differentiated adipocytes showed higher oxygen consumption rates than controls. PlGF induced AMPK phosphorylation and blockade of AMPK phosphorylation blunted UCP1 and OXPHOS expression in differentiated adipocytes. PlGF administration reduced cholesterol and triglyceride content in the liver and improved insulin sensitivity in db mice compared with control. In Conclusion, PlGF could activate BAT function. Downregulation of PlGF might contribute to the reduced BAT activity in GDM.