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The mechanism of the development of hepatic insulin sensitivity in chromogranin a null mice


Chromogranin A (CHGA/Chga), a proprotein distributed in endocrine and neuroendorcrine tissues. Pancreastatin (PST), CHGA derivative, has been reported to interfere with insulin action. Chga knock-out (KO) mouse was generated by targeted deletion of Chga gene in neuroendocrine tissues. KO mice displayed hypertension, decreased insulin level despite being euglycemic indicating increase insulin sensitivity, and inhibition of gluconeogenesis which was reversed after PST supplementation. Hepatic and plasma lipid concentrations in KO mice were lower than wild type mice. KO mice had increased adipose tissue mass suggesting hepatic and plasma lipids were sequestered and stored in adipose tissue, and PST deficiency influenced both glucose and lipid metabolism. To better understand the effect of PST on lipid metabolism, mRNA expression levels of lipogenic, oxidative and lipolytic genes were measured in WT, KO and KO plus PST (40[mu]g/g bw ip for 7 days)- treated mice. Expression of gluconeogenic genes, phosphoenolpyruvate carboxykinase (Pepck) and glucose6- phosphatase (G6pase), were studied. The varying effect of catestatin and PST were compared to determine which active peptide of CHGA affects lipid metabolism and insulin sensitivity. Our results demonstrated that lipogenesis and fatty acid oxidation in adipose tissue of KO mice were lower than liver. PST reversed inhibition of expression of Pepck and G6Pase in KO mice. In conclusion, PST deficiency in KO mice enhanced hepatic insulin sensitivity towards glucose production and lipid disposal by suppressing Pepck and G6Pase expression and stimulating fatty acid oxidation. Decreased hepatic and plasma lipid concentrations in KO mice helped maintain higher insulin sensitivity in KO mice

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