One Liver, Two Paths: Comparison of Molecular Mechanisms of Metformin in Laying Hens and GLP-1 Agonists in Humans

This manuscript presents a comparative review of the molecular mechanisms of metformin in laying hens and GLP-1 receptor agonists in humans, with the liver as the common target. The liver plays a central role in regulating energy reserves and reproductive function across species. In humans, the goal of pharmacological intervention is to reduce liver fat and improve insulin sensitivity. In laying hens, the goal is to preserve the capacity for yolk precursor synthesis to sustain egg production. This manuscript asks how a single target follows two different paths. The review compares two drug families. In humans, GLP-1 agonists — particularly survodutide and retatrutide — significantly reduce liver fat by activating the AMPK pathway and stimulating the glucagon receptor. Meta-analyses show reductions in ALT and AST and in liver fat; however, their effect on histological fibrosis remains uncertain. In laying hens, metformin increases the expression of yolk precursor genes (VTG2, APOB, APOV1) through hepatic AMPK activation. Its efficacy, however, depends on age and duration of intervention: in older hens (73 weeks) with a short 8-week period, egg production did not improve and the percentage of broken eggs increased. The manuscript analyses the discrepancy between two key studies — Weaver and Ramachandran (2025) and Hatami et al. (2024) — along three axes: timing of intervention, duration of intervention, and breed-specific reproductive physiology. It concludes that the liver, as a common target, is directed toward fat reduction in humans and toward preservation of reproductive capacity in hens. The difference in effect direction stems from evolutionary differences in reproductive biology. A glossary of technical terms (ALT, AST, AMPK, GLP-1, MASLD, VTG2, APOB, APOV1, ATGL, and others) is provided at the end of the manuscript. Keywords: metformin; GLP-1 agonists; liver; AMPK; laying hen; reproduction; metabolism; MASLD. Related publications by the author:- Akbari Shadbad, C. (2026). Matrix Inconsistency and Calcium–Energy Interactions in Broiler Diets: A Field-Based Mechanistic Analysis of Post-15-Day Diarrhea and Abdominal Fat Deposition. Zenodo. https://zenodo.org/records/23467515- Akbari Shadbad, C. (2026). Potential Synergy of Organic Acidifiers, Calcium Soaps of Fatty Acids, and Emulsifiers in Poultry Nutrition: A Conceptual Model and Hypothetical Formulation. Zenodo. https://zenodo.org/records/23413517- ORCID: 0009-0008-2065-8340