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.
Highlights
Obesity and conditions with hyperinsulinemia such as type 2 diabetes mellitus, metabolic syndrome, and polycystic ovary syndrome (PCOS) are often accompanied by infertility in females [1]
These results indicate that absence of the insulin receptor in gonadotropin-releasing hormone (GnRH) neurons does not affect peripheral glucose metabolism and that the degree of hyperinsulinemia was similar between genotypes
Obesity is marked by a complex metabolic phenotype that includes hyperinsulinemia and hyperleptinemia, with insulin and leptin resistance that each could contribute to the reproductive dysfunction associated with obesity
Summary
Obesity and conditions with hyperinsulinemia such as type 2 diabetes mellitus, metabolic syndrome, and polycystic ovary syndrome (PCOS) are often accompanied by infertility in females [1]. The role of hyperinsulinism in female reproductive dysfunction is undisputed [2]. Insulin is a co-gonadotropin with LH, causing increased steroidogenesis and altered follicular maturation in animal models [3] and women with PCOS [2]. The effect of hyperinsulinemia on central reproductive tissues such as the pituitary and hypothalamus is not well defined
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