Obesity is a multifactorial disease due to genetic predisposition and environmental factors. Whilst polygenic variants are frequent, they confer small effect sizes, whilst rare pathogenic variants in single genes with large effect sizes account for ~5% of pediatric obesity (1). Clinically, patients with monogenic obesity present with impaired satiety and hyperphagia in early childhood with severe early-onset obesity due to dysregulation of the central leptin-melanocortin neuronal pathways (2, 3). We have recently characterized two novel homozygous variants that yielded antagonistic proteins to leptin receptor activation resulting in intense hyperphagia and severe obesity in one child in Qatar (4). We have also identified pathogenic variants in around 14.8% of 243 individuals with early-onset obesity, in whom variants in the MC4R gene accounted for 19% (2), far higher than other studies (0.5–8.5%) (5). MC4R is expressed on neurons in the hypothalamus and prefrontal cortex, which regulate hunger and satiety (6, 7).

Lifestyle interventions in patients with MC4R mutations have shown minimal benefit (8–10) and even bariatric surgery has shown limited long-term benefit (11–13). Targeted agonism of the MC4R with setmelanotide showed ~10% body weight loss in patients with POMC deficiency and LEPR deficiency (14), and there are case reports showing weight loss after GLP-1 therapy in individuals with pathogenic variants of MC4R (15–17). A recent case report of a 13-year-old female with a heterozygous c.206T>G(p.I69R) variant in the MC4R gene showed that treatment with liraglutide achieved a 19.2% reduction in body weight at 32 weeks, but significant gastrointestinal side-effects led to cessation of treatment and a return to her former weight within 13 weeks (18).

GLP-1 receptor agonism leads to improvements in weight, blood pressure, lipids with a decrease in reactive oxygen species (ROS) and inflammation which could impact on neurons (19). Indeed, GLP-1R-mediated ERK-signaling in diabetic rodents has been shown to protect large motor fiber function and small fiber structure by a mechanism independent of glycemic control (20). We have previously shown corneal nerve regeneration after bariatric surgery (21) and after treatment with the once weekly GLP-1 agonist exenatide (22). More recently, in 14 patients with type 2 diabetes, treatment with semaglutide or dulaglutide improved nerve area and sural nerve amplitude (23). We have now undertaken corneal confocal microscopy to assess for evidence of nerve regeneration following treatment with the once weekly GLP-1 RA semaglutide, in two siblings with MC4R gene mutation.

Two siblings, a 10-year-old boy (patient A) and an 8-year-old girl (patient B) with intense hyperphagia, impaired satiety, and severe, early onset obesity and a 10-year-old healthy boy were studied.

Clinical demographics of the cases are described in Table 1 . Child A weighed 100.3kg and child B weighed 58.6kg. Both siblings carry a heterozygous missense variant c.508A>G, p.Ille170Val in the MC4R gene, a rare variant with Minor allele frequency (MAF) in gnomAD of 0.00009. The variant is predicted to have PM1/PM2/PP3/PP5/BS2 classes, which is classified as a pathogenic variant according to the ACMG variant classification. It is located in the transmembrane helix of the MC4R gene and is known to impair cyclic-AMP, leading to severe obesity (32, 33).

This study shows evidence of sub-clinical nerve degeneration with regeneration following treatment with the GLP-1 agonist semaglutide in two children with a MC4R gene mutation and severe obesity. First, we show evidence of corneal small nerve fiber degeneration, with preserved vibration perception and sensation to the 10g monofilament, and normal DN4 indicative of subclinical neurodegeneration, detected with corneal confocal microscopy. Clinical neuropathy has been reported in a 27-year old male with a MC4R gene mutation and morbid obesity, but this was attributed to the presence of T2DM (34).

We also show that 6 months of treatment with semaglutide was associated with small nerve fiber regeneration, but with a no major effect on weight, HbA1c and lipids, arguing for alternate mechanisms beyond an improvement in weight and glycemia as a basis for nerve regeneration in these two children with MC4R gene mutation. Obesity perse is a risk factor for small fiber neuropathy (35, 36) and we have previously shown nerve regeneration with an improvement in weight and metabolic parameters after bariatric surgery (37, 38). Furthermore, GLP-1 receptor agonists reduce weight and improve many of the risk factors for neuropathy including hyperglycemia, blood pressure and hyperlipidemia (39). Indeed, previous case reports with the daily GLP-1 agonist liraglutide have shown a reduction in weight and improvement in glycemia (15–17). However, in our recent cohort study we showed no major impact of liraglutide on weight or HbA1c in children with obesity (40).

There is a body of evidence that MC4R mediates neuropathic (41) and inflammatory pain (42) and the MC4R antagonist HS014 has been shown to increase paw withdrawal threshold and heat withdrawal latency in rat models of neuropathic pain (43). In the present study there was no evidence of neuropathic pain based on the DN4 score in children with MC4R mutation and it did not change with semaglutide. DN4 has not been validated in children with obesity, but it has been used to assess neuropathic pain in children with leprosy-related neuropathic pain (44) and sickle cell disease (45).

With regard to alternate mechanisms for nerve regeneration, sirtuin-1 (SIRT-1) inactivation has been implicated in obesity and neurodegeneration and SIRT-1 activation is associated with nerve regeneration following peripheral nerve injury (46, 47). Of note, GLP-1 therapies are SIRT-1 activators (48, 49) which may be associated with the nerve regeneration observed in our patients, independent of change in weight and glycemia. Additionally, GLP-1 receptors are expressed in the dorsal root ganglion and peripheral nerves (50–53) and in a T1DM animal model, GLP-1 treatment led to intraepidermal nerve fiber regeneration without a change in weight or glucose (20). Furthermore, previously, in adults with T2DM treated with once weekly exenatide and pioglitazone, we showed evidence of small nerve fiber regeneration, despite an increase in weight (22).

We acknowledge this is a study of only two children with the MC4R mutation with a limited duration of follow up after treatment with semaglutide. However, we believe that our study provides novel insights into the complications associated with MC4R gene mutation as evidenced by subclinical neurodegeneration. Furthermore, we show nerve regeneration after treatment with semaglutide, without an improvement in weight or glycemia, indicating an independent effect of GLP-1 therapy, which merits further study.

The original contributions presented in the study are included in the article/supplementary materials, further inquiries can be directed to the corresponding author/s.

The studies involving humans were approved by Sidra Medicine and WCM-Q IRB committees. The studies were conducted in accordance with the local legislation and institutional requirements. Written informed consent for participation in this study was provided by the participants’ legal guardians/next of kin. Written informed consent was obtained from the individual(s), and minor(s)’ legal guardian/next of kin, for the publication of any potentially identifiable images or data included in this article.

HG: Writing – original draft, Project administration, Methodology, Investigation, Formal analysis, Data curation, Conceptualization. IM: Writing – review & editing, Data curation. HD: Writing – review & editing, Data curation. MP: Writing – review & editing, Data curation. TA: Writing – review & editing, Data curation. KH: Writing – review & editing, Supervision. RM: Writing – review & editing, Supervision.