title: Novel α-MSH analog causes weight loss in obese rats and minipigs and improves insulin sensitivity.
abstract: Obesity is a major burden to people and to health care systems around the world. The aim of the study was to characterize the effect of a novel selective α-MSH analog on obesity and insulin sensitivity. The subchronic effects of the selective MC4-R peptide agonist MC4-NN1-0182 were investigated in diet-induced obese (DIO) rats and DIO minipigs by assessing the effects on food intake, energy consumption, and body weight. The acute effect of MC4-NN1-0182 on insulin sensitivity was assessed by a euglycemic-hyperinsulinemic clamp study in normal rats. Three weeks of treatment of DIO rats with MC4-NN1-0182 caused a decrease in food intake and a significant decrease in body weight 7±1%, P<0.05 compared with 3±1% increase with the vehicle control. In DIO minipigs, 8 weeks of treatment with MC4-NN1-0182 resulted in a body weight loss of 13.3±2.5 kg (13±3%), whereas the vehicle control group had gained 3.7±1.4 kg (4±1%). Finally, clamp studies in normal rats showed that acute treatment with MC4-NN1-0182 caused a significant increase in glucose disposal (Rd) compared with vehicle control (Rd, mg/kg per min, 17.0±0.7 vs 13.9±0.6, P<0.01). We demonstrate that treatment of DIO rats or minipigs with a selective MC4-R peptide agonist causes weight loss. Moreover, we have demonstrated weight-independent effects on insulin sensitivity. Our observations identify MC4 agonism as a viable target for the treatment of obesity and insulin resistance.
authors.affiliation: Novo Nordisk Diabetes Research Unit, Novo Nordisk A/S, Novo Nordisk Park, DK-2760 Maaloev, Denmark.
authors.forename: Keld
authors.initials: K
authors.lastname: Fosgerau
authors.forename: Kirsten
authors.initials: K
authors.lastname: Raun
authors.forename: Cecilia
authors.initials: C
authors.lastname: Nilsson
authors.forename: Kirsten
authors.initials: K
authors.lastname: Dahl
authors.forename: Birgitte S
authors.initials: BS
authors.lastname: Wulff
mesh_terms: D000818:Animals; D019440:Anti-Obesity Agents / Q000494:pharmacology*; D004032:Diet; D004353:Drug Evaluation, Preclinical; D005260:Female; D007333:Insulin Resistance / Q000502:physiology; D008297:Male; D009765:Obesity / Q000188:drug therapy / Q000209:etiology / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013552:Swine; D013556:Swine, Miniature; D015431:Weight Loss / Q000187:drug effects*; D000521:alpha-MSH / Q000031:analogs & derivatives* / Q000494:pharmacology* / Q000627:therapeutic use
chemical_list: D019440:Anti-Obesity Agents; C586898:MC4-NN1-0182; D000521:alpha-MSH
keywords: ISI; agonist; hyperinsulinemic–euglycemic clamp; insulin resistance; melanocortin receptor 4; obesity