Ablating astrocyte insulin receptors leads to delayed puberty and hypogonadism in mice

Abstract

Insulin resistance and obesity are associated with reduced gonadotropin-releasing hormone (GnRH) release and infertility. Mice that lack insulin receptors (IRs) throughout development in both neuronal and non-neuronal brain cells are known to exhibit subfertility due to hypogonadotropic hypogonadism. However, attempts to recapitulate this phenotype by targeting specific neurons have failed. To determine whether astrocytic insulin sensing plays a role in the regulation of fertility, we generated mice lacking IRs in astrocytes (astrocyte-specific insulin receptor deletion [IRKO GFAP ] mice). IRKO GFAP males and females showed a delay in balanopreputial separation or vaginal opening and first estrous, respectively. In adulthood, IRKO GFAP female mice also exhibited longer, irregular estrus cycles, decreased pregnancy rates, and reduced litter sizes. IRKO GFAP mice show normal sexual behavior but hypothalamic-pituitary-gonadotropin (HPG) axis dysregulation, likely explaining their low fecundity. Histological examination of testes and ovaries showed impaired spermatogenesis and ovarian follicle maturation. Finally, reduced prostaglandin E synthase 2 (PGES2) levels were found in astrocytes isolated from these mice, suggesting a mechanism for low GnRH/luteinizing hormone (LH) secretion. These findings demonstrate that insulin sensing by astrocytes is indispensable for the function of the reproductive axis. Additional work is needed to elucidate the role of astrocytes in the maturation of hypothalamic reproductive circuits.

Astrocytes in neuroendocrine systems: An overview

“…A second hormone, namely insulin, also acts directly on astrocytes and deletion of insulin receptors from astrocytes causes reproductive dysfunction in mice. Astrocytes in these animals show lower levels of PGE2 than wild‐type controls, suggesting that insulin acts on hypothalamic astrocytes to stimulate GnRH neurones via PGE2 gliotransmission . PGE2 also negatively regulates synaptic input to GnRH neurones in an activity‐dependent manner, suggesting that astrocytes can decrease GnRH neuronal firing .…”

Role of insulin in the neuroendocrine control of reproduction

“…95 Very recently, we demonstrated that mice lacking Insr in astrocytes exhibited delayed puberty, irregular and lengthened oestrous cycles, low gonadotrophin and sex steroid levels, impaired spermatogenesis and ovarian follicle maturation, and subfertility. 96 These findings demonstrate that insulin sensing by astrocytes, unlike the neuronal populations studied to date, is indispensable for the function of the reproductive axis even under normal dietary conditions.…”

Spatial dynamics of the insulin receptor in living neurons

“…Biochemical analyses requiring cell lysis are limited by the fact that they do not discriminate between insulin receptor derived from neurons or non‐neuronal cells. Insulin has been shown to exercise effects through activation of astrocytical insulin receptor in several brain regions (Cai et al, 2018; Garcia‐Caceres et al, 2016; Manaserh et al, 2019), whereas the immediate downstream effects of insulin on neurons are more difficult to define (Boyd et al, 1985; Duarte et al, 2006; Werner et al, 1989). It is therefore important to show in any model that the insulin receptor is present in neurons, as we have done here for our dissociated hippocampal cultures.…”