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Reduced Anorexigenic Efficacy of Leptin, But Not of the Melanocortin Receptor Agonist Melanotan-II, Predicts Diet-Induced Obesity in Rats

Department of Animal Physiology, Biological Center (G.v.D., K.d.V., B.B., T.A., A.J.W.S.), 9751 NN Haren, The Netherlands; Department of Pediatrics (F.K.), Center for Liver, Digestive, and Metabolic Diseases, University Medical Center Groningen, 9747 AG Groningen, The Netherlands; Brain Physiology Research Group of Hungarian Academy of Sciences (C.N.), Semmelweis University, 1085 Budapest, Hungary; Department of Pharmacology and Anatomy (M.K., R.A.H.A.), Rudolf Magnus Institute of Neurosciences, University Medical Center Utrecht, Utrecht, The Netherlands; Department of Psychiatry and Behavioral Sciences, University of Washington (C.W.W.), Geriatric Research, Education and Clinical Center, Veterans Affairs Puget Sound Health Care System, and Department of Psychiatry and Behavioral Sciences, University of Washington, Seattle, Washington 98108; and Department of Psychology (T.E.T.), University of North Carolina, Chapel Hill, North Carolina 27514

Address all correspondence and requests for reprints to: Gertjan van Dijk, Kerklaan 30, 9751 NN Haren, The Netherlands. E-mail: gertjan.van.dijk{at}rug.nl.

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 [Nle⁴,D-Phe⁷]-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.