Leptin restores markers of female fertility in lipodystrophy.

Objectives: Female reproductive dysfunction occurs in patients with pathological loss of adipose tissue, i.e. lipodystrophy (LD). However, mechanisms remain largely unclear and treatment effects of adipocyte-derived leptin have not been assessed in LD animals.

Methods: In the current study, C57Bl/6 LD mice on a low-density lipoprotein receptor knockout background were treated with leptin or saline for 8 weeks and compared to non-LD controls.

Results: The number of pups born was 37% lower in breeding pairs consisting of LD female mice x non-LD male mice (n = 3.3) compared to LD male mice x non-LD female mice (n = 5.2) (p < 0.05). Mean uterus weight was significantly lower in the saline-treated LD group (18.8 mg) compared to non-LD controls (52.9 mg; p < 0.0001) and increased significantly upon leptin treatment (46.5 mg; p < 0.001). The mean number of corpora lutea per ovary was significantly lower in saline-treated LD animals compared to non-LD controls (p < 0.01) and was restored to non-LD control levels by leptin (p < 0.05). Mechanistically, mRNA expression of ovarian follicle-stimulating hormone receptor (p < 0.01) and estrogen receptor β (p < 0.05), as well as of pituitary luteinizing hormone β subunit (p < 0.001) and follicle-stimulating hormone β subunit (p < 0.05), was significantly upregulated in LD mice compared to non-LD controls. In addition, mean time to vaginal opening as a marker of puberty onset was delayed by 12.5 days in LD mice (50.9 days) compared to non-LD controls (38.4 days; p < 0.001).

Conclusions: Female LD animals show impaired fertility which is restored by leptin. Future studies should assess leptin as a subfertility treatment in human leptin-deficiency disorders.