Abstract
Reproduction requires adequate energy stores for parents and offspring to survive. Kiss1 neurons, which are essential for fertility, have the potential to serve as the central sensors of metabolic factors that signal to the reproductive axis the presence of stored calories. Paradoxically, obesity is often accompanied by infertility. Despite excess circulating levels of insulin and leptin, obese individuals exhibit resistance to both metabolic factors in many neuron types. Thus, resistance to insulin or leptin in Kiss1 neurons could lead to infertility. Single deletion of the receptors for either insulin or the adipokine leptin from Kiss1 neurons does not impair adult reproductive dysfunction. However, insulin and leptin signaling pathways may interact in such a way as to obscure their individual functions. We hypothesized that in the presence of genetic or obesity-induced concurrent insulin and leptin resistance, Kiss1 neurons would be unable to maintain reproductive function. We therefore induced a chronic hyperinsulinemic and hyperleptinemic state in mice lacking insulin receptors in Kiss1 neurons through high fat feeding and examined the impact on fertility. In an additional, genetic model, we ablated both leptin and insulin signaling in Kiss1 neurons (IR/LepRKiss mice). Counter to our hypothesis, we found that the addition of leptin insensitivity did not alter the reproductive phenotype of IRKiss mice. We also found that weight gain, body composition, glucose and insulin tolerance were normal in mice of both genders. Nonetheless, leptin and insulin receptor deletion altered pubertal timing as well as LH and FSH levels in mid-puberty in a reciprocal manner. Our results confirm that Kiss1 neurons do not directly mediate the critical role that insulin and leptin play in reproduction. However, during puberty kisspeptin neurons may experience a critical window of susceptibility to the influence of metabolic factors that can modify the onset of fertility.
Highlights
Obesity and hyperinsulinemia are associated with infertility [1]
To determine if these neurons are insulin-responsive, we first examined the responsiveness of Kiss1 neurons to insulin in mice that produce enhanced green fluorescent protein (EGFP) in cre-expressing neurons
Evans and colleagues reported that only 5% of kisspeptin-immunoreactive cells in the hypothalamus showed co-labeling with insulin receptor (IR)-β [43]
Summary
Obesity and hyperinsulinemia are associated with infertility [1]. Hypogonadotrophic hypogonadism, a state in which the release of hormones from all levels of the reproductive axis is reduced, is the most common reproductive consequence of type 2 diabetes and obesity [2, 3]. LH [4, 5], LH pulse amplitude [6], follicle-stimulating hormone (FSH) [2, 4, 5], and progesterone [4,5,6] are significantly lower than in normal weight women. LH pulse amplitude is lower in obese men [7]. More than 25% of men with type 2 diabetes have hypothalamic hypogonadism [8]. While obesity and insulin resistance are each independently associated with lower plasma testosterone levels [9, 10], obese men with T2DM appear to be at high risk [11, 12]
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