Obesity, lipodystrophy, diabetes and hypertension collectively constitute 'Metabolic Syndrome' (MS). MS generally causes cardiovascular disease (CVD), which is the leading cause of mortality and morbidity in the United States. Insulin resistance is a central component defining the MS. The primary goal of this proposal is to reduce hypertension and at the same time minimize hyperglycemia and glucose intolerance associated with insulin resistance. We have identified that chromogranin A (Chga)-derived peptide, catestatin (CST), lowers blood pressure (BP) and heart rate (HR) by inhibiting release of catecholamines. Chga, an index member of the chromogranin/secretogranin protein family, is a pro-protein that is ubiquitously expressed in neuroendocrine tissues. Proteolytic processing of Chga gives rise to biologically active peptides such as the dysglycemic hormone pancreastatin, vasodilator vasostatin, and the catecholamine release inhibitory peptide CST. To gain a better insight into the role of Chga in metabolic disorder, we have generated Chga knockout mice (Chga-KO), which display hypertension, high plasma catecholamines, increased hepatic sensitivity to insulin and muscle insulin resistance. CST replacement in Chga-KO mice normalizes BP, suppresses insulin clearance, elevates insulin level to normal and improves glucose disposal. One of the intriguing functions of CST is the regulation of metabolic insulin clearance (MIC) in liver. Strong association exists between essential hypertension and decreased MIC. CST deficient Chga-KO mice show high MIC, as judged by C-peptide/insulin molar ratio, leading to low level of insulin. We hypothesize that essential hypertension-induced decrease in MIC requires interaction with CST. Therefore, CST could play an important role in regulation of MIC. In absence of CST, when challenged with glucose, insulin secretion from pancreatic 2-cells alone will not be adequate to dispose blood glucose. Therefore, CST is required to maintain euglycemia through suppression of hepatic insulin clearance. CST maintains glucose homeostasis by balancing increased gluconeogenesis with increased glucose disposal and decreased glycogenolysis. CST transiently stimulates gluconeogenesis by attenuating endothelial nitric oxide synthase (eNOS) and 5'-adenosine monophosphate-activated protein kinase (AMPK), and enhances glucose disposal and glycogen storage by preventing desensitization of adrenergic receptor actions via suppression of insulin clearance and by maintaining of low NO levels. In addition, CST promotes lipid and glucose disposal and thereby protects against excessive rise in glucose level. Moreover, CST pretreatment 'rescues' Chga-KO mice from elevated BP and higher plasma catecholamines. This proposal will focus on the discovery of novel pathways for regulation of insulin and glucose levels by CST in genetically engineered Chga-KO and CST-KO mice. On the basis of our findings on Chga-KO mice, we propose to test CST functions in a well-established type 2 diabetic (db/db) mouse model. Towards that end, we propose two Specific Aims: 1. Determine the pathway of CST-induced regulation of insulin sensitivity, insulin clearance and glucose homeostasis in wild-type, Chga-KO and CST-KO mice. 2. Evaluate the potential therapeutic effects of CST and its variants on insulin sensitivity and baroreflex sensitivity and heart rate variability in high fat diet-induced insulin resistant and in db/db diabetic mice.