title: Chronic intracerebroventricular insulin attenuates the leptin-mediated but not alpha melanocyte stimulating hormone increase in sympathetic and cardiovascular responses.
abstract: The co-existence of hyperinsulinemia and hyperleptinemia of obesity is well established. Additionally, both insulin resistance and leptin resistance are also characteristic of these states. Possible central nervous system (CNS) mechanisms could mediate these responses in that leptin receptors are located on hypothalamic neurons that coexpress neuropeptide-Y (NPY) or proopiomelanocortin (POMC) and both peptides that have been implicated as mediators of the CNS action of leptin. Leptin has been demonstrated to decrease or down regulate NPY expression and increase POMC expression. Insulin also has been demonstrated to decrease NPY and insulin insufficiency is associated with an increased POMC. Since both leptin and insulin share and modulate the same effector systems, we investigated the effect of CNS-induced hyperinsulinemia on the subsequent cardiovascular and sympathetic nervous response to leptin. Normal rats were implanted with intracerebroventricular (i.c.v.) cannula and allowed to recover. They were treated with insulin via i.c.v. cannula for 3 days. Following treatment, they were instrumented for the recording of cardiovascular and sympathetic nervous responses. Intracerebroventricular leptin administration in normal animals result in a progressive increase in both lumbar sympathetic nerve activity and mean arterial pressure. However, in animals pretreated with insulin for 3 days the leptin-induced response was completely attenuated. However, insulin treatment did not affect the POMC peptide product, alpha-melanocyte stimulating hormone (alphaMSH), mediated sympathetic nervous and cardiovascular responses. From these studies we conclude that CNS hyperinsulinemia can act to attenuate the leptin-induced increases in sympathetic nervous and cardiovascular system activity. The decreased responsiveness is not due to decreased sensitivity of the melanocortin, alphaMSH, mediated pathway.We suggest that the hyperinsulinemia of obesity may play a role in the obesity-induced leptin resistance.
authors.affiliation: Department of Physiology, Wayne State University School of Medicine, Detroit, MI 48201, USA. jdunbar@med.wayne.edu
authors.forename: J C
authors.initials: JC
authors.lastname: Dunbar
authors.forename: H
authors.initials: H
authors.lastname: Lu
mesh_terms: D000818:Animals; D001794:Blood Pressure / Q000187:drug effects*; D001835:Body Weight / Q000187:drug effects; D002552:Cerebral Ventricles / Q000187:drug effects / Q000502:physiology*; D004334:Drug Administration Schedule; D006339:Heart Rate / Q000187:drug effects*; D006946:Hyperinsulinism / Q000503:physiopathology; D007276:Injections, Intraventricular; D007328:Insulin / Q000008:administration & dosage / Q000494:pharmacology*; D020738:Leptin / Q000008:administration & dosage / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D008297:Male; D051381:Rats; D017208:Rats, Wistar; D013564:Sympathetic Nervous System / Q000187:drug effects / Q000502:physiology; D000521:alpha-MSH / Q000008:administration & dosage / Q000494:pharmacology*
chemical_list: D007328:Insulin; D020738:Leptin; D000521:alpha-MSH