Monogenic obesity is a rare and severe disease most often resulting from melanocortin4 receptor (MC4R) mutations that disrupt the neuronal pathways in the hypothalamus and prefrontal cortex. Following 6 months of treatment with semaglutide, a glucagon like peptide-1 (GLP-1) receptor agonist, the investigators observed that two siblings with monogenic obesity, had evidence of corneal nerve regeneration.1
First author Hoda Gad, BSc, MSc, PhD from the Research Department, Weill Cornell Medicine-Qatar, Doha, Qatar, reported their findings in Frontiers in Endocrinology.
According to the researchers, 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
They explained that changes in lifestyle in patients with MC4R mutations have shown minimal benefit4-6 and even bariatric surgery provided limited long-term benefit.7-9
However, use of GLP-1 receptor agonists can achieve beneficial changes in weight, blood pressure and lipids with a decrease in reactive oxygen species (ROS) and inflammation, which could impact neurons,10 they explained.
Specifically, they reported that GLP-1R-mediated extracellular signal-regulated kinase signalling in diabetic rodents protected large motor fibre function and small fibre structure by a mechanism independent of glycaemic control.11 They also previously reported corneal nerve regeneration after bariatric surgery12 and with the once-weekly GLP-1 agonist exenatide,13 and in 14 patients with type 2 diabetes semaglutide or dulaglutide improved nerve area and sural nerve amplitude.14
In this case report, Gad and colleagues performed corneal confocal microscopy to assess for evidence of nerve regeneration after treatment with semaglutide in siblings with an MC4R gene mutation, a 10-year-old boy (weight, 100.3 kg; body mass index [BMI], 39.7 kg/m2) and his 8-year-old sister (weight, 58.6 kg; BMI, 32.2 kg/m2) (Figure 1).
Their respective baseline haemoglobin A1c (HbA1c) values were 5.8% and 5.6%, the total cholesterol 4.4 and 3.4 mmol/L, low-density lipoprotein 2.3 and 2.0 mmol/L, high-density lipoprotein 2.1 and 1.0 mmol/L, and triglycerides 1.0 and 1.4 mmol/L. Both children exhibited intense hyperphagia, impaired satiety and severe, early-onset obesity.
The siblings had a heterozygous missense variant c.508A>G, p.Ille170Val in the MC4R gene, a rare variant with minor allele frequency in gnomAD of 0.00009. They both were treated with semaglutide 0.5 mg weekly for 1 month and then 1.0 mg weekly for 5 months.
Results of semaglutide therapy
Corneal confocal microscopy showed corneal small nerve fibre degeneration in the two siblings before treatment.
The authors reported, “We also showed that 6 months of treatment with semaglutide was associated with small nerve fibre regeneration, but with no major effect on weight, HbA1c, and lipids, which argues for alternate mechanisms beyond an improvement in weight and glycemia as a basis for nerve regeneration in these two children with MC4R gene mutation.”
The investigators observed nerve regeneration (Figure 2) evidenced by increases in corneal nerve fibre density of 13.9% in the brother and 14.7% in the sister; corneal nerve branch density, 110.2% and 58.7%, respectively, and corneal nerve fibre length, 21.5% and 44.0%, respectively.
Hypothesis for nerve regeneration without other changes
The investigators explained that obesity is a risk factor for small fibre neuropathy,15,16 and they had reported previously that nerve regeneration occurred with an improvement in weight and metabolic parameters after bariatric surgery.17,18 GLP-1 receptor agonists also reduce weight and improve many neuropathy risk factors including hyperglycaemia, blood pressure and hyperlipidemia.19 Previous case reports on use of the daily GLP-1 agonist liraglutide have shown reduced weight and improved glycaemia.20-22 However, their recent cohort study showed no major impact of liraglutide on weight or HbA1c in obese children.23
It is noteworthy, Gad and colleagues explained, that GLP-1 therapies activate sirtuin1,24,25 which may be associated with the nerve regeneration seen in the patients under discussion, independent of weight and glycaemia changes. In addition, GLP-1 receptors are expressed in the dorsal root ganglion and peripheral nerves,26-29 and in an animal model of type 1 diabetes mellitus, GLP-1 treatment led to intraepidermal nerve fibre regeneration without weight or glucose changes.11 Further, adults with type 2 diabetes mellitus treated with once-weekly exenatide and pioglitazone had small nerve fibre regeneration, despite an increase in weight.13
They concluded, “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.”
References
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