Background: Mice lacking the neurosecretory protein Chromogranin A are obese, presumably because of resistance to catecholamines and leptin. Results: Catestatin (CST) reduces adiposity, an effect likely mediated by restoring leptin sensitivity and modulating adrenergic signaling. Conclusion: CST promotes lipolysis by blocking ␣-AR signaling and stimulating fatty acid oxidation. Significance: We propose CST as a candidate antiobesity agent.

Chromogranin A knockout (Chga-KO) mice exhibit enhanced insulin sensitivity despite obesity. Here, we probed the role of the chromogranin A-derived peptide pancreastatin (PST: CHGA ) by investigating the effect of diet-induced obesity (DIO) on insulin sensitivity of these mice. We found that on a high-fat diet (HFD), Chga-KO mice (KO-DIO) remain more insulin sensitive than wild-type DIO (WT-DIO) mice. Concomitant with this phenotype is enhanced Akt and AMPK signaling in muscle and white adipose tissue (WAT) as well as increased FoxO1 phosphorylation and expression of mature Srebp-1c in liver and downregulation of the hepatic gluconeogenic genes, Pepck and G6pase. KO-DIO mice also exhibited downregulation of cytokines and proinflammatory genes and upregulation of anti-inflammatory genes in WAT, and peritoneal macrophages from KO mice displayed similarly reduced proinflammatory gene expression. The insulin-sensitive, anti-inflammatory phenotype of KO-DIO mice is masked by supplementing PST. Conversely, a PST variant peptide PSTv1 (PST-ND3: CHGA 276-301 ), lacking PST activity, simulated the KO phenotype by sensitizing WT-DIO mice to insulin. In summary, the reduced inflammation due to PST deficiency prevented the development of insulin resistance in KO-DIO mice. Thus, obesity manifests insulin resistance only in the presence of PST, and in its absence obesity is dissociated from insulin resistance.The chromogranin A (human CHGA/mouse Chga) proprotein (1-4) undergoes proteolysis and gives rise to bioactive peptides including the antihypertensive catestatin (CHGA 352-372 ) (5-8) and the diabetogenic pancreastatin (PST: CHGA 250-301 ) (9-12). We have shown that Chgadeficient mice (Chga-KO) are obese, hyperadrenergic, and hypertensive. They display elevated levels of circulating leptin and catecholamines but lower levels of interleukin (IL)-6 and Mcp-1 (11,13-16). Despite these abnormalities, Chga-KO mice exhibit enhanced insulin sensitivity (11), a phenotype masked by supplementing PST. PST regulates hepatic insulin signaling through conventional (c) PKC and Srebp-1c (11). Increased plasma PST levels in diabetic populations correlate with insulin resistance (10). Similarly, increased circulating levels of PST in diet-induced obesity (DIO) and db/ db mice are associated with insulin resistance. Despite high levels of plasma leptin and catecholamines, Chga-KO mice are obese owing to peripheral leptin and catecholamine resistance (17).Since normal chow diet (NCD)-fed Chga-KO mice displayed increased insulin sensitivity (11), we hypothesized that Chga-KO mice may be able to maintain insulin sensitivity when exposed to the dysglycemic stress of a highfat diet (HFD). The hallmarks of insulin resistance in DIO mice are obesity, hyperinsulinemia, and increased inflammation (18)(19)(20)(21)(22). Suppression of inflammation in DIO mice can improve insulin sensitivity (23-25). For example, rosiglitazone can improve inflammation and insulin sensitivity in DIO mice without reducing obesity significantly (23-25). Chga-KO mice are...

Cigarette smoking causes insulin resistance. However, nicotine induces anti-inflammation and improves glucose tolerance in insulin-resistant animal models. Here, we determined the effects of nicotine on glucose metabolism in insulin-sensitive C57BL/J6 mice. Acute nicotine administration (30 min) caused fasting hyperglycemia and lowered insulin sensitivity acutely, which depended on the activation of nicotinic-acetylcholine receptors (nAChRs) and correlated with increased catecholamine secretion, nitric oxide (NO) production, and glycogenolysis. Chlorisondamine, an inhibitor of nAChRs, reduced acute nicotine-induced hyperglycemia. qRT-PCR analysis revealed that the liver and muscle express predominantly β4 > α10 > α3 > α7 and β4 > α10 > β1 > α1 mRNA for nAChR subunits respectively, whereas the adrenal gland expresses β4 > α3 > α7 > α10 mRNA. Chronic nicotine treatment significantly suppressed expression of α3-nAChR (predominant peripheral α-subunit) in liver. Whereas acute nicotine treatment raised plasma norepinephrine (NE) and epinephrine (Epi) levels, chronic nicotine exposure raised only Epi. Acute nicotine treatment raised both basal and glucose-stimulated insulin secretion (GSIS). After chronic nicotine treatment, basal insulin level was elevated, but GSIS after acute saline or nicotine treatment was blunted. Chronic nicotine exposure caused an increased buildup of NO in plasma and liver, leading to decreased glycogen storage, along with a concomitant suppression of Pepck and G6Pase mRNA, thus preventing hyperglycemia. The insulin-sensitizing effect of chronic nicotine was independent of weight loss. Chronic nicotine treatment enhanced PI-3-kinase activities and increased Akt and glycogen synthase kinase (GSK)-3β phosphorylation in an nAChR-dependent manner coupled with decreased cAMP response element-binding protein (CREB) phosphorylation. The latter effects caused suppression of Pepck and G6Pase gene expression. Thus, nicotine causes both insulin resistance and insulin sensitivity depending on the duration of the treatment.

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BACKGROUND: The secretory proprotein Chromogranin A (CHGA in humans, Chga in mice) gives rise to several peptides of biological importance, which include the dysglycemic hormone pancreastatin (PST: CHGA250-301), the vasodilator vasostatin (CHGA1-76), and the antihypertensive, antiadrenergic, cardiosuppressive and angiogenic peptide catestatin (CST: CHGA352-372). The increased adiposity in hyperadrenergic, hyperleptinemic and insulin-sensitive Chga knockout (Chga-KO) mice is due to resistance to catecholamines and leptin.