Insulin Receptor Signaling in the GnRH Neuron Plays a Role in the Abnormal GnRH Pulsatility of Obese Female Mice

Abstract

Infertility associated with obesity is characterized by abnormal hormone release from reproductive tissues in the hypothalamus, pituitary, and ovary. These tissues maintain insulin sensitivity upon peripheral insulin resistance. Insulin receptor signaling may play a role in the dysregulation of gonadotropin-releasing hormone (GnRH) secretion in obesity, but the interdependence of hormone secretion in the reproductive axis and the multi-hormone and tissue dysfunction in obesity hinders investigations of putative contributing factors to the disrupted GnRH secretion. To determine the role of GnRH insulin receptor signaling in the dysregulation of GnRH secretion in obesity, we created murine models of diet-induced obesity (DIO) with and without intact insulin signaling in the GnRH neuron. Obese control female mice were infertile with higher luteinizing hormone levels and higher GnRH pulse amplitude and total pulsatile secretion compared to lean control mice. In contrast, DIO mice with a GnRH specific knockout of insulin receptor had improved fertility, luteinizing hormone levels approaching lean mice, and GnRH pulse amplitude and total secretion similar to lean mice. Pituitary responsiveness was similar between genotypes. These results suggest that in the obese state, insulin receptor signaling in GnRH neurons increases GnRH pulsatile secretion and consequent LH secretion, contributing to reproductive dysfunction.

Neuroendocrine integration of nutritional signals on reproduction

“…This is not to say they are not important modulators of GNRH drive, but rather highlights sufficient compensation can occur in their absence to preserve reproductive function. However, pathological insulin signaling via GNRH neurons due to diet-induced obesity promotes infertility (DiVall et al 2015), demonstrating insulin can directly influence HPG axis function. Furthermore, it remains a possibility that insulin critically regulates reproductive function through its combined actions on the hypothalamus and pituitary (Brothers et al 2010).…”

“…For example, although mice exhibiting brain-specific deletion of InsR (Bruning et al 2000) or forebrain neuron-specific deletion of LepR (Quennell et al 2009) were subfertile and infertile, respectively, GNRH-specific deletion of InsR (GNRH-IRKO mice) (Divall et al 2010) or LepR (Quennell et al 2009) did not result in any reproductive perturbations. Interestingly, however, GNRH-IRKO mice were protected from high-fat diet-induced infertility (DiVall et al 2015), suggesting direct insulin-GNRH signaling may play a role in obesity-related infertility. With regard to ghrelin, although it can modulate GNRH neurons directly, at least in brain slice preparations (Farkas et al 2013), many of its neuroendocrine effects appear to be mediated through hypothalamic circuitry afferent to GNRH neurons (Forbes et al 2009, Schaeffer et al 2013.…”

“…Indeed, GNRH neurons themselves can directly detect some nutritional signals, including insulin and ghrelin (Farkas et al 2013, Evans et al 2014a, DiVall et al 2015, as well as glucose , PYY (Pinilla et al 2007) and adiponectin (Klenke et al 2014). Although it might be speculated that disruption of metabolic regulation at the level of the final common output of the GNRH neuronal network would have more profound effects than at the level of individual afferent neurons, in most cases, direct hormone-GNRH communication does not play a critical role when it comes to the regulation of fertility by nutritional factors.…”

Decreasing Insulin Sensitivity in Women Induces Alterations in LH Pulsatility

“…Therefore, the increase observed in LH pulse frequency is likely a reflection of a hypothalamic effect of our intervention (38,39). Rodent data showing an acceleration of the frequency of pulsatile GnRH secretion from hypothalamic explants obtained from diet-induced obese (DIO) mice suggest that this effect could be mediated by GnRH neurons (40). In contrast, the origin of the decrease in LH peak amplitude could be either at the hypothalamic or at the pituitary level (38).…”

Efeitos do exercício sobre os aspectos metabólicos e reprodutivos de modelos murinos de síndrome dos ovários policísticos

“…De fato, camundongos com obesidade induzida por dieta rica em gordura apresentam aumento dos pulsos de GnRH/LH e disfunção na fertilidade. Quando há o nocaute do gene que codifica o receptor de insulina, ocorre a normalização da secreção de GnRH/LH e melhora da fertilidade (14).…”