Insulin potentiates the synchronous firing of arcuate nucleus Kiss1 neurons that protects against diet-induced obesity

Kisspeptin neurons in the hypothalamic arcuate nucleus (Kiss1ARH) co-express kisspeptin, neurokinin B, dynorphin and provide an episodic, excitatory drive to gonadotropin-releasing hormone (GnRH) neurons, which is critical for pubertal development and fertility. Previously, we showed that high frequency firing of Kiss1ARH neurons co-releases NKB and dynorphin onto neighboring Kiss1ARH neurons to generate a slow excitatory postsynaptic potential (EPSP) that entrains intermittent, synchronous firing of Kiss1ARH neurons (Qiu et al., 2016). Presently, we discovered that insulin significantly increased the amplitude of the slow EPSP, which we documented is mediated by TRPC5 channels, and augmented synchronous GCaMP6s ([Ca]i) oscillations in Kiss1ARH neurons. Deletion of the endoplasmic reticulum calcium-sensing protein stromal interaction molecule 1 in Kiss1ARH neurons amplified insulin9s actions and protected ovariectomized female mice from developing obesity and glucose intolerance with high-fat dieting. Therefore, insulin appears to be critical for facilitating synchronous firing of Kiss1ARH neurons and coordinating energy homeostasis with fertility.