Obesity-associated carcinogenesis offers a model to explore the transition from metabolic dysregulation to genomic instability and carcinogenesis. AMPK, the principal cellular energy sensor, coordinates ATP production with metabolic demand; however, in obesity, AMPK activity is impaired, resulting in reduced ATP, elevated AMP, and cellular energy stress. DNA polymerases ε (Pol ε) and δ (Pol δ) maintain replication fidelity via a 3′→5′ exonuclease proofreading activity that removes misincorporated nucleotides. Elevated AMP directly binds and selectively inhibits the exonuclease, conserving energy at the expense of genomic accuracy. As a result, replication errors escape correction and accumulate, some conferring selective advantage and driving carcinogenic evolution. Therapeutic and lifestyle interventions that activate AMPK — including weight loss, exercise, metformin, and aspirin — restore ATP production, lower AMP, and relieve inhibition of exonuclease proofreading, thereby preserving genomic integrity and slowing mutation-driven carcinogenesis. This framework reveals two core biological principles: 1. Energy metabolism and DNA replication fidelity are mechanistically coupled at the DNA polymerase active site. 2. The mutation rate is an adaptive metabolic phenotype, modulated by AMP levels. These concepts redefine the metabolic-genetic interface in carcinogenesis and highlight AMPK activation as a rational target for obesity associated cancer prevention.