Stressors generate adaptive responses, including transient suppression of reproductive function. Natural selection depends on successful reproduction, but inhibition of reproduction to survive famine or escape predation allows animals to survive to reproduce at a later time. The cellular locations and mechanisms responsible for inhibiting and reactivating the reproductive axis during and after stress, respectively, are not well understood. We demonstrated that stress-induced elevation in glucocorticoids affects hypothalamic neurons that secrete kisspeptin (KISS1), an important reproductive hormone. Stressors that stimulated glucocorticoid secretion, as well as glucocorticoid administration itself, inhibited Kiss1 mRNA expression, while conditions that did not change glucocorticoid secretion did not alter Kiss1 mRNA expression. In mice lacking glucocorticoid receptor specifically in kisspeptin-containing neurons, Kiss1 mRNA expression was no longer inhibited during restraint stress despite a rise in corticosterone, and both testosterone and copulatory behaviors showed accelerated recovery in the post-traumatic period. We also demonstrated that increased glucocorticoid secretion contributed to infertility and obesity in leptin-deficient mice. Leptin deficiency creates a chronic state of perceived starvation, and leptin-deficient mice exhibit elevated plasma glucocorticoid concentrations, morbid obesity, and infertility. Leptin-deficient, glucocorticoid-deficient mice exhibited decreased body weight and fat composition, decreased hyperphagia, and normal fertility. When supplemented with glucocorticoids back to the initial levels present in leptin deficiency, these mice gained weight and became infertile. Thus, leptin is not required for fertility as previously believed, and glucocorticoids can contribute to obesity and suppress fertility independently of leptin signaling. Together, these findings implicate glucocorticoids in the regulation of obesity and reproductive inhibition during stress, including perceived starvation caused by leptin deficiency. These studies may provide novel mechanisms and molecular targets in the reproductive and metabolic aspects of disorders characterized by glucocorticoid dysregulation, including post-traumatic stress disorder, anorexia nervosa, and mood disorders.
| Identifer | oai:union.ndltd.org:harvard.edu/oai:dash.harvard.edu:1/9453704 |
| Date | 18 December 2012 |
| Creators | Wang, Oulu |
| Contributors | Majzoub, Joseph Ahmad |
| Publisher | Harvard University |
| Source Sets | Harvard University |
| Language | en_US |
| Detected Language | English |
| Type | Thesis or Dissertation |
| Rights | open |
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