Leptin and inflammatory factors play a synergistic role in the regulation of reproduction in male mice through hypothalamic kisspeptin-mediated energy balance

Abstract

Background Energy balance is closely related to reproductive function, wherein hypothalamic kisspeptin mediates regulation of the energy balance. However, the central mechanism of kisspeptin in the regulation of male reproductive function under different energy balance states is unclear. Here, high-fat diet (HFD) and exercise were used to change the energy balance to explore the role of leptin and inflammation in the regulation of kisspeptin and the hypothalamic-pituitary-testis (HPT) axis. Methods Four-week-old male C57BL/6 J mice were randomly assigned to a normal control group (n = 16) or an HFD (n = 49) group. After 10 weeks of HFD feeding, obese mice were randomly divided into obesity control (n = 16), obesity moderate-load exercise (n = 16), or obesity high-load exercise (n = 17) groups. The obesity moderate-load exercise and obesity high-load exercise groups performed exercise (swimming) for 120 min/day and 120 min × 2 times/day (6 h interval), 5 days/week for 8 weeks, respectively. Results Compared to the mice in the normal group, in obese mice, the mRNA and protein expression of the leptin receptor, kiss, interleukin-10 (IL-10), and gonadotropin-releasing hormone (GnRH) decreased in the hypothalamus; serum luteinizing hormone (LH), follicle-stimulating hormone (FSH), and testosterone levels and sperm quality decreased; and serum leptin, estradiol, and tumor necrosis factor-α (TNF-α) levels and sperm apoptosis increased. Moderate- and high-load exercise effectively reduced body fat and serum leptin levels but had the opposite effects on the hypothalamus and serum IL-10 and TNF-α levels. Moderate-load exercise had anti-inflammatory effects accompanied by increased mRNA and protein expression of kiss and GnRH in the hypothalamus and increased serum FSH, LH, and testosterone levels and improved sperm quality. High-load exercise also promoted inflammation, with no significant effect on the mRNA and protein expression of kiss and GnRH in the hypothalamus, serum sex hormone level, or sperm quality. Moderate-load exercise improved leptin resistance and inflammation and reduced the inhibition of kisspeptin and the HPT axis in obese mice. The inflammatory response induced by high-load exercise may counteract the positive effect of improving leptin resistance on kisspeptin and HPT. Conclusion During changes in energy balance, leptin and inflammation jointly regulate kisspeptin expression on the HPT axis.

Obesity in Pediatric-Onset Multiple Sclerosis

“…Mice models support the hypothesis that the low-grade inflammatory state mediated by obesity and increased leptin in obese males could be responsible for testosterone depletion via downregulation of kisspeptin neurons and inhibition of the gonadotropic axis. 31 Testosterone, known for its anti-inflammatory actions at the cerebral level, through its depletion during puberty, could explain the stronger association in our study between POMS and obesity in boys. In adult men with MS, testosterone depletion is associated with increased disease severity and neuroinflammation progression.…”

Presence of leptin and its receptor in the ram reproductive system and in vitro effect of leptin on sperm quality

“…Leptin deficiency and mutation of its receptors are associated with various disorders including obesity, diabetes, heart disease and neurodegenerative diseases ( Kang, Ok & Lee, 2020 ; Calio et al, 2021 ; Hontsariuk et al, 2020 ). In addition, leptin plays an important role in mammalian reproduction, particularly in males ( Childs et al, 2021 ; Chang et al, 2021 ). For instance, the level of leptin in the semen of varicocele patients was significantly higher than that in the normal subjects.…”

Diet and exercise interventions reduce serum asprosin and the corresponding hypothalamic– pituitary–gonad-axis dysfunction in obese men

“…However, the fat factor, leptin, can stimulate GnRH release via kisspeptin, which in turn stimulates LH and T secretion ( Thompson et al, 2004 ; Zhang and Gong, 2018 ). However, in obesity, massive secretion of leptin by adipose tissues triggers hyperleptinemia, which leads to resistance of the HPG-axis to leptin signaling, thus negatively affecting male fertility ( Chang et al, 2021 ; Childs et al, 2021 ). Therefore, we speculate that in the obesity state, ASP may also excessively activate some negative feedback regulation mechanism, leading to “ASP resistance” and thus inhibiting the HPG axis.…”