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

• Published in: Peptides (New York, N.Y. : 1980) Vol. 159; p. 170902
• Main Authors: Goand, Umesh K., Verma, Saurabh, Gupta, Anand P., Garg, Richa, Dadge, Shailesh, Gayen, Jiaur R.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.01.2023
• Subjects: Adipose tissue; Adipose Tissue - metabolism; Animals; Chromogranin A; Diet, High-Fat - adverse effects; Energy expenditure; Homeostasis; Inflammation; Inflammation - drug therapy; Inflammation - metabolism; Insulin Resistance; Macrophages; Mice; Mice, Inbred C57BL; Obesity; Obesity - drug therapy; Obesity - metabolism; T-cells; T-cells; Obesity; Adipose tissue; Energy expenditure; Insulin resistance; Inflammation; Macrophages
• ISSN: 0196-9781; 1873-5169
• DOI: 10.1016/j.peptides.2022.170902

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 inflammation 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. [Display omitted] •Increased PST level imbalances the metabolic profile in DIO mice.•Inhibition of PST decreased insulin resistance and improved insulin sensitivity.•PSTi8 combated adipose tissue inflammation by attenuating pro-inflammatory cells.•PSTi8 increased the M1 macrophages polarization towards M2 macrophages.•PSTi8 improved mitochondrial function and improved energy expenditure.