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.

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The purpose of this study was to determine the role of insulin signaling in gonadotropin‐releasing hormone (GnRH) pulse generation. The Cre‐lox system was used to generate mice without insulin receptors in GnRH neurons (GnRH Cre+ IR fl/fl; GnRHIRKO). Hypothalami from female GnRHIRKO or littermate controls with intact insulin receptors in GnRH neurons (GnRH Cre‐), in the lean or diet induced obesity (DIO) state were incubated in static culture. Media collected every seven minutes was subjected to radioimmunoassay for GnRH. The pulse pattern in the control DIO state was visually less regular than other states. GnRH pulse amplitude was not different between GnRHIRKO or control mice in the lean or DIO state. Pulse frequency was trended lower in the control DIO state than in lean controls or GnRHIRKO lean or DIO hypothalami. However, this result was not statistically significant. Pulse interval was also longer in the control DIO state compared to the control lean or GnRHIRKO hypothalami. Insulin signaling in the GnRH neuron may play a role in GnRH pulse generation in the DIO but not the lean state. Grant Funding Source: Supported by: NIH K08HD056139 and APS Undergraduate Summer Research Fellowship