The promise of new anti-obesity therapies arising from knowledge of genetic obesity traits

Obesity is a multifactorial and complex disease that often manifests in early childhood with a lifelong burden. Polygenic and monogenic obesity are driven by the interaction between genetic predisposition and environmental factors. Polygenic variants are frequent and confer small effect sizes. Rare monogenic obesity syndromes are caused by defined pathogenic variants in single genes with large effect sizes. Most of these genes are involved in the central nervous regulation of body weight; for example, genes of the leptin-melanocortin pathway. Clinically, patients with monogenic obesity present with impaired satiety, hyperphagia and pronounced food-seeking behaviour in early childhood, which leads to severe early-onset obesity. With the advent of novel pharmacological treatment options emerging for monogenic obesity syndromes that target the central melanocortin pathway, genetic testing is recommended for patients with rapid weight gain in infancy and additional clinical suggestive features. Likewise, patients with obesity associated with hypothalamic damage or other forms of syndromic obesity involving energy regulatory circuits could benefit from these novel pharmacological treatment options. Early identification of patients affected by syndromic obesity will lead to appropriate treatment, thereby preventing the development of obesity sequelae, avoiding failure of conservative treatment approaches and alleviating stigmatization of patients and their families. Rare monogenic obesity is caused by pathogenic variants in single genes, while common obesity mostly has a polygenic basis. This Review discusses genetic obesity traits, the emergence of novel pharmacological treatment options that target the central melanocortin pathway and future innovative therapies.

Automated summary

Obesity is a complex and multifactorial disease that starts in early childhood and has lifelong consequences. It is influenced by both genetic predisposition and environmental factors. While polygenic obesity is common and has small effects, rare monogenic obesity syndromes are caused by specific pathogenic variants in a single gene with large effects. These genes are mainly involved in the central nervous regulation of body weight, such as the leptin-melanocortin pathway. Genetic testing is recommended for patients with rapid weight gain in infancy and other clinical suggestive features, as novel pharmacological treatments targeting the central melanocortin pathway are emerging. Early identification of syndromic obesity patients can lead to appropriate treatment, preventing obesity-related complications and stigma.