PI3K: An Attractive Candidate for the Central Integration of Metabolism and Reproduction

Abstract

In neurons, as in a variety of other cell types, the enzyme phosphatidylinositol-3-kinase (PI3K) is a key intermediate that is common to the signaling pathways of a number of peripheral metabolic cues, including insulin and leptin, which are well known to regulate both metabolic and reproductive functions. This review article will explore the possibility that PI3K is a key integrator of metabolic and neural signals regulating gonadotropin releasing hormone (GnRH)/luteinizing hormone (LH) release and explore the hypothesis that this enzyme is pivotal in many disorders where gonadotropin release is at risk. Although the mechanisms mediating the influence of metabolism and nutrition on fertility are currently unclear, the strong association between metabolic disorders and infertility is undeniable. For example, women suffering from anorectic disorders experience amenorrhea as a consequence of malnutrition-induced impairment of LH release, and at the other extreme, obesity is also commonly co-morbid with menstrual dysfunction and infertility. Impaired hypothalamic insulin and leptin receptor signaling is thought to be at the core of reproductive disorders associated with metabolic dysfunction. While low levels of leptin and insulin characterize states of negative energy balance, prolonged nutrient excess is associated with insulin and leptin resistance. Metabolic models known to alter GnRH/LH release such as diabetes, diet-induced obesity, and caloric restriction are also accompanied by impairment of PI3K signaling in insulin and leptin sensitive tissues including the hypothalamus. However, a clear link between this signaling pathway and the control of GnRH release by peripheral metabolic cues has not been established. Investigating the role of the signaling pathways shared by metabolic cues that are critical for a normal reproductive state can help identify possible targets in the treatment of metabolic and reproductive disorders such as polycystic ovarian syndrome.

Keywords: GnRH; LH; PI3K; insulin; leptin; metabolism; obesity; puberty.

Figure 1

Neuropeptide neurons such as kisspeptin could serve as intermediaries for peripheral metabolic cues to communicate changes in energy status to the GnRH network. In addition, metabolic signals could be “sensed” by interneurons that in turn communicate with GnRH neurons to regulate their activity. Several upstream regulators of PI3K signaling such as the LepR, IR, IGF-1R, and ERα, are critical for the normal initiation and maintenance of reproductive function in mammals. In this model, PI3K serves as an integrator of E₂, leptin, insulin, and IGF-1 indirect effects on GnRH neuronal function and hence on the HPG axis.

Figure 2

States of metabolic imbalance such as malnutrition and obesity have detrimental effects on the HPG axis, principally altering normal GnRH pulsatile release. Alterations in the levels and sensitivity to peripheral hormones and metabolic signals, including IGF-1, E₂, leptin, and insulin, play a major role in the dysfunction of the HPG axis during chronic metabolic disturbances. PI3K is a major signaling pathway activated by the same upstream regulators that are affected during such states. In rodents, PI3K participates in the central control of sexual behavior and LH release. In this model altered PI3K signaling is linked to the negative effects that metabolic imbalance has on the HPG axis.