ESPE Yearbook of Paediatric Endocrinology

Brief Summary: This review evaluated the impact of gene mutations in the leptin-melanocortin pathway on short- and long-term outcomes after bariatric surgery, which is still the most effective treatment for severe obesity. This topic is of high clinical relevance, since such mutations play an important role in hunger regulation and energy homeostasis [1, 2] and may therefore confer weight regain after bariatric surgery [3]. To date there have been few publications, often with only small numbers of cases, and some with contradictory results [4, 5, 6].

This meta-analysis identified 7 publications from 2003 to 2023, including 13 datasets with a total of 301 mutation carriers (n=182 with MC4R mutations and n=119 with mutations in the whole pathway) and 1966 control patients. Meta-regression was used to quantify the effect of mutations on short-term (<12 months) and long-term (2– 6 years) weight loss after bariatric intervention. Patients with mutations in the leptin-melanocortin pathway achieved less total weight loss after bariatric surgery (mean difference between groups: -3.03%; 95% CI: -3.63 to -2.44), which was primarily evident in reduced long-term (2-6 years) postoperative weight loss (-3.43%; 95% CI: -4.09 to -2.77). By contrast, up to 12 months after surgery, mutation carriers showed similar weight loss than those without mutations (-1.13%; 95% CI: -2.57 to 0.31).

Due to the still limited number of cases and non-existent information, it was not possible to examine differences in outcomes based on genetic subgroups, surgical procedures or patient baseline conditions. Large international cohort studies with detailed phenotyping are needed to investigate the influence of genetic and other factors in more detail. However, this review makes an important contribution to the understanding of genetic factors influencing bariatric outcomes, by showing a lower but still distinct weight loss in mutations carriers after bariatric surgery. Against the average ~25-30% weight loss after bariatric intervention [7-8], a difference of only 3% indicates that a mutation in the leptin-melanocortin pathway is not a contraindication for bariatric surgery.

Genetic screenings could predict weight loss outcome after bariatric surgery, which might help tailor surgical procedures to individual patients, optimize outcome by additional intervention such as e.g. medication and thus improving long-term success rates.

References: 1. Loos RJF Yeo GSH. The genetics of obesity: from discovery to biology. Nat. Rev Genet. 2022; 23(2): 120-1332. Farooqi S, O’Rahilly S. Genetics of obesity in humans. Endocr. Rev. 2006; 27:710–718. doi:10.1210/er.2006-0040.3. Hatoum IJ, Stylopoulous N, Vanhoose AM et al. Melanocortin-4 receptor signaling is required for weight loss after gastric bypass surgery. J Clin Endocrinol Metab. 2012; 97(6):E1023-10314. Mirshahi UL, Still CD, Msker KK et al. The MC4R(I251L) allele is associated with better metabolic status and more weight loss…. J Clin Endocrinol Metab. 2011;96(12):E2088-E20965. Valette M, Poitou C, Le Beyec J, et al. Melanocortin-4 receptor mutations and polymorphisms do not affect weight loss after bariatric surgery. PloS One. 2012; 7(11):e482216. Cooiman MI, Alsters SIM, Duquesnoy M, et al. Long-term weight outcome after bariatric surgery… Obes Surg. 2022;32(3):837-8447. Inge TH. Five-Year Outcomes of Gastric Bypass in Adolescents as Compared with Adults. N Engl J Med. 2019 May 30; 380(22): 2136–2145. doi:10.1056/NEJMoa1813909.8. Courcoulas AP et al. Seven-Year Weight Trajectories and Health Outcomes in the Longitudinal Assessment of Bariatric Surgery (LABS) Study. JAMA JAMA Surg. 2018 May; 153(5): 427–434.