Mechanisms and physiological roles of regulation of orexin-producing neurons by leptin and TNF-alfa

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An adipose tissue derived hormone, leptin plays a role in the maintenance of the energy homeostasis. Leptin regulates the hypothalamic neurons activity and gene expression in the neurons. It has been already reported that leptin inhibited or activated hypothalamic arcuate neurons, but the detail mechanism remains to be unknown. Effects of leptin on other hypothalamic nucleus, especially lateral hypothalamic (LH) neurons, such as ones that express orexins, which are also crucial for energy regulation, have been yet unclear. We examined the mechanisms which underlie the leptin-induced regulation of these hypothalamic neurons.We examined the effects of leptin on the hypothalamic neurons by patch-clamp recording from EGFP-expressing neurons. Leptin hyperpolarized orexin and NPY neurons, and both of the responses was completely inhibited in the presence of the PI3K inhibitor or JAK2 inhibitor. Furthermore, tolbutamide, which is a blocker of KATP channels, completely abolished the leptin-induced hyperpolarization. We also found that another adipocyte derived factor, TNF-alfa inhibits orexin-producing neurons. This effect was also completely abolished in the presence of the PI3K inhibitor. These mechanisms might be important for the physiological regulation of hypothalamic neurons, especially for the coordination of energy balance as well as sleep/wakefulness.