Obesity etiology is complex with interplay between genetic and environmental factors. Early twin studies indicate that 40%–70% of obesity is hereditary (1). “Simple obesity” is mostly a polygenic disorder. However, several, albeit rare, monogenic forms are recognized. The commonly reported genetic dysregulations include mutations in the leptin and receptor (LEP/LEPR), proopiomelanocortin (POMC), proprotein convertase subtilisin/kexin type 1 (PCSK1) and melanocortin-4 receptor (MC4R) genes (2, 3).

Of those genes, the most common monogenic mutation with a prevalence of up to 6% have been reported to be alterations in the MC4R alleles (4–6). Melanocortin-4 receptor (MC4R) is an integral part of the leptin–melanocortin pathway, which is responsible for central energy homeostasis and body weight regulation (7). MC4R is a transmembrane G-protein-coupled receptor expressed in the hypothalamic neurons and follows an autosomal dominant mode of inheritance. Phenotypic characteristics in individuals with homozygous and also heterozygous MC4R mutation include excessive hunger and hyperphagia, which is the main driver of the significant and rapid weight gain (8, 9). As this is a genetic effect, it carries a substantial behavioral impact, especially in feeding and satiety (10, 11). In the UK, a recent study has estimated the frequency of heterozygous MC4R loss-of-function mutations at 0.30%, a considerably higher rate compared to previous approximations (12).

Treatment of obesity, in general, is a major challenge. Lifestyle interventions and pharmacotherapy may lead to some weight loss, but relapse is common (13, 14). Bariatric surgery (BS) is currently the most efficacious treatment for obesity with good short-term and long-term outcomes (15). However even when BS is part of the treatment algorithm for cases of “simple obesity”, there is risk of weight regain in the long term (16).

Treatment of monogenic obesity (MO) may be even more challenging as MO is rare, and data on efficacy of different interventions are also sparse. Failure to lose sufficient weight or weight regain may be more common in patients with MO as their biological drive to eat may be unaffected by the standard interventions, including BS. Previous studies published in 2011 and 2014 suggest that patients with heterozygosity of the MC4R gene can be treated effectively in the short term with BS, but the longer-term success rates are not well described (17, 18). Similar observation in a patient with homozygous MC4R deficiency (MC4R-d) was reported in 2015 (19). A systematic review in 2021 synthesized outcomes of BS among patients with monogenic forms of obesity and found that weight loss results were inconsistent for patients with MC4R-d (20). Our group has previously reported short-term effects of BS in three patients with homozygous MC4R mutations, the youngest of whom was only 4 years old when a laparoscopic vertical sleeve gastrectomy (LSG) was performed (21). Here, we report longer-term BS efficacy results up to 10 years in these patients with homozygous MC4R mutation with a novel report on revisional BS long-term outcomes in a sibling pair. Three additional cases of heterozygous MC4R mutations are presented, and pharmacotherapeutic outcomes are also discussed.

Patients who have had genetic screening were identified from the Imperial College London Diabetes Centre (ICLDC) electronic database. Genetic screening is performed in patients suspected to have a genetic component for obesity such as morbid obesity and strong family history. MC4R mutations were screened through either targeted sequencing for MC4R gene, whole exome sequencing, or Diabetes-Obesity New Generation Sequencing panel. Patients who tested positive for MC4R-d (study group, SG) and age- and sex-matched individuals with normal MC4R genotype (control group, CG) were identified based on the reported results from the genetic screening. The study flow diagram is presented in Figure 1 .

Case history and pertinent details such as age, weight, and HbA1c before and after BS and pharmacotherapy were derived from electronic medical records. Weight was measured and recorded as part of vitals assessment. HbA1c test was performed in the in-house laboratory. Medication compliance was assessed based on physicians’ or clinic notes. Patients’ glycemic control was managed at ICDLC. BS was performed in different centers locally and abroad. For patients who had multiple or revisional BS, the last surgery was used for pertinent analyses. Data were analyzed and presented as median (interquartile range—IQR).

Written informed consent for using medical data for research purpose in an anonymized form was obtained from all participants at the time of first visit. The study was approved by the Research Ethics Committee at ICLDC and followed the Declaration of Helsinki, 1996.

Genetic screening for MC4R mutation(s) was performed on 70 ICLDC patients between 2010 and 2020. Twenty-one patients were tested positive to have a mutation in MC4R gene. Three mutations were identified: c.485C>T (T162I), 508A>G (I170V), and 307G>A (V103I). Six individuals composed the SG [four females, two males; 18 (10–27) years old at BS; 50.3 (41.8–61.9) kg/m² at BS; three patients with homozygous T162I mutations, two patients with heterozygous T162I mutations, and one patient with heterozygous I170V mutation]. Eight individuals composed the CG [four females, four males; 19.0 (17.8–36.8) years old at BS, 46.2 (42.0–48.3) kg/m² at BS or phamacotherapeutic intervention]. All patients are Emirati.

The melanocortin system regulates appetite and an intact leptin–melanocortin signaling is required for normal physiological response to calorie restriction (22–24). Lifestyle modification for weight loss is difficult for people with MC4R-d as they are less responsive to diet and exercise. Hence, BS is often considered as the obesity treatment of choice for individuals with MC4R-d. Our previous work has indicated that MC4R signaling may not be needed for short-term response to sleeve gastrectomy, with continuous weight loss observed several months post-BS (21). Here we report the short- and long-term outcomes of BS on weight and glycemic control in Emirati patients with MC4R-d, including two siblings (male and female) who had a revision of their previous LSG to a RYGB. The mutations reported in our study, both T162I and I170V, are missense mutations and result in partial (T162I) and complete (I170V) loss of function of MC4R gene (25, 26). A recent article reported long-term weight loss outcome on bi-allelic mutation in the MC4R gene in a patient who underwent sleeve gastrectomy only (27). The recent systematic review reported that most of the studies on outcomes of BS in MC4R mutation found no association of MC4R mutations with weight loss (20). We are reporting, for the first time to our knowledge, long-term outcomes of revisional surgery (RYGB) in both sexes with the MC4R null genotype. Our results suggest that longer-term response may be determined by factors other than MC4R genotype. These factors may include sex and gut microbiome as well as other environmental factors, as may be the case in patients with “simple obesity” (28–30).

Although the role of genetics in the case of P1 and P2 cannot be delineated, how mutation type and zygosity affect BS outcomes in these patients has been observed. Weight loss 6 months post-BS was not significantly different among patients without and with heterozygous MC4R-d, suggesting that in terms of weight reduction, patients with heterozygous T162I and I170V mutations may benefit from BS as much as MC4R-normal individuals, a finding similar to a previous report (17). Another recent study has reported no significant weight loss on a patient with compound heterozygous mutation (c.105C>A; p.Y35X, c.110A>T; p.D37V) (27). Individuals with homozygous T1621 mutation in MC4R and those with compound heterozygous MC4R-d might require multiple surgeries or continued pharmacological intervention to maintain weight loss over a longer period of time. It is also noteworthy that our younger patient had a more favorable outcome in terms of weight loss, suggesting that earlier intervention in homozygous T162I is more likely to be beneficial; increasing BMI from 12 months post-BS warrant longer-term monitoring. On glycemic control, mutation type and zygosity do not appear to influence the outcomes suggesting the significance and interplay of other factors (31, 32). Adherence to a strict diet as in the case of P2 may be required for best glycemic control regardless of BS (33). The lack of diet information on the other patients as well as physical activity profile of the cohort including the control group is a limitation of the study, which may be addressed in prospective studies.

With liraglutide treatment, we have observed that response was comparable in patients with heterozygous T1621 mutation in MC4R and controls (34). Liraglutide treatment for 16 weeks has been reported to result in comparable weight loss and decrease in HbA1c in patients with MC4R-d and controls (35, 36). However, the difference in % weight loss of BS compared to liraglutide use on individuals with heterozygous T162I may still be vast (14.2% for P5). Again, the outcome of P2’s diet program on her weight and glycemic control underscores the importance of diet and lifestyle modification on MC4R deficits, in addition to pharmacotherapeutic course of treatment and BS. The effect of dietary and lifestyle interventions may depend on the type of mutation (37). An additional finding here is that short-term orlistat treatment did not seem to have any beneficial effects on weight loss or glycemic control for our patient with heterozygous I170V mutation.

In conclusion, we have described here outcomes of BS with or without selected pharmacotherapy in a cohort of patients with heterozygous and homozygous MC4R mutations. Our data indicate beneficial but varied long-term effects of BS on these patients, which suggests that life-long monitoring and additional therapies including adjunct pharmacotherapy and revisional BS should be considered. Further elucidation of the mechanisms behind these results requires a larger cohort of patients in multicenter studies.

The data presented in the study are deposited in the ClinVar repository, accession numbers SCV002014765.1, SCV002014763.1, SCV002014764.1.

The studies involving human participants were reviewed and approved by the Research Ethics Committee, Imperial College London Diabetes Centre. Written informed consent to participate in this study was provided by the participants and/or participants’ legal guardian/next of kin.

EF: study design, data acquisition and interpretation, and manuscript writing; SR: data acquisition, statistical analyses and manuscript writing; TA: study design and manuscript writing; EN: manuscript writing; NL: study design, data interpretation, and manuscript writing.

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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