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Abnormal fat accumulation, enhanced free fatty acids (FFA) release, and their metabolites cause insulin resistance (IR) in major glucose-lipid metabolic organs such as skeletal muscle and adipose tissue. However, excessive lipolysis and FFA release from adipose tissue elevate plasma FFA levels leading to oxidative stress and skeletal muscle IR. Indeed, in obese individuals, there is enhanced pro-inflammatory secretion from adipose tissue influencing insulin signaling in skeletal muscles. Here, we investigated the effect of PSTi8 on FFA-induced IR in both in vitro and in vivo models. Palmitate (Pal)-treated 3T3-L1 cells increased lipid accumulation as well as lipolysis, which reduced the insulin-stimulated glucose uptake. PSTi8 treatment significantly prevented Pal-induced lipid accumulation, and release and enhanced insulin-stimulated glucose uptake. It further reduced the release of pro-inflammatory cytokines from Pal-treated 3T3-L1 cells as well as from adipose tissue explants. In addition, PSTi8 treatment decreases M1 surface markers in Pal-treated bone marrow-derived monocytes (BMDM). PSTi8 treatment also significantly enhanced the Pal-mediated reduced skeletal muscle glucose disposal and reduced intracellular oxidative stress. In vitro effect of PSTi8 was consistent with in vivo HFD-fed mice IR model. PSTi8 treatment in HFD-fed mice significantly improved glucose metabolism and enhanced skeletal muscle insulin sensitivity with reduced adiposity and pro-inflammatory cytokines. Taken together, our results support that PSTi8 treatment can protect both adipose and skeletal muscles from FFA-induced IR. [ABSTRACT FROM AUTHOR]

Chromogranin A (ChgA) is an acidic pro-protein found in neuroendocrine organs, pheochromocytoma chromaffin granules, and tumor cells. Proteolytic processing of ChgA gives rise to an array of biologically active peptides such as pancreastatin (PST), vasostatin, WE14, catestatin (CST), and serpinin, which have diverse roles in regulating cardiovascular functions and metabolism, as well as inflammation. Intricate tissue-specific role of ChgA-derived peptide activity in preclinical rodent models of metabolic syndrome reveals complex effects on carbohydrate and lipid metabolism. Indeed, ChgA-derived peptides, PST and CST, play a pivotal role in metabolic syndrome such as obesity, insulin resistance, and diabetes mellitus. Additionally, supplementation of specific peptide in ChgA-KO mice have an opposing effect on physiological functions, such as PST supplementation reduces insulin sensitivity and enhances inflammatory response. In contrast, CST supplementation enhances insulin sensitivity and reduces inflammatory response. In this review, we focus on the tissue-specific role of PST and CST as therapeutic targets in regulating carbohydrate and lipid metabolism, along with the associated risk factors. [ABSTRACT FROM AUTHOR]