Arcuate Kisspeptin Neurons Coordinate Reproductive Activities with Metabolism

Abstract

Hypothalamic control of fertility is the quintessential homeostatic function. However, fertility is metabolically demanding; so, there must be coordination between energy states and reproductive functions. Because gonadotropin-releasing hormone (GnRH) neurons are devoid of many of the critical metabolic hormone receptors for sensing nutrient levels, it has long been recognized that the sensing of energy stores had to be done by neurons presynaptic to GnRH neurons. Some of the obvious players have been the anorexigenic proopiomelanocortin (POMC) and orexigenic neuropeptide Y (NPY)/agouti-related peptide (AgRP) neurons, both of which are in close apposition to the median eminence, a circumventricular organ. Indeed, POMC and NPY/AgRP neurons are inversely regulated by glucose and metabolic hormones including insulin and leptin. However, their synaptic connections with GnRH neurons are sparse and/or GnRH neurons are lacking the postsynaptic receptors to mediate the appropriate physiological response. Kisspeptin neurons were discovered in the early part of this century and subsequently shown to project to and control GnRH neuronal excitability. In fact, more recently the arcuate kisspeptin neurons have been identified as the command neurons driving pulsatile release of GnRH. Subsequently, it was shown that arcuate kisspeptin neurons express not only steroid hormone receptors but also metabolic hormone receptors such that similar to POMC neurons, they are excited by insulin and leptin. Therefore, based on the premise that arcuate kisspeptin neurons are the key neurons coordinating energy states with reproduction, we will review not only how these vital neurons control pulsatile GnRH release but how they control energy homeostasis through their synaptic connections with POMC and NPY/AgRP neurons and ultimately how E2 can regulate their excitability.

Deletion of Stim1 in hypothalamic arcuate nucleus Kiss1 neurons potentiates synchronous GCaMP activity and protects against diet-induced obesity

“…The tyrosine phosphatase through its dephosphorylation of STAT3 inhibits downstream signaling of leptin and insulin in POMC neurons (Dodd Garron T. et al, 2018). Moreover, Kiss1 ARH neurons are an integral part of an anorexigenic circuit in the hypothalamus (Navarro Víctor M., 2020; Qiu J., Rivera, et al, 2018; Rønnekleiv et al, 2019) and may provide the excitatory glutamatergic drive to the paraventricular hypothalamus to generate rapid satiety following a meal (Fenselau et al, 2017). However, future experiments will need to test this directly by using ChR2-assisted circuit mapping along with high frequency stimulation of Kiss1 ARH neurons to further document this pathway (Qiu J., Rivera, et al, 2018)…”

“…Presently, there is compelling evidence that Kiss1 ARH neurons are the critical “command” neuron for coordinating energy states with reproductive functions (see (Navarro Víctor M., 2020; Rønnekleiv et al, 2019) for review). Insulin may be the critical metabolic hormone providing feedback since neuron-specific deletion of insulin receptors causes hypothalamic hypogonadism and infertility (Bruning et al, 2000).…”

“…Moreover, insulin stimulates pulsatile LH secretion by the pituitary gland in diabetic animal models (Bucholtz et al, 2000), and administration of kisspeptin in type 2 diabetic males with central hypogonadism increases LH pulses and enhances gonadal testosterone secretion (George et al, 2013). While it is unclear if GnRH neurons are directly regulated by insulin (Sliwowska et al, 2014), Kiss1 ARH neurons express insulin receptors and are robustly depolarized by physiological levels of insulin (Qiu J. et al, 2014; Rønnekleiv et al, 2019). Not only does insulin depolarize Kiss1 ARH neurons via opening TRPC5 channels (Qiu J. et al, 2011; Qiu J. et al, 2014), presently we found that insulin increases the excitatory response to NKB to augment synchronous firing of Kiss1 ARH neurons.…”

Caloric restriction in female reproduction: is it beneficial or detrimental?

“…Although in vitro mice study discovered that insulin can directly modulate GnRH neurons, in vivo studies of adult ewes and mice gave an opposite evidence [ 29 , 30 ]. Indeed, insulin activates Kiss1 ARC in mice via functional insulin receptors [ 31 ]. Also, in laboratory animals, insulin excites ARC POMC neurons and suppresses NPY/AgRP neurons [ 30 ].…”

“…Interestingly, CR enhances the negative feedback (mice) [ 2 , 36 ] and attenuates the positive feedback (rhesus monkeys) [ 46 ] of E 2 on HPO axis. It is also found that E 2 as an anorexigenic factor enables to inhibit ARC NPY/AgRP neurons and activate ARC POMC neurons [ 31 ]. Therefore, low E 2 level caused by CR also contributes to the inhibition of HPO axis.…”