The role of hepatic kisspeptin as a link between the reproductive axis and metabolic status
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Date
2014-04-25
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Johns Hopkins University
Abstract
In mammals, the reproductive neuroendocrine axis is a feedback loop system consisting of the hypothalamus, the pituitary, and the gonads. Kisspeptin and its receptor Kiss1R (formerly, GPR54) have been established as key regulators of the reproductive axis in mammals, and mediate the neuronal output that is necessary for the preovulatory luteinizing hormone (LH) surge in females. The gonadotropin-releasing hormone (GnRH) neurons of the brain express Kiss1r and synapse with kisspeptin neurons. Kisspeptinergic neurons also express the estrogen receptor alpha (ERα), and are potently regulated by estrogen in a positive feedback mechanism. Previous studies have shown strong evidence of estrogen involvement in metabolic syndrome. To evaluate whether the reproductive peptide kisspeptin is affected by estrogen under altered metabolic states, we induced a 24-hour starvation in 5-6 week old male and female wild type 129SVJ mice examined whether there was a correlation between ERα and Kiss1 expression in acute fasting states. We also generated a liver-specific knockout of the ERα gene in 5-6 week old male and female ERα floxed mice and measured the expression of Kisspeptin in the liver, estrous cyclicity in females, and serum gonadotropin levels. We have demonstrated that in rodents, Kiss1 expression by the liver is highly upregulated in states of energy deficiency, while ERα is reduced in acute fasting states. Our data show that serum concentrations of the gonadotropin hormones LH and FSH are also affected by starvation. By virtue of its location outside the blood-brain barrier, the pituitary detects changes in levels of physiological molecules. The observations from our study provide substantial evidence for the further exploration of the reproductive response of the HPG axis under acute metabolic stress.
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kisspeptin, caloric restriction