Kisspeptin

In my last post, I wrote about GnRH (gonadotrophin releasing hormone), which stimulates the release of LH and FSH from the anterior pituitary. In this post, I will be talking about kisspeptin, which stimulates the release of GnRH from the hypothalamus.

Effects of kisspeptin on GnRH

Kisspeptin, which is encoded by the Kiss1 gene, comes in several forms, but the most common form is Kisspeptin-54 (a.k.a. metastin). Kisspeptin binds to the GPR54 receptor (a.k.a. Kiss1r), expressed on most GnRH neurons. In fact, GnRH neurons are almost always located next to kisspeptin neurons. Most kisspeptin-releasing neurons are located either in the more rostral AVPV (anteroventral periventricular nucleus) or in the more caudal ARC (arcuate nucleus). The AVPV and ARC neurons are thought to have somewhat different effects.

ARC kisspeptin neurons project to the median eminence, where they may impact the release of GnRH. ARC neurons, in contrast to AVPV neurons, also express neurokinin B and dynorphin, and are thus sometimes known as KNDy neurons (stands for "Kisspeptin, Neurokinin B, Dynorphin"). They also have receptors for these neurotransmitters, so they can act on themselves in an autocrine fashion. Neurokinin B is thought to stimulate pulse generation by KNDy neurons, whereas dynorphin is thought to inhibit it. KNDy neurons may be stimulated by pheromones (chemicals excreted by other animals).

ARC and AVPV kisspeptin neurons are also affected differently by sex steroids, as I will talk about in the next section.

Regulation by sex steroids

Kiss1 cells have receptors for sex steroids (GnRH neurons do not). These sex steroid receptors include ERα (oestrogen receptor α), ERβ (oestrogen receptor β), PR (progesterone receptor) and AR (androgen receptor). All four receptors are found in ARC kisspeptin neurons, but the AVPV neurons mainly have only ERα and ERβ receptors.

An interesting finding in female mice is that ARC neurons appear to be stimulated by low oestrogen, whereas AVPV neurons appear to be stimulated by high oestrogen. It has been suggested that ARC neurons may be responsible for negative feedback, whereas AVPV neurons may be responsible for positive feedback.

Another interesting finding is that androgen receptors, at least in mice, may be important in Kiss1 expression. Female mice with androgen receptor knockout have reduced Kiss1 expression in the AVPV and increased Kiss1 expression in the ARC relative to wild-type mice.

Puberty

I don't think there's much to say here, other than that puberty is thought to be stimulated by kisspeptin binding to GPR54 receptors. Moving on...

Energy balance

Kisspeptin may also be involved in energy balance and satiety, which is a topic that I've spoken about here and here. The main neurons involved in satiety are Agrp/Npy neurons, which are orexigenic (appetite-stimulating), and Pomc/Cart neurons, which are anorexigenic (appetite-inhibiting). Kiss1r knockout mice have been found to have an increase in Pomc expression, which means that they tend to eat less. Despite this, however, they tend to gain weight. The weight gain may be due to reduced energy expenditure due to less UCP1 expression (a protein I have spoken about here).