Obesity-Associated Genetic Variants and AMPK Signaling in Cardiovascular Disease: A Systematic Review of Mechanisms and Clinical Implications

ObjectiveTo investigate how genetic variations in obesity-related genes affect the AMPK signaling pathway and contribute to the pathophysiology of cardiovascular disease in the context of obesity. BackgroundThe global rise in obesity presents serious public health challenges, significantly increasing the risk of comorbidities such as type 2 diabetes and cardiovascular disease. Genetic predisposition plays a critical role in obesity, with several genes influencing metabolic regulation. AMP-activated protein kinase (AMPK) is a central regulator of cellular energy homeostasis. Disruptions in its signaling pathway may contribute to metabolic dysfunction and cardiovascular complications. Understanding how genetic variations impact AMPK signaling is essential for the development of targeted interventions. MethodsA systematic literature review was conducted using databases including PubMed, MEDLINE, Google Scholar, and both open-access and subscription-based journals. The search focused on studies examining genetic variations in obesity-associated genes--FTO, MC4R, LEP, LEPR, PCSK1, PPARG, BDNF, SIM1, TBC1D1, ADRB3, UCP1, and SH2B1--and their impact on AMPK signaling. No date restrictions were applied. Articles were selected based on predefined inclusion criteria and assessed in accordance with PRISMA guidelines to evaluate the mechanisms linking genetic variants with AMPK modulation, energy balance, inflammation, and cardiovascular risk. ResultsGenetic variants in the selected obesity-related genes were found to significantly influence AMPK activation. These alterations led to impaired energy expenditure, increased lipid storage, and disturbances in glucose metabolism. Dysregulation of AMPK signaling also promoted chronic low-grade inflammation and endothelial dysfunction--factors closely associated with elevated cardiovascular disease risk. The findings underscore the pivotal role of gene-AMPK interactions in metabolic and cardiovascular health. ConclusionGenetic variations in obesity-related genes impair AMPK activation, disrupting energy metabolism and promoting inflammation and vascular dysfunction. This contributes to increased cardiovascular risk in obese individuals. Personalized therapies targeting AMPK activation and gene-specific pathways may offer promising strategies to counteract obesity-induced metabolic dysregulation and improve cardiovascular outcomes.