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.

Keywords: Energy balance; Hypogonadotropic hypogonadism; Inflammation; Kisspeptin; Leptin.

Fig. 1

Influence of high-fat diet and exercise on body weight and abdominal fat content. Values are reported as the mean ± standard error (SE). NC, normal control; OC, obesity control; OME, obesity moderate-load exercise; OHE, obesity high-load exercise; vs. *P < 0.05, **P < 0.01

Fig. 2

Effects of high-fat diet and exercise on the weight of reproductive organs in male mice. Values are reported as the mean ± standard error (SE). NC, normal control; OC, obesity control; OME, obesity moderate-load exercise; OHE, obesity high-load exercise; vs. *P < 0.05, **P < 0.01

Fig. 3

Effects of high-fat diet and exercise on serum leptin and sex hormones in male mice. Values are reported as the mean ± standard error (SE). NC, normal control; OC, obesity control; OME, obesity moderate-load exercise; OHE, obesity high-load exercise; vs. *P < 0.05, **P < 0.01

Fig. 4

Effects of high-fat diet and exercise on serum TNF-α and IL-10 in male mice. Values are reported as the mean ± standard error (SE). NC, normal control; OC, obesity control; OME, obesity moderate exercise; OHE, obesity heavy loads exercise; vs. *P < 0.05, **P < 0.01

Fig. 5

Effect of high-fat diet and exercise on sperm quality in male mice. Values are reported as the mean ± standard error (SE). NC, normal control; OC, obesity control; OME, obesity moderate-load exercise; OHE, obesity high-load exercise; vs. *P < 0.05, **P < 0.01

Fig. 6

Effect of high-fat diet and exercise on sperm apoptosis rate in male mice. a Normal control (NC) group; b high-fat diet obesity control (OC) group; c obesity moderate-load exercise (OME) group; d obesity high-load exercise (OHE) group

Fig. 7

Effects of high-fat diet and exercise on various molecules in the hypothalamus of male mice. The expression of leptin receptor, TNF-α, IL-10, kiss1, kiss1R, and GnRH in the hypothalamus of male mice was determined. The values are reported as the mean ± standard error (SE). NC, normal control; OC, obesity control; OME, obesity moderate-load exercise; OHE, obesity high-load exercise, vs. *P < 0.05, **P < 0.01