Catestatin improves glucose homeostasis and insulin sensitivity in diet-induced obese mice

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Project Summary. Obesity represents a state of chronic, low-grade tissue inflammation that contributes to insulin resistance (IR) steatosis and type 2 diabetes mellitus (T2DM). The demands for effective therapy call for improved understanding of the disease. There is a significant gap in our understanding of the endogenous factors that regulate both inflammatory responses and insulin sensitivity. In this application, we showed that a peptide, catestatin (CST), derived from a gene product, chromogranin A (CgA), directly improves lipid disposal and inflammation leading to reversal of insulin resistance (IR) in a mouse model of obesity. CST improved IR in diet-induced obese (DIO) mice without weight loss. We generated CST-deficient knockout (CST-KO) mice, which are obese and insulin resistant in normal chow diet. As a possible mechanism, our data suggested that CST raised AMP levels by inhibiting AMP-deaminase (AMPD), stimulated AMP-dependent Kinase (AMPK) signaling and AKT phosphorylation in DIO liver as well as in hepatocyte cultures, signifying a direct CST effect. This activation of AMPK and AKT signaling by CST suppresses gluconeogenesis via phosphorylation of CRTC2 and FoxO1 and elevates glycogen production via activation of phosphoglucomutase (PGM). Another consequence of CST action is to attenuate inflammation, mediated by macrophages, in an AMPK-dependent manner. This is accomplished by suppressing cytokine production and proinflammatory signaling, which in turn, could enhance AKT signaling. Analysis by transmission electron microscopy (TEM) of the sections of liver and adipose tissue of DIO mice after CST treatment indicated diminished infiltration or recruitment of proinflammatory macrophages. We hypothesize that CST inhibits activity of AMPD2 giving rise to elevated level of AMP, and activation of AMPK, which in turn, reduces steatosis and macrophage-mediated inflammation leading to enhancement of insulin signaling and suppression of gluconeogenesis in DIO and CST-KO mice. We will verify our hypothesis by working with two specific aims: Aim I. To test whether CST suppresses hepatic glucose production through activation of AMPK via inhibition of AMP-deaminase 2 (AMPD2) which elevates AMP levels necessary for AMPK activation. In this aim, we will examine the mechanism of CST action in liver and hepatocyte focusing on AMPK and PGM activation. Aim II. To test the hypothesis that CST-mediated activation of AMPK leads to suppression of inflammation and glucose production via enhancement of AKT signaling in DIO and CST-KO mice. In this aim, we will analyze the pathways invoked by CST-mediated AMPK activation that lead to suppression of inflammation and glucose production. We will execute these specific aims by knocking down activities of AMPD2 and AMPKα and analyzing their impacts on CST mediated signaling, AMP/ATP ratio, PGM activity, cytokine and glucose production. Through investigation with this proposal, we believe we will discover a novel pathway for regulation of insulin sensitivity and glucose homeostasis.