Piperine protects against pancreatic β-cell dysfunction by alleviating macrophage inflammation in obese mice

Aims: Piperine, the major pharmacological ingredient of pepper, can delay the procession of "obesity to diabetes". However, the underlying mechanism remains unclear. This study aims to investigate whether piperine protects against beta-cell dysfunction by inhibiting macrophage accumulation and M-1-like polarization.Materials and methods: Pre-diabetic model was induced by feeding 60% high-fat diet (HFD) in C57BL/6C mice, piperine (15 or 30 mg/kg/day) and rosiglitazone (4 mg/kg/day) were given orally for 8 weeks. Oral glucose tolerance test (OGTT), insulin tolerance test (ITT), fasting blood glucose (FBG), total cholesterol (TC) and triglyceride (TG) were used to assay the disorder of glycolipid metabolism. Serum levels of cytokines and insulin were measured by Elisa. Hyperglycemic clamp assay was carried out to evaluate beta-cell function. RT-PCR, immunofluorescence and western blot were used to detect the expression of biomarkers associated with macrophage polarization and beta-cell dedifferentiation.Key findings: Piperine protected against beta-cell dysfunction, indicated by the improvement of hyperinsulinemia, OGTT and increased glucose infusion rate (GIR). Piperine dramatically reduced the serum levels of lipopolysaccharide (LPS), interleukin-1 beta (IL-1 beta) and Galectin-3 (Gal-3), suppressed the expression of M-1-like cytokines (CD11c, IL-1 beta and Gal-3) in epididymal adipose tissues and islets. Furthermore, piperine partially reversed the down-regulation of Pdx1, inhibited the up-regulation of ALDH1A3 in beta-cell, and these effects were closely related to the mTOR/S6/4E-BP1 signal pathway.Significance: Piperine markedly ameliorates the dedifferentiation and dysfunction of beta-cell by inhibiting the accumulation and M-1-like polarization of macrophages in visceral adipose tissues and islets.