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Review
. 2023 May 29;15(2):108-119.
doi: 10.4274/jcrpe.galenos.2023.2023-3-2. Epub 2023 May 16.

Current Treatments for Patients with Genetic Obesity

Nathan Faccioli  1   2   3 , Christine Poitou  2   3   4 , Karine Clément  2   3   4 , Béatrice Dubern  1   2   3
Affiliations
Review

Current Treatments for Patients with Genetic Obesity

Nathan Faccioli et al. J Clin Res Pediatr Endocrinol. .

Abstract

Obesity derives from impaired central control of body weight, implying interaction between environment and an individual genetic predisposition. Genetic obesities, including monogenic and syndromic obesities, are rare and complex neuro-endocrine pathologies where the genetic contribution is predominant. Severe and early-onset obesity with eating disorders associated with frequent comorbidities make these diseases challenging. Their current estimated prevalence of 5-10% in severely obese children is probably underestimated due to the limited access to genetic diagnosis. A central alteration of hypothalamic regulation of weight implies that the leptin-melanocortin pathway is responsible for the symptoms. The management of genetic obesity has so far been only based, above all, on lifestyle intervention, especially regarding nutrition and physical activity. New therapeutic options have emerged in the last years for these patients, raising great hope to manage their complex situation and improve quality of life. Implementation of genetic diagnosis in clinical practice is thus of paramount importance to allow individualized care. This review describes the current clinical management of genetic obesity and the evidence on which it is based. Some insights will also be provided into new therapies under evaluation.

Keywords: Genetic obesity; syndromic obesity; personalized medicine; setmelanotide.

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Figures

Figure 1
Figure 1
Schematic representation of the leptin-melanocortin pathway in the hypothalamic nuclei. Peak-ended arrows represent stimulation, circle-ended arrows represent inhibition. SH2B1 and SRC are activated secondary to leptin liaison on its receptor and potentialize its effect on POMC and PCSK1 in anorexigenic neurons, and SH2B1 potentialize LEPR inhibition effect on Agouti-related protein in orexigenic neuron. GLP1-R activation facilitates LEPR activation in both neuron populations. BBSome is an octameric complex composed of BBS1, BBS2, BBS4, BBS5, BBS7, BBS8 and BBS9 proteins which mediates transmembrane proteins localization in the primary cilium, including ADCY3. MRAP2 addresses MC4R to the cellular membrane. α-MSH: melanocyte stimulating hormone type α, BBSome: Bardet-Biedl syndrome associated protein complex, BDNF: brain-derived neurotrophic factor, GLP1: glucagon-like peptide 1, GLP1-R: GPL1 receptor, LEPR: leptin receptor, MC4R: melanocortin receptor type 4, MRAP2: melanocortin receptor accessory protein 2, NTRK2: neurotrophic receptor tyrosine kinase 2, PCSK1: prohormone convertase subtilisin-kexin 1, POMC: pro-opiomelanocortin, SH2B1: SRC homology 2 B adapter protein 1, SRC1: steroid receptor coactivator 1
Figure 2
Figure 2
Emerging strategy for management of genetic and syndromic obesity. OSA: obstructive sleep apnea, T2D: type 2 diabetes
See this image and copyright information in PMC

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