Metformin Treatment of High-fat Diet-fed Obese Male Mice Restores Sperm Function and Fetal Growth, Without Requiring Weight Loss

Male obesity is associated with subfertility and increased disease risk of offspring. It is unknown if effects can be reversed through pharmacological interventions. Five- to 6-week-old C57BL6 male mice were fed control diet (n = 10, CD) or high-fat diet (n = 20, HFD) for 16 weeks. Animals fed with a HFD were then allocated to continuation of HFD (n = 8) or HFD with metformin 28 mg kg day (n = 8) for 6 weeks. Animals fed with CD continued on a CD (n = 9). Males were mated with fertile C57BL6 females for the assessment of pregnancy and fetal growth. Sperm motility, spermatozoa and testicular morphology, sperm-zona pellucida binding, sperm reactive oxygen species (ROS) (intracellular [DCFDA], superoxide [MSR], and oxidative DNA lesions [8OHdG]), and mitochondrial membrane potential (JC1) were assessed. Metformin treatment of HFD males improved glucose tolerance (+12%, P < 0.05) and reduced Homeostatic Model Assessment of Insulin Resistance (HOMA-IR; -36%, P < 0.05). This occurred in the absence of a change in body weight or adiposity. Metformin treatment of HFD-fed males restored testicular morphology (+33%, P < 0.05), sperm motility (+66%, P < 0.05), sperm-zona pellucida binding (+25%, P < 0.05), sperm intracellular ROS concentrations (-32%, P < 0.05), and oxidative DNA lesions (-45%, P < 0.05) to the levels of the CD males. Metformin treatment of HFD fathers increased fetal weights and lengths compared with those born to HFD fathers (+8%, P < 0.05), with fetal lengths restored to those of fetuses of CD males. Short-term metformin treatment in men who are obese could be a potential intervention for the treatment of subfertility, without the need for a reduction in body weight/adiposity.