IMPE Abstracts

Introduction: The melanocortin-4 receptor (MC4R) pathway is an important regulator of energy balance and body weight. Several key genes are associated with the MC4R pathway, including POMC, PCSK1, LEPR, NCOA1, and SH2B1. These genes work in concert within the hypothalamus to regulate leptin signaling and activation of MC4R. However, the molecular mechanisms of these genes and the clinical characteristics of individuals with heterozygous variants in POMC, PCSK1, and LEPR, or heterozygous or biallelic variants in NCOA1and SH2B1, may differ and thus affect individualized treatment strategies for these patients.

Methods: A nonsystematic literature search was conducted in PubMed of articles published through August 2022 with search strings to identify publications reporting on the etiology and clinical characteristics of patients with heterozygous variants in POMC, PCSK1, and LEPR or heterozygous or biallelic variants in NCOA1and SH2B1. Abstracts of identified manuscripts were reviewed for relevance. Results were summarized narratively.

Results: Published research suggests that heterozygous variants in POMC, PCSK1, and LEPRand deficiencies in SRC1 and SH2B1 are all associated with pathologic insatiable hunger (or hyperphagia) and early-onset, severe obesity. Patients with these variants and associated deficiencies also share commonalities in clinical manifestations beyond hyperphagia and early-onset, severe obesity, including hypogonadism and leptin and insulin resistance. A limitation of this analysis is the nonsystematic search approach. Current efforts to address the underlying hyperphagia and obesity associated with heterozygous variants in POMC, PCSK1, and LEPRand variants in NCOA1and SH2B1include targeting the MC4R pathway through the MC4R agonist setmelanotide. In Phase 2 clinical trials, administration of setmelanotide led to reduced hunger scores and body weight in patients with these variants.

Conclusion: This analysis of published literature supports the concept that individuals with heterozygous or biallelic variants in the MC4R pathway (POMC, PCSK1, LEPR, NCOA1, and SH2B1) share many common clinical characteristics related to early-onset obesity and hunger, as well as obesity-associated comorbidities.