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Metformin treatment of high-fat diet-fed obese male mice restores sperm function and fetal growth, without requiring weight loss


1 Robinson Research Institute, School of Medicine, University of Adelaide, Adelaide 5005, Australia
2 Freemasons Foundation Centre for Men's Health, University of Adelaide, Adelaide 5005, Australia
3 Repromed, Dulwich 5065, Australia
4 Monash IVF Group, Melbourne 3000, Australia

Correspondence Address:
Nicole O McPherson,
Robinson Research Institute, School of Medicine, University of Adelaide, Adelaide 5005; Freemasons Foundation Centre for Men's Health, University of Adelaide, Adelaide 5005; Repromed, Dulwich 5065
Australia
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/aja.aja_141_19

PMID: 32098932

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−1 day−1 (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.


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