Responsiveness to Peripherally Administered Melanocortins in Lean and Obese Mice

Responsiveness to Peripherally Administered Melanocortins in Lean and Obese Mice Susann Blüher 1 , Mary Ziotopoulou 1 , John W. Bullen, Jr 1 , Stergios J. Moschos 1 , Linda Ungsunan 1 , Efi Kokkotou 2 , Eleftheria Maratos-Flier 2 and Christos S. Mantzoros 1 1 Department of Medicine, Division of Endocrinology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts 2 Joslin Diabetes Center, Harvard Medical School, Boston, Massachusetts Address correspondence and reprint requests to C.S. Mantzoros, MD, Division of Endocrinology, RN 325, Beth Israel Deaconess Medical Center, Harvard Medical School, 99 Brookline Ave., Boston, MA 02215. E-mail: cmantzor{at}caregroup.harvard.edu Abstract To elucidate mechanisms of melanocortin action, we investigated the effects of a melanocortin receptor agonist (melanotetan II [MTII]) in lean C57BL/6J and obese (DIO, ob/ob , UCP1-DTA) mice. MTII administration (100 μg q.i.d. i.p.) for 24 h results in similar weight loss but a more pronounced decrease of food intake in DIO mice. After 4 and 8 days of MTII treatment, however, the reduction in both food intake and body weight is more pronounced in DIO mice than in lean mice. MTII administration for 24 h prevents food deprivation-induced alterations in hypothalamic neuropeptide Y (NPY) and liver adiponectin receptor 1 and adiponectin receptor 2 mRNA expression, but does not alter hypothalamic mRNA expression of melanocortin 4 receptor or adiponectin serum and mRNA expression levels. NPY and agouti gene-related protein (AgRP) mRNA expression after 8 days of MTII is increased to levels comparable to pair-fed mice. In summary, 1 ) MTII is an effective treatment for obesity and related metabolic defects in leptin-resistant (DIO, UCP1-DTA) and leptin-sensitive ( ob / ob ) mouse models of obesity; 2 ) the effects of MTII on food intake and body weight are more pronounced in DIO mice than in lean mice; 3 ) the tachyphylactic effect after prolonged MTII administration appears to be, at least in part, caused by a compensatory upregulation of NPY and AgRP mRNA levels, whereas decreasing leptin levels may play a very minor role in mediating tachyphylaxis; and 4 ) alterations in adiponectin receptor mRNA expression after fasting or MTII treatment may contribute to altered insulin sensitivity and needs to be studied further. AdipoR, adiponectin receptor AgRP, agouti gene-related protein MC4R, melanocortin 4 receptor MCH, melanocyte concentrating hormone MTII, melano