ESPE Yearbook of Paediatric Endocrinology

To read the full abstract: Cell Metabolism 2018; 28: 23–32

Pathogenic mutations in the melanocortin-4 receptor gene (MC4R) are the most common cause of monogenic obesity. However, very limited treatment options exist. Therefore, these authors investigated a glucagon-like peptide-1 receptor agonist (GLP-1 RA) as a treatment option for these patients. The findings are of major significance.

They assessed the effect of the GLP-1 RA liraglutide in n=14 obese individuals with pathogenic MC4R mutations and n=28 matched controls. Daily s.c. injections of liraglutide 3 mg for 16 weeks decreased body weight, body fat, waist circumference, and fasting and postprandial glucose levels by the same amount in both groups. Therefore GLP-1 RA likely reduces body weight independently of the MC4R pathway. The effect of liraglutide on weight loss in patients with pathogenic MC4R mutations was much higher than any previously reported intervention in this group (1–4).

This is the first study to show that monogenic obesity caused by pathogenic MC4R mutations can be effectively treated with a GLP-1 RA; hence the results are of major importance. Limitations of this study include the small number of participants, the fact that cases and controls were recruited within the same family or as friends, and the absence of an untreated placebo control group. Furthermore, the mechanism of GLP-1 RA-mediated weight loss is not fully understood.

References: 1. Bonnefond A, Keller R, Meyre D, Stutzmann F, Thuillier D, Stefanov DG, et al. Eating Behavior, Low-Frequency Functional Mutations in the Melanocortin-4 Receptor (MC4R) Gene, and Outcomes of Bariatric Operations: A 6-Year Prospective Study. Diabetes Care. 2016;39(8):1384–92.

2. Collet TH, Dubern B, Mokrosinski J, Connors H, Keogh JM, Mendes de Oliveira E, et al. Evaluation of a melanocortin-4 receptor (MC4R) agonist (Setmelanotide) in MC4R deficiency. Molecular Metabolism. 2017;6(10):1321–9.

3. Danielsson P, Janson A, Norgren S, Marcus C. Impact sibutramine therapy in children with hypothalamic obesity or obesity with aggravating syndromes. Journal of Clinical Endocrinology and Metabolism. 2007;92(11):4101–6.

4. Reinehr T, Hebebrand J, Friedel S, Toschke AM, Brumm H, Biebermann H, et al. Lifestyle intervention in obese children with variations in the melanocortin 4 receptor gene. Obesity (Silver Spring, Md). 2009;17(2):382–9.