Melanin-concentrating hormone directly inhibits GnRH neurons and blocks kisspeptin activation, linking energy balance to reproduction

Abstract

A link between energy balance and reproduction is critical for the survival of all species. Energy-consuming reproductive processes need to be aborted in the face of a negative energy balance, yet knowledge of the pathways mediating this link remains limited. Fasting and food restriction that inhibit fertility also upregulate the hypothalamic melanin-concentrating hormone (MCH) system that promotes feeding and decreases energy expenditure; MCH knockout mice are lean and have a higher metabolism but remain fertile. MCH also modulates sleep, drug abuse behavior, and mood, and MCH receptor antagonists are currently being developed as antiobesity and antidepressant drugs. Despite the clinical implications of MCH, the direct postsynaptic effects of MCH have never been reported in CNS neurons. Using patch-clamp recordings in brain slices from multiple lines of transgenic GFP mice, we demonstrate a strong inhibitory effect of MCH on an exclusive population of septal vGluT2-GnRH neurons that is activated by the puberty-triggering and preovulatory luteinizing hormone surge-mediating peptide, kisspeptin. MCH has no effect on kisspeptin-insensitive GnRH, vGluT2, cholinergic, or GABAergic neurons located within the same nucleus. The inhibitory effects of MCH are reproducible and nondesensitizing and are mediated via a direct postsynaptic Ba 2؉ -sensitive K ؉ channel mechanism involving the MCHR1 receptor. MCH immunoreactive fibers are in close proximity to vGluT2-GFP and GnRH-GFP neurons. Importantly, MCH blocks the excitatory effect of kisspeptin on vGluT2-GnRH neurons. Considering the role of MCH in regulating energy balance and of GnRH and kisspeptin in triggering puberty and maintaining fertility, MCH may provide a critical link between energy balance and reproduction directly at the level of the kisspeptin-activated vGluT2-GnRH neuron.fertility ͉ gonadotropins ͉ HPG axis ͉ obesity ͉ starvation N utritional status and availability of energy stores exert a profound impact on reproductive function (1-3). Reproduction is an expensive energy-consuming process, and thus it is important that puberty, pregnancy, and lactation occur only when metabolic fuel is available (4). Availability of metabolic fuel is conveyed to the brain by peripherally generated signals, such as leptin, insulin, and ghrelin, as well as by centrally released peptides such as neuropeptide Y, melanocortins, and melanin-concentrating hormone (MCH). One or more of these signals can directly or indirectly link energy balance with reproduction at one or more levels of the hypothalamic-pituitary-gonadal (HPG) axis. Thus, insulin and leptin may indirectly influence GnRH neurons (2, 5-7); leptin could regulate the HPG axis via kisspeptin-containing hypothalamic neurons (8, 9). Kisspeptin and its receptor are critical for reproduction (10-12); both kisspeptin and kisspeptin receptor knockout mice fail to enter puberty, and humans with loss of function mutations in the kisspeptin receptor exhibit hypogonadotropic hypogonadism and are infertile (13-15). Mechanisti...

Melanin-Concentrating Hormone Neurons Release Glutamate for Feedforward Inhibition of the Lateral Septum

“…MCH activates inhibitory G i -coupled MCHR1 receptors , reduces presynaptic activity (Gao, 2009), and suppresses neuronal firing (Wu et al, 2009;Sears et al, 2010). Stimulating MCH projections in the LS reduced action potential firing, but this does not reflect an inhibitory action of MCH but rather a glutamate-dependent GABA release.…”

The roles of melanin-concentrating hormone in energy balance and reproductive function: are they connected?

“…Anatomically, this is plausible since various studies in female rodents have reported the close apposition of MCH fibres to hypothalamic GNRH neurones (Smith & Grove 2002, Williamson-Hughes et al 2005, Wu et al 2009, and Mchr1 mRNA has been detected in GNRH neurones (Williamson-Hughes et al 2005). Approximately 85-90% of GNRH neurones were reportedly in contact with MCH-immunopositive projections (Williamson-Hughes et al 2005).…”

“…Specifically, there was a significant increase in MCH innervation of the ventrolateral subdivision of the ventromedial nucleus of the hypothalamus and the ventral premammillary nucleus, leading the authors to propose that MCH may be acting to inhibit reproductive function and behaviours during lactation via this pathway. A further finding that the MCH neurones of the mPOA co-express the inhibitory GABA-synthesising enzyme glutamic acid decarboxylase provoked the hypothesis that the MCH/GABA neurones may inhibit pulsatile LH secretion during lactation (Rondini et al 2010) via the close apposition of MCH and NEI terminals to GNRH cell bodies (Smith & Grove 2002, Williamson-Hughes et al 2005, Ward et al 2009, Wu et al 2009 or via MCHR1, which is co-expressed in a subpopulation of GNRH neurones (Williamson-Hughes et al 2005). Finally, since the mPOA MCH neurones of female rats were in close apposition to terminals immunoreactive for AgRP, a-melanocyte-stimulating hormone and CART, neurobiological regulators clearly implicated in energy balance (Rondini et al 2010), it could be that the mPOA is one site where MCH is active in the integration of ingestive and reproductive behaviours, at least in conditions of negative energy balance that are customary during lactation.…”

“…Electrophysiological recordings demonstrated not only that MCH exerted strong inhibitory effects on a subpopulation of GNRH neurones, but also that the excitatory effect of kisspeptin on GNRH was completely blocked by MCH (Wu et al 2009). In agreement with earlier work in rodents (Williamson-Hughes et al 2005, Ward et al 2009), MCH-ir fibres were also observed in close apposition with GNRH-GFP neurones in mice (Ward et al 2009, Wu et al 2009). These results are supportive of a modulatory role for MCH at the level of GNRH and add credence to the proposal that the MCH system may act to inhibit reproductive function under conditions of energy insufficiency, when MCH expression is up-regulated.…”

Kisspeptin and fertility

“…administration of an a-MSH-like agonist to ewes increases KISS1 mRNA in the POA and results in a rise in plasma LH (Backholer et al 2009). Conversely, the orexigenic peptide melanin-concentrating hormone, which is highly expressed in the lateral hypothalamus, inhibits the stimulatory effects of kisspeptin on GnRH neurons (Wu et al 2009). …”