title: Physiologic effect of leptin on insulin secretion is mediated mainly through central mechanisms.
abstract: Leptin has been shown to decrease glucose-stimulated insulin secretion in both in vivo and in vitro studies. As some of the effects of leptin have been elicited through both peripheral and central mechanisms, we assessed whether leptin modulates insulin secretion also through the central nervous system. We infused leptin or saline through implanted intracerebro-ventricular (ICV) catheters to chronically catheterized, conscious rats (n=15), 2 h after initiation of hyperglycemic (approximately 11 mM) clamp. On ICV administration of leptin, there was a gradual and progressive decrease in plasma insulin levels by 52% with 30 ng (P<0.005) and by 28% with 20 ng (P<0.05) of leptin compared with ICV saline. The effect of 20 ng leptin ICV was replicated by intravenous (IV) leptin infusion that achieved physiological leptin levels of approximately 17 ng/ml (n=5). When the melanocortin (MC) pathway was blocked with a nonselective MC-3/4 antagonist SHU 9119 administered ICV, and either saline or leptin (n=12) was infused IV, intravenous leptin failed to produce a decrease in glucose-stimulated insulin levels. We conclude that leptin decreases insulin levels by a predominantly central mechanism, probably via the melanocortin receptors; and peripheral leptin receptors on the beta-cells do not play a major role. The physiological features of this response suggest a possible role for leptin in the evolution of diabetes in overweight individuals.
authors.affiliation: Division of Pediatric Endocrinology, Montefiore Medical Center, Institute for Aging Research and Diabetes Research and Training Center, Department of Medicine, Albert Einstein College of Medicine, Bronx, New York 10461, USA.
authors.forename: Radhika
authors.initials: R
authors.lastname: Muzumdar
authors.forename: Xiaohui
authors.initials: X
authors.lastname: Ma
authors.forename: Xiaoman
authors.initials: X
authors.lastname: Yang
authors.forename: Gil
authors.initials: G
authors.lastname: Atzmon
authors.forename: Julia
authors.initials: J
authors.lastname: Bernstein
authors.forename: George
authors.initials: G
authors.lastname: Karkanias
authors.forename: Nir
authors.initials: N
authors.lastname: Barzilai
mesh_terms: D000818:Animals; D002552:Cerebral Ventricles; D004305:Dose-Response Relationship, Drug; D015309:Glucose Clamp Technique; D007031:Hypothalamus / Q000502:physiology*; D007328:Insulin / Q000097:blood* / Q000378:metabolism; D000078790:Insulin Secretion; D020738:Leptin / Q000008:administration & dosage / Q000494:pharmacology* / Q000502:physiology; D009074:Melanocyte-Stimulating Hormones / Q000494:pharmacology; D008959:Models, Neurological; D051381:Rats; D018043:Receptors, Corticotropin / Q000037:antagonists & inhibitors; D044101:Receptors, Melanocortin
chemical_list: D007328:Insulin; D020738:Leptin; D018043:Receptors, Corticotropin; D044101:Receptors, Melanocortin; C103272:SHU 9119; D009074:Melanocyte-Stimulating Hormones