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

Abstract

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.

Abstract

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.

Key points

• Obesity is a complex, multifactorial disease that can be classified into common polygenic obesity and rare obesity syndromes, including monogenic obesity.

• Most monogenic obesity traits result from pathogenic variants in single genes converging in the leptin–melanocortin pathway.

• Targeting central pathways of energy expenditure with, for example, MC4R agonists provides new and promising treatment options for patients with monogenic obesity.

• Polygenic obesity results from an interplay among numerous genetic and environmental factors.

• Polygenic risk scores and massively parallel sequencing approaches will help the early identification of obesity predisposition.

• New precision medicine approaches based on genetic obesity traits might help tackle the obesity pandemic.