Obesity is a major burden to people and to the health care systems around the world. This study aims at characterizing the effect of a novel selective alpha–MSH analogue on obesity and insulin sensitivity. The sub–chronic effects of the selective MC4–R peptide agonist MC4–NN1–0182 was investigated in diet induced obese (DIO) rats and DIO minipigs by assessing the effects on food intake, energy consumption, and body weight. Acute effect of MC4–NN1–0182 on insulin sensitivity was assessed by a euglycemic–hyperinsulinemic clamp study in normal rats. Three weeks 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 to 3 ± 1% increase in the vehicle control. In DIO minipigs, eight 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 to vehicle control (Rd, mg/kg/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.