UC San Diego

The intricate mechanisms involved in glucose sensing and regulation add to the complex puzzle of hypothalamic metabolism. Previous work has established glucose sensing in GnRH neurons, yet much remains unknown about the effects of glucose and estrogen on their metabolism; kisspeptin neuron responses remain largely unexplored. This study explores the potential impact of glucose, estrogen, and their interrelationship on metabolic genes that regulate energy balance in the hypothalamus. While kisspeptin plays a role in the hypothalamic-pituitary-gonadal axis, through quantitative PCR kisspeptin was not found to alter gene expression related to glucose transporters or metabolic regulators in a GnRH neuron cell line. However, in the kisspeptin neuronal cell line, KTaV-3, high physiological glucose levels did show an increase in the metabolic stress gene Txnip and other metabolic genes associated with increased metabolic activity, suggesting that metabolic regulatory mechanisms are at play. Notably, elevated estrogen levels in combination with the increasing glucose concentrations resulted in a significant increase in Txnip. The Xbp1 gene, another stress response gene was not shown to be expressed differently at the mRNA level, indicating that high or low glucose-induced stress was likely managed and did not cause generalized pre-apoptotic stress. Overall, the results show that kisspeptin neurons exhibit metabolic regulation through glucose availability and that there may be estrogen-mediated regulation of metabolism in kisspeptin neurons. These results advance our understanding of the interconnection of metabolic status, estrogen feedback, and reproduction and may provide insight into the underlying metabolic features of reproductive disorders such as polycystic ovary syndrome.