1: Diabetes. 2007 Dec;56(12):2872-7. Epub 2007 Sep 5. Central insulin regulates heart rate and arterial blood flow: an endothelial nitric oxide synthase-dependent mechanism altered during diabetes. Cabou C, Cani PD, Campistron G, Knauf C, Mathieu C, Sartori C, Amar J, Scherrer U, Burcelin R. Inserm U858, Institute of Molecular Medicine, IFR31, CHU Rangueil, BP 84225, 31432 Toulouse Cedex 4, France. OBJECTIVE: Central neural insulin regulates glucose homeostasis, but less is known about its cardiovascular effects. Endothelial nitric oxide synthase (eNOS)-derived nitric oxide (NO) represents a molecular link between metabolic and cardiovascular disease. Its role in the central nervous system remains to be determined. We studied the effects of central insulin infusion on femoral arterial blood flow and heart rate in normal chow-fed, high-fat diet-fed diabetic, and eNOS-null mice. RESEARCH DESIGN AND METHODS: We recorded heart rate and femoral blood flow (ultrasonic flow probe) during 3-h central insulin infusion in conscious, freely moving mice. To study the role of NO in this setting, we assessed total and phosphorylated eNOS in the hypothalamus and examined the effects of brain infusion of NO donors/NOS inhibitors on cardiovascular responsiveness to central insulin in these experimental mouse models. RESULTS: In normal mice, central insulin rapidly increased heart rate by 30% and more progressively increased blood flow by 40%. In high-fat diet-fed mice, the cardiovascular effects of insulin were blunted and associated with a 50% reduction of the total and phosphorylated eNOS expression in the hypothalamus, suggesting a causal link. In line with this hypothesis, in eNOS-null mice and central N(G)-monomethyl-L-arginine-infused normal mice, the cardiovascular effects of insulin were abolished, whereas central NO donor infusion restored these effects in eNOS-null mice. In high-fat diet-fed mice, central NO donor infusion mimicked the cardiovascular responses evoked by central insulin in normal mice. CONCLUSIONS: Central insulin has cardiovascular effects in conscious, freely moving mice that are mediated, at least in part, by central neural eNOS. These effects are impaired in insulin-resistant high-fat diet-fed mice. PMID: 17804761 [PubMed - in process] Related Links Partial gene deletion of endothelial nitric oxide synthase predisposes to exaggerated high-fat diet-induced insulin resistance and arterial hypertension. [Diabetes. 2004] PMID:15277387 Clustering of cardiovascular risk factors mimicking the human metabolic syndrome X in eNOS null mice. [Swiss Med Wkly. 2003] PMID:12947532 Insulin resistance, hyperlipidemia, and hypertension in mice lacking endothelial nitric oxide synthase. [Circulation. 2001] PMID:11457755 Diabetes induces endothelial dysfunction but does not increase neointimal formation in high-fat diet fed C57BL/6J mice. [Circ Res. 2005] PMID:15879311 Renal cortical and medullary blood flow responses to L-NAME and ANG II in wild-type, nNOS null mutant, and eNOS null mutant mice. [Am J Physiol Regul Integr Comp Physiol. 2005] PMID:15961532