Ann Pediatr Endocrinol Metab.  2022 Sep;27(3):169-175. 10.6065/apem.2244188.094.

Genetic obesity: an update with emerging therapeutic approaches

• Sohn YB

• KMID: 2533335
• DOI: http://doi.org/10.6065/apem.2244188.094

Abstract

Based on the genetic contribution, childhood obesity can be classified into 3 groups: common polygenic obesity, syndromic obesity, and monogenic obesity. More genetic causes of obesity are being identified along with the advances in the genetic testing. Genetic obesities including syndromic and monogenic obesity should be suspected and evaluated in children with early-onset morbid obesity and hyperphagia under 5 years of age. Patients with syndromic obesity have early-onset severe obesity associated specific genetic syndromes including Prader-Willi syndrome, Bardet-Biedle syndrome, and Alstrom syndrome. Syndromic obesity is often accompanied with neurodevelopmental delay or dysmorphic features. Nonsyndromic monogenic obesity is caused by variants in single gene which are usually involved in the regulation of hunger and satiety associated with the hypothalamic leptin-melanocortin pathway in central nervous system. Unlike syndromic obesity, patients with monogenic obesity usually show normal neurodevelopment. They would be presented with hyperphagia and early-onset severe obesity with additional clinical symptoms including short stature, red hair, adrenal insufficiency, hypothyroidism, hypogonadism, pituitary insufficiencies, diabetes insipidus, increased predisposition to infection or intractable recurrent diarrhea. Identifying patients with genetic obesity is critical as new innovative therapies including melanocortin 4 receptor agonist have become available. Early genetic evaluation enables to identify treatable obesity and provide timely intervention which may eventually achieve favorable outcome by establishing personalized management.

Keyword

Genetic obesity; Leptin-melanocortin pathway; Melanocortin 4 receptor agonist

Figure

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  Fig. 1. Leptin-melanocortin pathway. Leptin produced and secreted from adipose tissue acts at leptin receptor (LepR) in the arcuate nucleus of the hypothalamus. It activates increased production of pro-opiomelanocortin (POMC) in POMC neuron, which is further processed to melanocyte-stimulating hormones (MSH) by proprotein convertase subtilisin/kexin type 1 (PCSK1). MSH acts centrally at the melanocortin receptors, including the melanocortin 4 receptor (MC4R). Activation of MC4 neurons leads to reduction of food intake and increased energy expenditure. Brain-derived neurotrophic factor (BDNF) modulates leptin-mediated synaptic plasticity of neurons via its receptor neurotrophic receptor tyrosine kinase 2 (NTRK2).

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  Fig. 2. Diagnostic algorithm for genetic obesity. BMI, body mass index; POMC, production of pro-opiomelanocortin; PCSK1, proprotein convertase subtilisin/kexin type 1; SH2B1, SH2B adapter protein 1.

Reference

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