Patients with Obesity Caused by Melanocortin-4 Receptor Mutations Can Be Treated with a Glucagon-like Peptide-1 Receptor Agonist

Abstract

Pathogenic mutations in the appetite-regulating melanocortin-4 receptor (MC4R) represent the most common cause of monogenic obesity with limited treatment options. Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) cause weight loss by reducing appetite. We assessed the effect of the GLP-1 RA liraglutide 3.0 mg for 16 weeks in 14 obese individuals with pathogenic MC4R mutations (BMI 37.5 ± 6.8) and 28 matched control participants without MC4R mutation (BMI 36.8 ± 4.8). Liraglutide decreased body weight by 6.8 kg ± 1.8 kg in individuals with pathogenic MC4R mutations and by 6.1 kg ± 1.2 kg in control participants. Total body fat, waist circumference, and fasting and postprandial glucose concentrations similarly decreased in both groups. Thus, liraglutide induced an equal, clinically significant weight loss of 6% in both groups, indicating that the appetite-reducing effect of liraglutide is preserved in MC4R causal obesity and that liraglutide acts independently of the MC4R pathway. Thus, liraglutide could be an effective treatment of the most common form of monogenic obesity.

Identifying underlying medical causes of pediatric obesity: Results of a systematic diagnostic approach in a pediatric obesity center

“…[51] These GLP-1 agonists might also be a future treatment option for patients with genetic obesity disorders, as they have been shown to be equally as effective in adults with heterozygous MC4R mutations compared to adults without. [52] Recently, it was suggested that a subgroup of patients with severe early-onset obesity might have relative leptin deficiency and therefore might benefit from recombinant leptin administration. [53] However, the (long-term) effects of these new potential treatment options remain to be investigated.…”

MECHANISMS IN ENDOCRINOLOGY: Update on treatments for patients with genetic obesity

“…More recently, GLP-1 analogs, including liraglutide, have been tested in patients with MC4R variants. Weight loss of MC4R variant carriers on 3 mg liraglutide/day for 16 weeks was equivalent to that of non-carriers (approximately 6% weight loss), suggesting that the molecule can also be pro-satietogenic in MC4Rlinked obesity (86). However, given the importance of leptin/melanocortin pathway alterations in monogenic and syndromic obesity, specifically targeting this pathway should be valuable in treating these severe clinical conditions.…”

“…These promising results have paved the way to launching clinical trials with this molecule in patients with genetic alterations in the melanocortin pathway upstream of MC4R (Table 1). The use of this MC4R agonist indeed now makes it possible to replace the lack or inefficiency of the endogenous MC4R ligand (aMSH), in particular in the case of homozygous variants of POMC (31) Iepsen et al (86) This table summarizes ongoing and completed (with or without published results) pharmaceutical interventions in syndromic and monogenic non syndromic obesity, targeting weight loss or food behavior. Search was performed using Pubmed research (keywords: syndrome name AND therapy OR treatment OR clinical trial OR therapeutics) and using ClinicalTrials.gov website.…”

AMPK in the Ventromedial Nucleus of the Hypothalamus: A Key Regulator for Thermogenesis

“…On top of improving glucose control, liraglutide also reduces body weight in obese individuals (90). The weight reducing effects of liraglutide on human subjects have been confirmed by many clinical studies, although whether the decrease in body weight is linked to increased energy expenditure or not remains elusive (91,92). Recently, the US Food and Drug Administration (FDA) committee has approved the application of liraglutide as an anti-obesity therapy.…”