The role of insulin receptor signalling in γ-Aminobutyric Acid (GABA) Neurons in the regulation of reproductive and metabolic function in mice — ASN Events

The role of insulin receptor signalling in γ-Aminobutyric Acid (GABA) Neurons in the regulation of reproductive and metabolic function in mice (#165)

Maggie Corr 1 , Greg M Anderson 1
  1. University of Otago, Dunedin, Otago, New Zealand

Insulin signalling in the brain plays a critical role in the metabolic regulation of fertility, such that mice exhibiting brain-specific deletion of insulin receptors (InsR) display hypothalamic hypogonadism [1]. However, the specific neurons mediating insulin’s central effects on fertility remain unidentified. Evidence suggests that direct insulin actions on the gonadotropin-releasing hormone (GnRH) neurons are not required for fertility, as mice lacking InsR specifically in GnRH neurons exhibit normal reproductive function [2]. The neurotransmitter GABA is an important upstream modulator of GnRH neurons [3], and GABAergic neurons are widely distributed throughout the hypothalamus, with high expression in the insulin-responsive arcuate, lateral hypothalamic and dorsomedial nuclei. We therefore hypothesized that insulin’s central effects on fertility are mediated indirectly via insulin signalling on GABAergic neurons. We used the Cre-loxP system to generate mice with a selective inactivation of the InsR gene from GABAergic (Vgat+) cells by crossing InsR-flox mice with Vgat-Cre mice. Multiple reproductive and metabolic parameters were then compared between knockout (KO) mice (InsR-flox/Vgat-Cre+) and their control littermates (InsR-flox/Vgat-Cre-). Surprisingly, given the widespread nature of GABA expression in the hypothalamus, KO mice exhibited normal reproductive function compared to controls. No difference in the age of puberty onset was observed between male or female KOs and controls, and mean estrous cycle length did not differ between female KOs and controls. Furthermore, KO mice exhibited normal fertility compared with controls, which was assessed by individually pairing experimental animals with a wild-type mate for at least 100 days to determine mean litter size and mean inter-litter interval. However, female KO mice exhibited significantly increased adulthood body weight, adiposity, and fasting plasma insulin and leptin concentrations. We conclude that GABAergic cells do not mediate insulin’s central effects on reproductive function in mice, but are involved in mediating insulin’s central effects on energy homeostasis. 

  1. Bruning, J.C., et al., Role of brain insulin receptor in control of body weight and reproduction. Science, 2000. 289(5487): p. 2122-5.
  2. Divall, S.A., et al., Divergent roles of growth factors in the GnRH regulation of puberty in mice. The Journal of Clinical Investigation, 2010. 120(8): p. 2900-9.
  3. Sullivan, S.D. and S.M. Moenter, Gamma-aminobutyric acid neurons integrate and rapidly transmit permissive and inhibitory metabolic cues to gonadotropin-releasing hormone neurons. Endocrinology, 2004. 145(3): p. 1194-202.