Genetic architecture of obesity and advances in precision pharmacotherapy: a comprehensive review.

Abstract

Obesity, a global health catastrophe, arises from complex interactions between environmental factors and genetic predispositions. This review summarizes the current state of knowledge on the genetic basis of obesity and contrasts rare monogenic forms caused by mutations in a single gene with common polygenic forms caused by hundreds of genetic variants with small effects. We highlight important genes in neuroendocrine signaling pathways, particularly the leptin-melanocortin system involving MC4R, LEP, and POMC, as well as newly identified loci from genome-wide association studies such as FTO and SEC16B. The interplay between genetic probability and environmental factors underscores the heterogeneity of obesity phenotypes. Recent advances in pharmacotherapy, such as GLP-1 receptor agonists and dual/triple incretin agonists, demonstrate strong efficacy across various genetic backgrounds and underscore the translational relevance of genetic insights. New findings from different groups support the use of polygenic risk scores to identify individuals at risk and suggest prevention strategies. This review discusses the genomic data on clinical practice and emphasizes the possibilities and challenges of precision medicine in obesity treatment. Future research should focus on length of genetic screening and elucidating gene-environment interactions to optimize treatment outcomes.