Responsiveness to Peripherally Administered Melanocortins in Lean and Obese Mice

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 g 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 leptinsensitive (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. Diabetes 53: 82-90, 2004 T he melanocortin pathway, one of the direct targets of leptin action in the brain (1), plays an important role in energy homeostasis. Mice with targeted deletion of the pro-opiomelanocortin (POMC) gene (2) or the melanocortin 4 receptor (MC4R) gene develop obesity associated primarily with hyperphagia and hyperinsulinemia (3). In addition, MC3 receptor knockout mice have increased fat mass and reduced lean body mass, but normal food intake, suggesting defects in energy partitioning (4).Peripheral or central administration of the synthetic nonspecific melanocortin receptor agonist melanotetan II (MTII) to fasted or neuropeptide Y (NPY)-treated mice as well as obesity-prone or genetically obese animals, such as Sprague-Dawley rats or rhesus macaques, acutely and chronically suppresses food intake and increases sympathetic nervous system activity (5-9), whereas melanocortin antagonism has opposite effects (10 -13). We recently reported that MTII treatment decreases body weight, primarily by suppressing food intake and secondarily by increasing energy expenditure, and improves insulin resistance in mice (14). However, the mechanisms underlying improvement of weight loss and insulin resistance, as well as the development of tachyphylaxis after prolonged MTII administration, remain largely unknown. RESEARCH DESIGN AND METHODSMale C57BL/6J (3-week-old) and ob/ob (6-week-old) mice were purchased fro...

Lean rats with hypothalamic pro-opiomelanocortin overexpression exhibit greater diet-induced obesity and impaired central melanocortin responsiveness

“…Activation of the central melanocortin system by MTII and other melanocortin analogues is efficacious in reducing body weight, food consumption and adiposity in animals with diet-induced obesity [21,22,24,25]. Similarly, we demonstrated that central Pomc gene delivery alleviates obesity and insulin intolerance in rats with genetic or adultonset obesity [26,27].…”

“…Such resistance renders the use of leptin futile in treating obesity in animals and humans with diet-induced obesity. On the contrary, melanotan II (MTII) and other melanocortin analogues ameliorate obesity effectively in leptin-resistant rodents [21][22][23][24][25]. Furthermore, chronic hypothalamic overexpression of Pomc by delivery of the Pomc gene via recombinant adeno-associated virus (rAAV) partially reverses the obese and diabetic phenotypes in genetically obese fa/fa (Lepr/Lepr) rats and those with adult-onset obesity [26,27].…”

Impaired Expression of Cardiac Adiponectin in Leptin-Deficient Mice With Viral Myocarditis

“…Similarly to our data, it has been demonstrated in another experiment that elevation of liver AdipoR1 expression and reduction in the AdipoR2 expression were observed in obese mice given a combination of leptin and a melanocortin receptor agonist, although there were no alterations in the AdipoR1 or AdipoR2 expression in the mice receiving the melanocortin receptor agonist alone. 29) In addition, changes in AdipoR1/R2 expression in skeletal muscle and adipose tissue have been reported in type 2 diabetic patients during PPAR-γ agonist therapy. 30) AdipoR1 expression was up-regulated in adipose tissue but down-regulated in muscle by rosiglitazone.…”

Glucocorticoids exacerbate obesity and insulin resistance in neuron-specific proopiomelanocortin-deficient mice

“…Thus, a contribution of peripheral melanocortin peptides to the obesity phenotype independently of glucocorticoid secretion cannot totally be excluded from our study, since the phenotype of Pomc -/-Tg + mice in the absence of circulating corticosterone has not been evaluated. Peripheral administration of αMSH agonists has been shown to cause weight loss in mice with high-fat diet-induced obesity and genetically obese mice (65)(66)(67), and in fa/fa rats (68,69). In addition, systemic injection of [Nle 4 , D-Phe 7 ]-melanocyte-stimulating hormone reduced food intake and weight gain in Pomc -/-mice (7).…”