Pancreastatin inhibitor PSTi8 balances energy homeostasis by attenuating adipose tissue inflammation in high fat diet fed mice

Pancreastatin (PST) is an endogenous bioactive peptide. PST is generated from chromogranin A (Chga) protein which is released by chromaffin and neuroendocrine cells. PST exhibits diabetogenic effect by antagonizing the action of insulin in adipocytes. The level of PST rises during obesity, resulting in persistent low-grade inflam-mation in adipocytes. Pancreastatin inhibitor 8 (PSTi8), which is developed by modification of PST sequence which antagonizes the action of PST. In this study, we investigated the immunometabolic effect of PSTi8 in the diet-induced obesity (DIO) model in C57BL/6 mice. Here we found PSTi8 decreased the body weight gain, fat mass and increased the lean mass in (DIO) mice. It also showed reduction of adipocyte hypertrophy in eWAT and lipid accumulation in liver of DIO mice. Immunoprofiling of stromal vascular fraction isolated from eWAT of PTSi8 treated mice showed increased anti-inflammatory M2 macrophages, Eosinophil, T-regulatory cells and reduced pro-inflammatory M1 macrophages, CD4 and CD8 T cell population. Apart from this, PSTi8 also improved the mitochondrial function by decreasing reactive oxygen species and increasing mitochondrial membrane potential, NADPH/NADP ratio and citrate synthase activity in eWAT of DIO mice. It also increased the protein expression of pAMPK, pAKT, Arginase-1 and decreased the expression of MHC-II and iNOS in eWAT of DIO mice. In conclusion, PSTi8 exerted its beneficial effect on restoring energy expenditure by reducing adipose tissue inflammation.

Automated summary

This study investigated the immunometabolic effect of PSTi8 in a diet-induced obesity (DIO) model in mice. The results showed that PSTi8 reduced body weight gain and fat mass while increasing lean mass. It also decreased adipocyte hypertrophy and lipid accumulation in the liver. Additionally, PSTi8 increased the number of anti-inflammatory cells, reduced the number of pro-inflammatory cells, and improved mitochondrial function. Overall, PSTi8 exerted beneficial effects on energy expenditure by reducing adipose tissue inflammation.