title: Reduced anorexigenic efficacy of leptin, but not of the melanocortin receptor agonist melanotan-II, predicts diet-induced obesity in rats.
abstract: Leptin gains access to the central nervous system where it influences activity of neuronal networks involved in ingestive behavior, neuroendocrine activity, and metabolism. In particular, the brain melanocortin (MC) system is important in leptin signaling and maintenance of energy balance. Although leptin or MC receptor insensitivity has been proposed to be associated with obesity, the present study compared central leptin and MC receptor stimulation on some of the above-mentioned parameters and investigated whether these treatments predict proneness to diet-induced obesity (DIO) in outbred Wistar rats. Third-cerebroventricular administration of equi-anorexigenic doses of leptin and of the MC agonist melanotan-II caused comparable increases in plasma ACTH and corticosterone levels and c-Fos-labeling in approximately 70% of paraventricular hypothalamic (PVN) neuronal cell bodies containing CRH. This reinforces involvement of paraventricular CRH neurons in the short-term neuroendocrine and ingestive effects of leptin and melanocortins. In the DIO prediction study, anorexigenic efficacy of melanotan-II was not correlated with any parameter linked to DIO but was highly correlated with MC in situ binding (with labeled [Nle(4),D-Phe(7)]alpha-MSH) as well as CRH immunoreactivity in the PVN of DIO rats. This suggests intricate relationships among MC signaling, the CRH system, and ingestive behavior unrelated to DIO. In the same animals, leptin's anorexigenic efficacy was not correlated with PVN MC in situ binding or CRH immunoreactivity but correlated inversely to post-DIO plasma leptin, liver weight, and abdominal adiposity, the latter being correlated to insulin resistance. Thus, differences in leptin but not MC signaling might underlie DIO, visceral obesity, and insulin resistance.
authors.affiliation: Department of Animal Physiology, Biological Center, Haren, The Netherlands. gertjan.van.dijk@rug.nl
authors.forename: Gertjan
authors.initials: G
authors.lastname: van Dijk
authors.forename: Koert
authors.initials: K
authors.lastname: de Vries
authors.forename: Csaba
authors.initials: C
authors.lastname: Nyakas
authors.forename: Bauke
authors.initials: B
authors.lastname: Buwalda
authors.forename: Tiziana
authors.initials: T
authors.lastname: Adage
authors.forename: Folkert
authors.initials: F
authors.lastname: Kuipers
authors.forename: Martien J H
authors.initials: MJ
authors.lastname: Kas
authors.forename: Roger A H
authors.initials: RA
authors.lastname: Adan
authors.forename: Charles W
authors.initials: CW
authors.lastname: Wilkinson
authors.forename: Todd E
authors.initials: TE
authors.lastname: Thiele
authors.forename: Anton J W
authors.initials: AJ
authors.lastname: Scheurink
mesh_terms: D000818:Animals; D000855:Anorexia / Q000139:chemically induced*; D004032:Diet; D004435:Eating / Q000187:drug effects; D006801:Humans; D007276:Injections, Intraventricular; D020738:Leptin / Q000008:administration & dosage / Q000494:pharmacology; D008297:Male; D009474:Neurons / Q000187:drug effects; D009490:Neurosecretory Systems / Q000187:drug effects; D009765:Obesity / Q000209:etiology*; D010286:Paraventricular Hypothalamic Nucleus / Q000187:drug effects / Q000503:physiopathology; D010456:Peptides, Cyclic / Q000008:administration & dosage* / Q000494:pharmacology; D011237:Predictive Value of Tests; D051381:Rats; D017208:Rats, Wistar; D054411:Receptors, Leptin; D044101:Receptors, Melanocortin / Q000819:agonists*; D000521:alpha-MSH / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology
chemical_list: C515448:LEPR protein, human; D020738:Leptin; D010456:Peptides, Cyclic; D054411:Receptors, Leptin; D044101:Receptors, Melanocortin; C079282:melanotan-II; D000521:alpha-MSH