Estrogenic regulation of reproduction and energy homeostasis by a triumvirate of hypothalamic arcuate neurons

Abstract

Pregnancy is energetically demanding and therefore, by necessity, reproduction and energy balance are inextricably linked. With insufficient or excessive energy stores a female is liable to suffer complications during pregnancy or produce unhealthy offspring. Gonadotropin-releasing hormone neurons are responsible for initiating both the pulsatile and subsequent surge release of luteinizing hormone to control ovulation. Meticulous work has identified two hypothalamic populations of kisspeptin (Kiss1) neurons that are critical for this pattern of release. The involvement of the hypothalamus is unsurprising because its quintessential function is to couple the endocrine and nervous systems, coordinating energy balance and reproduction. Estrogens, more specifically 17β-estradiol (E₂ ), orchestrate the activity of a triumvirate of hypothalamic neurons within the arcuate nucleus (ARH) that govern the physiological underpinnings of these behavioral dynamics. Arising from a common progenitor pool, these cells differentiate into ARH kisspeptin, pro-opiomelanocortin (POMC), and agouti related peptide/neuropeptide Y (AgRP) neurons. Although the excitability of all these subpopulations is subject to genomic and rapid estrogenic regulation, Kiss1 neurons are the most sensitive, reflecting their integral function in female fertility. Based on the premise that E₂ coordinates autonomic functions around reproduction, we review recent findings on how Kiss1 neurons interact with gonadotropin-releasing hormone, AgRP and POMC neurons, as well as how the rapid membrane-initiated and intracellular signaling cascades activated by E₂ in these neurons are critical for control of homeostatic functions supporting reproduction. In particular, we highlight how Kiss1 and POMC neurons conspire to inhibit AgRP neurons and diminish food motivation in service of reproductive success.

Keywords: agouti-related peptide; hypothalamus; kisspeptin neurons; neuropeptide Y; pro-opiomelanocortin.

Figure 1.. Estradiol governs signaling between Kiss1 and GnRH neurons to drive LH release.

A) Prior to proestrus, estradiol (E2) levels are low and kisspeptin (Kiss1) neurons (bottom, magenta) in the arcuate nucleus of the hypothalamus (ARH, grey region) release neurokinin B (NKB, triangles) that depolarizes and recruits other Kiss1^ARH neurons. Dynorphin (Dyn, hexagons) is co-released and acts presynaptically to modulate (inhibit) the release of NKB. Together the two peptides govern the synchronous activity of Kiss1^ARH neurons and promote kisspeptin release (diamonds) that stimulates pulsatile gonadotrophin-releasing hormone (GnRH) release from fibers (cyan) in the median eminence (ME). As estradiol levels rise Kiss1^ARH neurons transition from peptidergic to primarily fast glutamatergic (circles) neurotransmission to communicate with the Kiss1^AVPV/PeN neurons, which stimulates burst-firing of Kiss1^AVPV/PeN neurons. E2 also enhances the excitability and kisspeptin release of these rostral Kiss1 neurons (top, red) to robustly excite GnRH neurons via activation of the GPR54 signaling cascade, thereby stimulating the release of GnRH at the time of the preovulatory surge. Kisspeptin, GPR54, NKB, Tacr3 and GnRH are all required for normal fertility. B) Confocal micrograph of the PeN containing Kiss1 neurons found along the third ventricle. C) Confocal micrograph showing labeled Kiss1 cell bodies (magenta) and a few GnRH cell bodies (cyan with white arrowheads) in the ARH as noted in Herde et al. (J. Neuroscience 2013; 33:12689-97). GnRH fibers from the preoptic run along the ventral ARH into the ME. (3V: third ventricle; AVPV: anteroventral periventricular; ARH: arcuate nucleus of the hypothalamus; Kiss1: kisspeptin; ME: median eminence; MnPO: median preoptic nucleus; OC: Optic Chiasm; PeN: periventricular nucleus)

Figure 2.. Tri-synaptic circuit in the arcuate nucleus of the hypothalamus.

(Left panel) When circulating estradiol levels are low, AgRP neurons will release the inhibitory neurotransmitter GABA onto Kiss1 and POMC neurons. POMC and Kiss1 neurons will release a trickle of glutamate onto AgRP neurons, exciting them through AMPA receptors. (Right panel) When circulating levels of E2 are high in proestrus or with E2-replacement in ovariectomized females, AgRP will display reduced neuronal excitability and GABA release. In POMC neurons the coupling of metabotropic GABA_B receptors to GIRK channels is attenuated, further diminishing GABAergic inhibition. Simultaneously in Kiss1^ARH neurons Vglut2, CaV3.1, and Hcn1,2 mRNA expression is upregulated to enhance glutamate release as well as the excitatory T-type calcium and h-currents (80). Therefore, POMC and Kiss1 neurons will be disinhibited/excited at the same time their glutamate release probability is enhanced through increased Vglut2 mRNA transcription. However, E2 will also increase expression of the inhibitory mGluR7 receptor in AgRP neurons such that the greater glutamate release will recruit these extrasynaptic receptors, causing an overall inhibitory input. Additionally, POMC neurons will produce more β-endorphin to further inhibit AgRP neurons. Taken together, reciprocal connections between POMC and Kiss1 neurons will act synergistically to increase their activity and excitability while both inhibiting AgRP neurons to decrease food motivation in favor of reproductive behavior. (AgRP: neuropeptide Y/agouti-related peptide; Kiss1: kisspeptin; mOR: μ-opioid receptor; mGluR1: Group I metabotropic glutamate receptor 1; mGluR7: Group III metabotropic glutamate receptor 7; POMC: proopiomelanocortin).