BACKGROUND: In vivo genome editing offers a long-term therapeutic approach for monogenic diseases by directly modifying genetic sequences. However, its application to non-monogenic, noncommunicable diseases, which are the leading causes of global mortality, remains limited due to the lack of well-defined genetic targets. METHODS: We developed an in vivo genome-editing approach to introduce a gene encoding the glucagon-like peptide-1 (GLP-1) receptor agonist Exendin-4, modified with a secretion signal peptide. Mice with obesity and pre-diabetic conditions received a single administration of genome editing. Blood Exendin-4 levels, food intake, body weight, and metabolic parameters were monitored over several months. RESULTS: Here we show that in vivo genome editing enables sustained Exendin-4 secretion from liver cells, leading to prolonged elevation of Exendin-4 levels in the bloodstream. Treated mice exhibited reduced food intake, attenuated weight gain, and improved glucose metabolism and insulin sensitivity without detectable adverse effects. CONCLUSIONS: This study demonstrates that a single administration of genome editing can achieve sustained therapeutic peptide secretion, providing a potential strategy for treating complex diseases without defined genetic causes.