ISSN 1662-4009 (online)

ESPE Yearbook of Paediatric Endocrinology (2021) 18 11.5 | DOI: 10.1530/ey.18.11.5

Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.

Int J Obes (Lond). 2021;45(1):66–76. doi:

This study investigated the influence of MC4R variants on treatment effectiveness in a large cohort undergoing an outpatient treatment program. Carriers of MC4R loss-of-function (LoF) variants showed a lack of improvement in BMI, in contrast to non LoF carriers.

As we learn that MC4R LoF variants are more common than expected (1, 2 also in this Yearbook paper 11.4) their impact gains importance, not only on the natural course of BMI, but also on treatment success.

The validated treatment program of the Children’s Obesity Clinic (TCOC) in Denmark shows on average a sustained BMI SDS reduction by 0.2-0.3 (3), which is comparable to other European outpatient programs, such as Obeldicks light (4). Remarkably, in this large study (n=1209), of the roughly 80% of patients who could be evaluated after a treatment period of on average 1 year (0.5–4.0 years), the 2.5% carriers of MC4R LoF variants (n=24) did not reduce their BMI-SDS – in contrast to non LoF carriers (n=982). Other treatment approaches, including Obeldicks, had actually found that wildtype MC4R variant carriers show the same BMI SDS reduction as LoF variant carriers, but are unable to uphold treatment success (5). One possible explanation for these divergent observations may be a more extensive treatment approach in former studies.

One challenge of this study was the definition LoF in MC4R variants. While some variants show consistently reduced ability to generate cAMP upon MC4R stimulation in a heterologous cell system expressing the MC4R variant, for others, results vary both on cAMP generation and other measures such as activation of extracellular signal-regulated kinase (ERK) 1/2 or receptor cell surface expression. Hence variants considered here to be functionally relevant have been viewed in other studies as wild-type like (1). Nonetheless, this study shows that knowledge on the genetic background can give both treatment centres and families more realistic expectation about treatment outcomes and may also pave the way for patient-tailored treatment approaches.

References: 1. Wade, K. H., B. Y. H. Lam, A. Melvin, W. et al. ‘Loss-of-function mutations in the melanocortin 4 receptor in a UK birth cohort’, Nat Med, 27: 1088–96.2. Brouwers B, de Oliveira EM, Marti-Solano M, et al. Human MC4R variants affect endocytosis, trafficking and dimerization revealing multiple cellular mechanisms involved in weight regulation. J. Cell Rep. 2021 Mar 23;34(12):108862. doi: 10.1016/j.celrep.2021.108862.3. Holm, J. C., M. Gamborg, D. S. Bille, K. Hn Gr Nb, L. C. Ward, and J. Faerk. 2011. ‘Chronic care treatment of obese children and adolescents’, Int J Pediatr Obes, 6: 188–96.4. Schaefer, A., K. Winkel, E. Finne, P. Kolip, and T. Reinehr. 2011. ‘An effective lifestyle intervention in overweight children: one-year follow-up after the randomized controlled trial on “Obeldicks light”’, Clin Nutr, 30: 629–33.5. Reinehr, T., J. Hebebrand, S. Friedel, A. M. Toschke, H. Brumm, H. Biebermann, and A. Hinney. 2009. ‘Lifestyle intervention in obese children with variations in the melanocortin 4 receptor gene’, Obesity (Silver Spring), 17: 382–9.

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