High-fat diet-induced obesity (DIO) in rodents is associated with hyperleptinemia and resistance to leptin, but the response to agents acting downstream of leptin receptors remains unknown. We assessed the response of mice with DIO to treatment with MTII, an ␣-melanocyte-stimulating hormone analog. MTII delivered four times daily by intraperitoneal injection to C57BL/6J mice produced a dose-responsive effect on food intake, body weight, leptin, corticosterone, insulin, and free fatty acids. In DIO mice, administration of MTII 100 g q.i.d. i.p. markedly suppressed feeding during the first 4 days of treatment, with food intake returning to control levels at day 5. Progressive weight loss also occurred over the first 4 days, after which weight plateaued at a level below control. After 8 days of treatment, MTIItreated DIO mice had major suppression of both leptin and insulin levels. Central administration of MTII for 4 days (10 nmol/day) in DIO mice significantly suppressed food intake, induced weight loss, and increased energy expenditure. These results indicate that 1) MTII administration to DIO mice causes suppression of food intake and body weight loss, and decreased food intake is primarily responsible for weight loss; 2) peripheral MTII improves insulin resistance in DIO mice; 3) "tachyphylaxis" to the effect of chronic MTII treatment on food intake occurs; and 4) at least some of the effects of MTII are exerted centrally. In conclusion, treatment with a melanocortin agonist is a promising therapeutic approach to DIO and associated insulin resistance.

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...

No abstract

. Shortterm resistance to diet-induced obesity in A/J mice is not associated with regulation of hypothalamic neuropeptides. Am J Physiol Endocrinol Metab 287: E662-E670, 2004; 10.1152/ajpendo.00114.2004.-To investigate the mechanisms underlying long-term resistance of the A/J mouse strain to diet-induced obesity, we studied, over a period of 4 wk, the expression of uncoupling proteins in brown adipose tissue and the expression of hypothalamic neuropeptides known to regulate energy homeostasis and then used microarray analysis to identify other potentially important hypothalamic peptides. Despite increased caloric intake after 2 days of high-fat feeding, body weights of A/J mice remained stable. On and after 1 wk of high-fat feeding, A/J mice adjusted their food intake to consume the same amount of calories as mice fed a low-fat diet; thus their body weight and insulin, corticosterone, free fatty acid, and glucose levels remained unchanged for 4 wk. We found no changes in hypothalamic expression of several orexigenic and/or anorexigenic neuropeptides known to play an important role in energy homeostasis for the duration of the study. Uncoupling protein-2 mRNA expression in brown adipose tissue, however, was significantly upregulated after 2 days of high-fat feeding and tended to remain elevated for the duration of the 4-wk study. Gene array analysis revealed that several genes are up-or downregulated in response to 2 days and 1 wk of high-fat feeding. Real-time PCR analysis confirmed that expression of the hypothalamic IL-1 pathway (IL-1␤, IL-1 type 1 and 2 receptors, and PPM1b/PP2C-␤, a molecule that has been implicated in the inhibition of transforming growth factor-␤-activated kinase-1-mediated IL-1 action) is altered after 2 days, but not 1 wk, of high-fat feeding. The role of additional molecules discovered by microarray analysis needs to be further explored in the future. neuropeptides; energy homeostasis; uncoupling protein-2; interleukin-1; microarray THE EPIDEMIC OF OBESITY in Western populations is associated with overconsumption of high-fat diets. The exact mechanism by which certain people (34) and certain strains of rodents (44) are susceptible to high-fat diet-induced obesity (DIO), whereas others are relatively resistant to its effects, is the subject of intensive investigation.The most thoroughly studied experimental model of DIO is the C57Bl/6J mouse strain, whereas one of the most commonly studied DIO-resistant models is the A/J mouse strain (33, 38 -40). Investigation of the physiological responses of neuroendocrine factors, hypothalamic neuropeptides, and uncoupling proteins (UCPs) to high-fat feeding in these strains of mice could extend our understanding of the pathogenesis of DIO in humans, leading to potentially important therapeutic advances. Although several studies have used the DIO-sensitive C57Bl/6J strain to examine the effect of diet composition on hypothalamic neuropeptides and/or neuroendocrine factors important in energy homeostasis, only one study has focused on the hypothalami...