Leptin affects spermatogenic function via activation of the Akt/ERK/AMPK signaling pathway

Obesity is often associated with elevated leptin levels and leptin resistance, which can lead to impaired reproductive function. While exogenous leptin is known to enhance reproductive capacity in leptin-deficient male mice, its effects on reproductive function in obese male mice and the underlying mechanisms remain unclear. This study aims to elucidate the effects of leptin on testicular tissue, semen, and associated signaling pathways in both normal and obese male mice.

A high-fat diet-induced obesity model was established in male C57BL/6 J mice, followed by the administration of exogenous leptin. Histological changes in testicular tissue were observed using HE staining, while RT-PCR was employed to investigate mRNA expression levels of leptin and its receptor. The expression of proteins involved in leptin-related signaling pathways was analyzed by Western blotting.

Both high-fat diet-induced obesity and exogenous leptin administration led to significant alterations in testicular histomorphology, semen parameters, and reproductive hormones, ultimately impairing fertility. Leptin intervention significantly decreased FSH and LH levels, along with a reduction in serum leptin levels and the expression of leptin and its receptor mRNA. Moreover, exogenous leptin promoted the phosphorylation of STAT3, ERK, and AMPK, suggesting activation of these signaling pathways.

Normal mice exhibited negligible responses to exogenous leptin, whereas obese mice showed significant leptin resistance, likely due to the opposing signaling pathways that modulate leptin's effects. This study highlights the differential impact of leptin on reproductive function between normal and obese mice, with leptin resistance in obese mice potentially serving as a protective mechanism against reproductive damage.