Genetic determinants of obesity: mechanisms, clinical implications, and targeted therapies

Abstract

Obesity is a major global health crisis with rising prevalence in both pediatric and adult populations, leading to an increased risk of cardiovascular, metabolic, and other chronic complications affecting all organ systems. A clear understanding of the genetic contributors to polygenic, syndromic, and monogenic obesity is essential for early diagnosis and targeted management. Advances in genome-wide association studies (GWAS) and sequencing technologies have greatly expanded our understanding of the genetic alterations underlying this multifaceted disease and have helped in delivering personalized treatment. The pathogenesis of common, polygenic obesity is related to a complex interplay between genetic susceptibility and environmental factors. Syndromic obesity, a less common form, is characterized by early-onset accompanied by additional features such as developmental delay, dysmorphic traits, and various organ system involvement. The rarest form, monogenic obesity, is characterized by severe early-onset non-syndromic obesity caused by mutations in single genes regulating appetite within the hypothalamus. These monogenic obesity cases, though infrequent, have been instrumental in elucidating key pathways involved in hunger and satiety. This review provides a comprehensive summary of the most recent findings on the genetic basis of obesity across all age groups, highlighting clinical implications and emerging therapeutic opportunities.