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.

Genetic obesity: an update with emerging therapeutic approaches

“…3,7) More than 80 distinct syndromic obesities have been described to date.8) Most common syndromes including PWS, BBS, and Alstrome syndrome share pathophysiology related to hypothalamic impairment. 3,7,8) 1. Prader-Willi syndrome…”

“…8,15,16) Treatment of obesity in BBS using MC4R agonist was evaluated and showed beneficial effect in clinical trials. 3,17,18)…”

“…1) The prevalence of extreme childhood obesity reported as ranges from 1.96% to 6.3%, depending on criteria, in the general population. 2,3) Childhood obesity leads to not only expansion of adipose tissue mass but also dysfunction of adipose tissue including adipocyte hypertrophy, inflammation, and dysregulation of adipokine secretion from early life. 4) The early-onset obesity is a serious health problem as it can cause cardiovascular and metabolic comorbidities, consequently related with increased mortality in adulthood.…”

“…Majority of childhood obesity is classified as "common polygenic obesity" which resulted from interaction of environmental factors and genetic susceptibilities. 3) "Syndromic obesity" is often considered when the child has obesity with developmental delay or dysmorphic features suggesting specific genetic syndromes including Prader-Willi syndrome (PWS), Bardet-Biedle syndrome (BBS), and Alstrom syndrome. "Monogenic obesity" is caused by variants in single gene which are usually involved in the regulation of hunger and satiety associated with the hypothalamic leptin-melanocortin pathway in central nervous system.…”

“…"Monogenic obesity" is caused by variants in single gene which are usually involved in the regulation of hunger and satiety associated with the hypothalamic leptin-melanocortin pathway in central nervous system. 3) If a patient has early-onset extreme obesity before 5 years of age, it would be a 'red flag sign' for genetic obesity and indicative subsequent genetic evaluation to identify underlying molecular genetic defect. As new precision medicine approaches based on genetic etiology are emerging, this review focuses on the genetic obesity including "syndromic obesity" and "monogenic obesity" associated with leptin-melanocortin pathway deficit.…”