Half the genome, half the story? Paternal metabolic health and offspring outcomes in the era of modern obesity pharmacotherapy

Abstract

Research on the developmental origins of health and disease has traditionally centered on maternal health and in utero exposures, with comparatively limited attention to paternal preconception factors. However, emerging evidence suggests that paternal metabolic health-particularly obesity and diabetes-may contribute to offspring metabolic risk. Observational studies associate higher paternal body mass index and cardiometabolic dysfunction with increased offspring adiposity, blood pressure, and markers of insulin resistance, although effect sizes are modest and confounding by shared genetics and environment remains a key limitation. Mechanistic data from animal models support sperm-mediated epigenetic pathways linking paternal metabolic status to offspring metabolic programming, yet human epigenetic evidence is inconsistent. At the same time, the widespread use of modern obesity pharmacotherapies, including glucagon-like peptide-1 receptor agonists and dual incretin agonists, has introduced a largely unexamined dimension of paternal exposure. Current data on paternal use of these agents and long-term offspring metabolic outcomes are sparse and fragmentary. As obesity pharmacotherapy expands among men of reproductive age, a shift beyond maternal-only frameworks is warranted. Rigorous studies integrating paternal metabolic profiling, medication exposure, and long-term offspring follow-up are urgently needed to inform clinical practice and public health guidance.

Keywords: Diabetes; GLP-1 receptor agonists; Obesity; Paternal health.