madman
Super Moderator
* The discovery of kisspeptin neurons in the early part of this century revolutionized our understanding of reproductive regulation. These neurons project to and control GnRH neuronal excitability. More recently, arcuate kisspeptin neurons (KNDy) have been identified as the command neurons driving pulsatile release of GnRH and are essential for the GnRH/LH surge. Notably, these neurons express both steroid hormone receptors and metabolic hormone receptors and, like POMC neurons, are excited by insulin and leptin. Therefore, arcuate kisspeptin neurons likely serve as a central hub in linking metabolic signals with reproduction.
Abstract
The hypothalamic control of fertility is a quintessential homeostatic function. Given that reproduction is metabolically demanding, coordination between energy status and reproductive function is essential. Since GnRH neurons lack receptors for key metabolic hormones, nutrient sensing must occur via presynaptic neurons. Among the candidates are anorexigenic POMC and orexigenic NPY/AgRP neurons, both of which are in close apposition to the median eminence, a circumventricular organ permissive to circulating signals. These neurons are inversely regulated by glucose and metabolic hormones, with POMC neurons generally excited by insulin and leptin, and NPY/AgRP neurons inhibited by them. However, their synaptic input to GnRH neurons is sparse, and GnRH neurons may lack the necessary postsynaptic receptors. The discovery of kisspeptin neurons in the early part of this century revolutionized our understanding of reproductive regulation. These neurons project to and control GnRH neuronal excitability. More recently, arcuate kisspeptin neurons (KNDy) have been identified as the command neurons driving pulsatile release of GnRH and are essential for the GnRH/LH surge. Notably, these neurons express both steroid hormone receptors and metabolic hormone receptors and, like POMC neurons, are excited by insulin and leptin. Therefore, arcuate kisspeptin neurons likely serve as a central hub in linking metabolic signals with reproduction. This review will examine how these vital neurons control pulsatile GnRH release, their reciprocal synaptic connections with POMC and NPY/AgRP neurons, and how E2 can regulate their excitability. Through integration of metabolic and hormonal cues, these neurons help align reproductive capacity with the organism's energy status.
9 Conclusion
Although Kiss1ARH neurons have recently been identified as the “pulse generator” neurons driving the episodic GnRH release via direct synaptic input to GnRH neurons, emerging evidence reveals their role in coordinating energy metabolism with reproductive function. Electrophysiological and molecular biological studies show that Kiss1ARH neurons express steroid hormone receptors (ERα) and also metabolic hormone receptors (LRb and insulin receptor) (Figure 4), and similar to POMC neurons, they are excited by insulin and leptin.
Kiss1ARH neurons project to and robustly excite POMC neurons via mGluR1 but inhibit NPY/AgRP neurons via mGluR7 metabotropic receptors. Estrogenic-dependent upregulation of inhibitory mGluR7 receptors ensures effective inhibition of NPY/AgRP neurons and thereby decreases the drive for the palatable food sucrose. Moreover, CRISPR/SaCas9 mutagenesis of Slc17a6 (vGlut2) in Kiss1ARH neurons abolishes their glutamatergic input not only to these vital anorexigenic and orexigenic neurons but also reduces the glutamatergic drive to Kiss1AVPV/PeN neurons, impairing the E2-induced LH surge. Clearly, Kiss1ARH neurons are a critical component of a metabolic-reproductive circuit (Figures 4 and 5), which is consistent with their essential physiological role in reproduction. Therefore, with insufficient energy stores, the chances of maintaining a successful pregnancy through to parturition are low, and thus, the drive for nutrients becomes a higher priority and reproductive activities are attenuated.
Finally, although kisspeptin, NKB, and dynorphin are all down-regulated in Kiss1ARH neurons during high estrogenic states, endogenous excitatory ion channels (e.g., T-type calcium, HCN, and persistent sodium currents) and transporters (vGlut2) expression and function are up-regulated through multiple estrogen receptor signaling pathways. All of these channels and transporters contribute to the increased excitability of Kiss1ARH neurons, which enables them to coordinate reproduction, via ionotropic and metabotropic glutamatergic excitatory input to Kiss1AVPV/PeN neurons, with energy homeostasis via metabotropic excitatory input to POMC neurons and metabotropic inhibitory input to NPY/AgRP neurons. Therefore, despite earlier beliefs that Kiss1ARH neurons are quiescent during high estrogenic states, they are clearly the quintessential command neurons to coordinate energy states with reproduction.
Abstract
The hypothalamic control of fertility is a quintessential homeostatic function. Given that reproduction is metabolically demanding, coordination between energy status and reproductive function is essential. Since GnRH neurons lack receptors for key metabolic hormones, nutrient sensing must occur via presynaptic neurons. Among the candidates are anorexigenic POMC and orexigenic NPY/AgRP neurons, both of which are in close apposition to the median eminence, a circumventricular organ permissive to circulating signals. These neurons are inversely regulated by glucose and metabolic hormones, with POMC neurons generally excited by insulin and leptin, and NPY/AgRP neurons inhibited by them. However, their synaptic input to GnRH neurons is sparse, and GnRH neurons may lack the necessary postsynaptic receptors. The discovery of kisspeptin neurons in the early part of this century revolutionized our understanding of reproductive regulation. These neurons project to and control GnRH neuronal excitability. More recently, arcuate kisspeptin neurons (KNDy) have been identified as the command neurons driving pulsatile release of GnRH and are essential for the GnRH/LH surge. Notably, these neurons express both steroid hormone receptors and metabolic hormone receptors and, like POMC neurons, are excited by insulin and leptin. Therefore, arcuate kisspeptin neurons likely serve as a central hub in linking metabolic signals with reproduction. This review will examine how these vital neurons control pulsatile GnRH release, their reciprocal synaptic connections with POMC and NPY/AgRP neurons, and how E2 can regulate their excitability. Through integration of metabolic and hormonal cues, these neurons help align reproductive capacity with the organism's energy status.
9 Conclusion
Although Kiss1ARH neurons have recently been identified as the “pulse generator” neurons driving the episodic GnRH release via direct synaptic input to GnRH neurons, emerging evidence reveals their role in coordinating energy metabolism with reproductive function. Electrophysiological and molecular biological studies show that Kiss1ARH neurons express steroid hormone receptors (ERα) and also metabolic hormone receptors (LRb and insulin receptor) (Figure 4), and similar to POMC neurons, they are excited by insulin and leptin.
Kiss1ARH neurons project to and robustly excite POMC neurons via mGluR1 but inhibit NPY/AgRP neurons via mGluR7 metabotropic receptors. Estrogenic-dependent upregulation of inhibitory mGluR7 receptors ensures effective inhibition of NPY/AgRP neurons and thereby decreases the drive for the palatable food sucrose. Moreover, CRISPR/SaCas9 mutagenesis of Slc17a6 (vGlut2) in Kiss1ARH neurons abolishes their glutamatergic input not only to these vital anorexigenic and orexigenic neurons but also reduces the glutamatergic drive to Kiss1AVPV/PeN neurons, impairing the E2-induced LH surge. Clearly, Kiss1ARH neurons are a critical component of a metabolic-reproductive circuit (Figures 4 and 5), which is consistent with their essential physiological role in reproduction. Therefore, with insufficient energy stores, the chances of maintaining a successful pregnancy through to parturition are low, and thus, the drive for nutrients becomes a higher priority and reproductive activities are attenuated.
Finally, although kisspeptin, NKB, and dynorphin are all down-regulated in Kiss1ARH neurons during high estrogenic states, endogenous excitatory ion channels (e.g., T-type calcium, HCN, and persistent sodium currents) and transporters (vGlut2) expression and function are up-regulated through multiple estrogen receptor signaling pathways. All of these channels and transporters contribute to the increased excitability of Kiss1ARH neurons, which enables them to coordinate reproduction, via ionotropic and metabotropic glutamatergic excitatory input to Kiss1AVPV/PeN neurons, with energy homeostasis via metabotropic excitatory input to POMC neurons and metabotropic inhibitory input to NPY/AgRP neurons. Therefore, despite earlier beliefs that Kiss1ARH neurons are quiescent during high estrogenic states, they are clearly the quintessential command neurons to coordinate energy states with reproduction.
