McPherson NO, Owens JA, Fullston T, Lane M. Preconception diet or exercise intervention in obese fathers normalizes sperm microRNA profile and metabolic syndrome in female offspring. Am J Physiol Endocrinol Metab 308: E805-E821, 2015. First published February 17, 2015 doi:10.1152/ajpendo.00013.2015.-Obesity and type 2 diabetes are increasingly prevalent across all demographics. Paternal obesity in humans and rodents can program obesity and impair insulin sensitivity in female offspring. It remains to be determined whether these perturbed offspring phenotypes can be improved through targeted lifestyle interventions in the obese father. Using a mouse model, we demonstrate that diet or exercise interventions for 8 wk (2 rounds of spermatogenesis) in obese founder males restores insulin sensitivity and normalized adiposity in female offspring. Founder diet and/or exercise also normalizes abundance of X-linked sperm microRNAs that target genes regulating cell cycle and apoptosis, pathways central to oocyte and early embryogenesis. Additionally, obesity-associated comorbidities, including inflammation, glucose intolerance, stress, and hypercholesterolemia, were good predictors for sperm microRNA abundance and offspring phenotypes. Interventions aimed at improving paternal metabolic health during specific windows prior to conception can partially normalize aberrant epigenetic signals in sperm and improve the metabolic health of female offspring. fertility; infertility; paternal programming; interventions; obesity THE INCIDENCE OF OBESITY HAS MORE THAN DOUBLED in children and tripled in adolescence (44). Obesity increases the risk of type 2 diabetes mellitus (T2DM), cancer, stroke, heart disease, and osteoarthritis in adulthood (49). It is widely accepted that increased maternal BMI and hyperglycemia during gestation or lactation is associated with obesity and T2DM in children through developmental programming separate from shared genetics or postnatal environment (27,48). Recent studies now suggest that paternal metabolic health at conception can also impact children's health, with obese fathers more likely to father an obese child (35). In rodents, diet-induced male obesity with or without diabetes induces a worsened metabolic phenotype in their female offspring, with glucose intolerance in female offspring due to pancreatic islet dysfunction and white adipose tissue dysfunction or insulin resistance and obesity, with some consequences evident across two generations (18,45,46). However, whether short-term lifestyle interventions in the obese father could rescue these programmed metabolic phenotypes in female offspring is currently unknown. This is an important question, because in western societies, greater than 70% of reproductive-aged men are overweight or obese (e.g., 74% in the US) (15, 44). Weight loss via diet and exercise interventions in obese men improves glucose control and insulin action (9), alters epigenetic marks (i.e., DNA methylation and microRNA) in their leucocytes (41,50), and also improves their r...