Monogenic obesity: what every doctor should know

Abstract

High-penetrance monogenic and syndromic obesities result from rare genetic variants with minimal environmental influence. These conditions can be differentiated from polygenic obesity based on key symptoms, such as hyperphagia (overwhelming hunger), severe early-onset obesity (before 5 years of age), and suboptimal responses to non-targeted therapies. Therefore, timely diagnosis is essential to guide management strategies and reduce the burden of disease.

A deep understanding of the underlying pathophysiology and the molecular mechanisms that define these pathologies substantially facilitates both diagnosis and the therapeutic approach. In recent years, advances in genetic analysis have made it possible to develop innovative pharmacological treatments for various forms of genetic obesity. It is now viable to identify specific patients who can benefit from targeted therapies based on their unique genetic mechanisms, through an understanding of the molecular pathways involved in the development of the disease.

As recently demonstrated, two drugs—metreleptin (an LPR agonist) and setmelanotide (MC4R agonists)—have been identified as potentially effective interventions in the treatment of certain rare forms of monogenic obesity caused by loss-of-function variants in genes involved in the leptin-melanocortin pathway. Evidence supports the efficacy and safety of these precision molecules in even younger age groups (from 2 years of age). Likewise, international regulatory indications have expanded, covering not only deficiencies in the leptinmelanocortin pathway (POMC, LEPR, PCSK1) and ciliopathies (Bardet-Biedl syndrome), but also complex forms of acquired hypothalamic obesity.

These precision medications have demonstrated robust clinical efficacy in intervening directly within hypothalamic signaling pathways, successfully achieving a reduction in BMI. Therefore, when faced with a clinical presentation of obesity in early childhood, implementing targeted genetic testing becomes a priority. The timely diagnosis of these variants is indispensable in clinical practice to effectively mitigate extreme hyperphagia and the increase in BMI.

The recognition of these distinctive features empowers medical personnel to abandon ineffective interventions and adopt individualized treatments that drastically improve long-term quality of life. Under this premise, it is essential to continue translational research on monogenic and syndromic diseases of the MC4R pathway, a/s multiple challenges remain to be addressed.