Dual Activation of MC3R and MC4R Drives Weight Loss and Reduces Food Intake in Obese Primates
Seiler, J. L.; Impastato, A. C.; Zhang, E. X.; Kelley, K. J.; Bennett, T. L.; Studnitzer, B.; Prindle, C. R.; Rajewski, B. H.; Badeau, B. A.; Jiang, X.; Potterfield, R.; Delev, J. Y.; Marks, D. L.
Show abstract
Introductory ParagraphThe melanocortin system plays a central role in regulating hunger and satiety, making it an attractive target for treating metabolic disease. However, the limited clinical success of selective melanocortin-4 receptor (MC4R) agonists prompted the investigation of whether concurrent melanocortin-3 receptor (MC3R) and MC4R activation is key to unlocking the melanocortin system for the treatment of general obesity. To test this hypothesis, we designed and synthesized novel peptides to probe the distinct and combined roles of MC3R and MC4R in nonhuman primates (NHPs). We show that selectively agonizing MC3R modulates food intake in a state-dependent manner. Moreover, co-agonism of MC3R and MC4R results in more substantial metabolic effects than selective MC4R agonism, highlighting both a non-redundant and a cooperative role of MC3R. To leverage these discoveries, we developed 710GO, an orally-available MC3R/MC4R dual agonist peptide that induces significant weight loss in diet-induced obese (DIO) NHPs. Oral 710GO treatment demonstrates limited weight rebound, has additive effects in combination with GLP-1s, and exhibits a clean safety profile. These results reestablish the melanocortin system, specifically concerted MC3R/MC4R agonism, as a viable mechanism for next-generation obesity therapeutics.
Matching journals
The top 9 journals account for 50% of the predicted probability mass.
Similar papers in this journal
- Ectopic, hepatic GLP-1R agonism enhances the weight loss efficacy of GLP-1 analogues. 95%
- Targeted and selective knockout of the TLQP-21 neuropeptide unmasks its unique role in energy homeostasis 95%
- Single-agent Foxo1 inhibition normalizes glycemia and induces gut β-like cells in streptozotocin-diabetic mice 94%
Similar papers in this journal
- The Novel Chimeric Multi-Agonist Peptide (GEP44) Reduces Energy Intake and Body Weight in Male and Female Diet-Induced Obese Mice in a Glucagon-Like Peptide-1 Receptor-Dependent Manner 94%
- Effects of systemic oxytocin and beta-3 receptor agonist (CL 316243) treatment on body weight and adiposity in male diet-induced obese rats 94%
- Sympathetic innervation of interscapular brown adipose tissue is not a predominant mediator of oxytocin-elicited reductions of body weight and adiposity in male diet-induced obese mice 92%
Similar papers in this journal
Similar papers in this journal
- Nucleus accumbens D1- and D2-expressing neurons control the balance between feeding and activity-mediated energy expenditure 94%
- Fasting is required for many of the benefits of calorie restriction in the 3xTg mouse model of Alzheimer&aposs disease 92%
- Adipose tissue-derived neurotrophic factor 3 regulates sympathetic innervation and thermogenesis in adipose tissue 92%
Similar papers in this journal
- A long-acting GDF15 analog causes robust, sustained weight loss and reduction of food intake in an obese non-human primate model 96%
- Acute pharmacodynamic responses to sitagliptin: Drug-induced increase in early insulin secretion in oral glucose tolerance test. 93%
- Savor the flavor — a randomized double-blind study on taste-enhanced placebo analgesia in healthy volunteers 91%
"Similar papers" are the closest papers from that journal in the model's embedding space. They show what the match is built on, but the ranking comes mostly from a classifier over the whole training set, not from these examples alone.