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Updated: May 6, 2026
Body Composition and Metabolic Caging Analysis in High Fat Fed Mice
Published on: May 24, 2018
Novel α-MSH analog causes weight loss in obese rats and minipigs and improves insulin sensitivity
Keld Fosgerau1, Kirsten Raun, Cecilia Nilsson
1Novo Nordisk Diabetes Research Unit, Novo Nordisk A/S, Novo Nordisk Park, DK-2760 Maaloev, Denmark.
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.
Insights
A novel selective alpha-melanocyte-stimulating hormone (α-MSH) analog, MC4-NN1-0182, effectively reduced body weight in diet-induced obese rats and minipigs. This compound also improved insulin sensitivity, suggesting MC4 agonism as a promising therapeutic target for obesity and related metabolic disorders.
Area of Science:
- Metabolic Research
- Endocrinology
- Pharmacology
Background:
- Obesity presents a significant global health and economic challenge.
- Current treatments for obesity and associated insulin resistance are limited.
- Targeting melanocortin 4 receptor (MC4-R) pathways offers a potential therapeutic strategy.
Purpose of the Study:
- To evaluate the efficacy of a novel selective MC4-R peptide agonist, MC4-NN1-0182, in managing obesity.
- To investigate the impact of MC4-NN1-0182 on insulin sensitivity.
- To characterize the subchronic effects of MC4-NN1-0182 in preclinical models of obesity.
Main Methods:
- Subchronic administration of MC4-NN1-0182 in diet-induced obese (DIO) rats and DIO minipigs.
- Assessment of food intake, energy consumption, and body weight changes.
- Acute euglycemic-hyperinsulinemic clamp studies in normal rats to determine insulin sensitivity.
Main Results:
- MC4-NN1-0182 treatment led to significant body weight reduction in DIO rats (7±1%) and DIO minipigs (13±3%) compared to vehicle controls.
- Food intake was decreased in treated DIO rats.
- Acute administration of MC4-NN1-0182 significantly increased glucose disposal (Rd) in normal rats, indicating improved insulin sensitivity independent of weight loss.
Conclusions:
- Selective MC4-R agonism with MC4-NN1-0182 effectively promotes weight loss in obese animal models.
- MC4-NN1-0182 demonstrates weight-independent improvements in insulin sensitivity.
- MC4 agonism represents a viable therapeutic target for treating obesity and insulin resistance.
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