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 microg 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.