Role and Mechanism of Chronic Restraint Stress in Regulating Energy Metabolism and Reproductive Function Through Hypothalamic Kisspeptin Neurons

Objectives: The purpose of this study was to investigate whether stress affected energy metabolism and reproductive function through the glucocorticoid receptor (GR) on Kisspeptin neurons in the hypothalamus. Methods: 1. The first part of this study focused on the effects of chronic restraint stress on energy metabolism and reproductive function in mice. 2. The second part of this study focused on the effects of chronic restraint stress on the expression of serum cortisol and prolactin and the expression of GR and Kiss1 genes in the hypothalamus.3. Based on the above research, we constructed Kisspeptin specific glucocorticoid receptor knock out (KGRKO) mice. The mice were subjected to restraint stress intervention, the body weight of the mice was monitored every day, and the vaginal smear was performed on the female mice to observe the estrous cycle. After 28 days of restraint stress, serum was collected to detect serum sex hormone levels, including LH, FSH and estrogen levels in female mice and testosterone level in male mice by ELISA. Results: 1.The body weight and energy intake of the restraint stress group were lower than those of the control. 2.After restraint stress, the female mice showed irregular estrous cycle. LH and FSH levels in the stress group were significantly decreased compared with the control group.3. After restraint stress, the levels of serum cortisol and prolactin in male and female mice were significantly higher than the control group, and the hypothalamus Kiss1 gene mRNA expression and Kisspeptin protein expression were significantly decreased.4. In female mice, compared with GR(flox/flox)/Kiss1(Cre-)control mice, the nadir serum cortisol increased significantly in the morning in GR(flox/flox)/Kiss1(Cre+) KGRKO mice, however, there was no significant difference in the serum peak cortisol in the afternoon. Compared with the control group, the restraint stress group and the KGRKO + restraint stress group had a significant weight loss compared with the KGRKO group. Compared with the restraint stress group, the KGRKO+restraint stress group had a reduced weight loss, suggesting that restraint stress might partially affect the energy metabolism through GR on Kisspeptin neurons. Conclusions: Chronic restraint stress induced weight loss in mice and reversed body weight gain induced by high-fat diet. Chronic restraint stress played a negative role in regulating reproductive function. The effects of chronic restraint stress on energy metabolism and reproduction were partially mediated by GR on Kisspeptin neurons in the hypothalamus. This study provided a central mechanism for chronic restraint stress in affecting energy metabolism and reproductive function, and was of great significance in revealing the relationship between the HPA axis with energy metabolism and reproduction.