Pancreastatin inhibitor PSTi8 prevents free fatty acid-induced oxidative stress and insulin resistance by modulating JNK pathway: In vitro and in vivo findings

Abstract

AimFree fatty acid-mediated obesity plays a crucial role in the pathogenesis of Type 2 Diabetes. FFA induced JNK activation acts as a central regulator in causing hepatic insulin resistance. Similarly, Pancreastatin, a chromogranin A peptide, serves as a crucial link between FFA-induced insulin resistance. Therefore, in the present work, we sought to test Pancreastatin inhibitor PSTi8 to ameliorate FFA-induced hepatic insulin resistance in in vitro and in vivo models. Material and methodsTo verify our objective, we exposed hepatocytes (HepG2 cells) with palmitate (0.3 mM) or palmitate + PSTi8 (200 nM). Parallelly mice were fed either HFD or HFD + PSTi8 (1 mg/kg). After 21 days animals were scanned for increased fat mass, along with GTT, ITT and PTT experiment to check glucose, and insulin tolerance. Furthermore, ROS generation and hepatic glycogen content was measured in FFA exposed hepatocytes. Gene expression and protein expression studies were further conducted to delineate the action mechanism of PSTi8. Key findingsPSTi8 exposure decreased ROS accumulation, lipid accumulation, and reduced glycogen content in FFA-induced groups. It also enhances glucose uptake and reduces gluconeogenesis to combat the FFA effect. Furthermore, gene expression studies indicate that PSTi8 treatment reduces NADPH oxidase3 (NOX3) expression and inhibits JNK signaling, a predominant source of ROS-induced insulin resistance. SignificanceTo summarize, the protective effect of PSTi8 on FFA-induced insulin resistance is mediated via inhibition of JNK signaling, which leads to decreased ROS generation and enhanced insulin sensitivity. Hence PSTi8 could be a therapeutic molecule to prevent western diet-induced insulin resistance.