Obesity and the Genome: Emerging Insights from Studies in 2024 and 2025

Obesity is an epidemic that currently impacts many nations. The persistence of this disease is shaped by both genetic and epigenetic factors that extend beyond calorie balance. Research in the past year has revealed that epigenetic and cellular memory within adipose tissue can predispose individuals to weight regain after initial fat loss, as shown by studies indicating persistent transcriptional and chromatin changes even after fat mass reduction. Independent studies also demonstrate long-lasting metabolic shifts, such as those triggered by glucose-dependent insulinotropic polypeptide receptor (GIPR)-induced thermogenesis and sarcolipin (SLN) stabilization that also support a form of "metabolic memory" that is associated with sustained weight loss. At the neural level, rare variants in synaptic genes like BSN (Bassoon presynaptic cytomatrix protein), a presynaptic scaffold protein, and APBA1 (amyloid beta precursor protein binding family A member 1), a neuronal adaptor involved in vesicular trafficking, disrupt communication in feeding circuits, elevating obesity risk and illustrating how synaptic integrity influences food intake regulation. Similarly, the spatial compartmentalization of metabolic signaling within neuronal cilia is emerging as crucial, with cilia-localized receptors G protein-coupled receptor 75 (GPR75) and G protein-coupled receptor 45 (GPR45) exerting opposing effects on energy balance and satiety. Meanwhile, genome-wide association studies (GWAS) have advanced through larger, more diverse cohorts and better integration of environmental and biological data. These studies have identified novel obesity-related loci and demonstrated the value of polygenic risk scores (PRS) in predicting treatment responses. For example, genetic variants in GLP-1R (glucagon-like peptide-1 receptor) and GIPR (glucose-dependent insulinotropic polypeptide receptor) may modulate the effectiveness of incretin-based therapies, while PRS for satiation can help match individuals to the most appropriate anti-obesity medications. This review focuses on studies in the last two years that highlight how advances in obesity genetics are driving a shift toward more personalized and mechanism-based treatment strategies.