Reproductive Tissues Maintain Insulin Sensitivity in Obesity
Reproductive Tissues Maintain Insulin Sensitivity in Obesity
Reproductive dysfunction is associated with obesity. We previously showed that female mice with diet-induced obesity (DIO) exhibit infertility and thus serve as a model of human polycystic ovary syndrome (PCOS). We postulated that differential insulin signaling of tissues leads to reproductive dysfunction; therefore, a comparison of insulin signaling in reproductive tissues and energy storage tissues was performed. Pituitary-specific insulin receptor knockout mice were used as controls. High-fat diet–induced stress, which leads to insulin resistance, was also investigated by assaying macrophage infiltration and phosphorylated Jun NH2-terminal kinase (pJNK) signaling. In lean mice, reproductive tissues exhibited reduced sensitivity to insulin compared with peripheral metabolic tissues. However, in obese mice, where metabolic tissues exhibited insulin resistance, the pituitary and ovary maintained insulin sensitivity. Pituitaries responded to insulin through insulin receptor substrate (IRS)2 but not IRS1, whereas in the ovary, both IRS1 and IRS2 were activated by insulin. Macrophage infiltration and pJNK signaling were not increased in the pituitary or ovary of lean mice relative to DIO mice. The lack of inflammation and cytokine signaling in the pituitary and ovary in DIO mice compared with lean mice may be one of the reasons that these tissues remained insulin sensitive. Retained sensitivity of the pituitary and ovary to insulin may contribute to the pathophysiology of PCOS.
Secretion of luteinizing hormone and follicle-stimulating hormone stimulates the maturation, development, and function of the gonads and, ultimately, through regulation of gonadal steroid hormone secretion, regulates reproduction. While nutritional deprivation inhibits reproductive function, it is becoming clear that nutritional excess can also impair reproductive function. Recently, the response of the reproductive axis to nutritional excess has gained attention because of the rise in obesity and its associated diseases, such as type 2 diabetes, metabolic syndrome, and polycystic ovary syndrome (PCOS), all of which are associated with reproductive dysfunction. PCOS is defined as hyperandrogenism with oligo/amenorrhea and accounts for >75% of cases of anovulatory infertility. PCOS is marked by an increase in luteinizing hormone pulsatility, often accompanied by high baseline luteinizing hormone levels, ovarian overproduction of testosterone, polycystic ovaries, and peripheral insulin resistance. The pathophysiologic mechanisms underlying the reproductive and metabolic derangements in PCOS have yet to be delineated. We recently revealed a role for insulin signaling in the pituitary in a mouse model of obesity-induced reproductive dysfunction and hyperandrogenism.
While insulin resistance in the energy-storing tissues has been extensively studied, the effects of chronic hyperinsulinemia and obesity in tissues of the female reproductive axis have been more superficially addressed. Analysis of the insulin receptor substrate (IRS)2 knockout (KO) mouse has confirmed the importance of the IRS2 scaffolding protein for normal reproductive function; yet, the role that IRS1 and -2 play in the function of reproductive tissues in obesity has not been explored. Therefore, an analysis of the insulin-signaling pathways in the pituitary and ovary in lean and diet-induced obesity (DIO) mice was performed in this study. We demonstrate that the mechanisms that induce insulin resistance at the level of IRS2 are absent in the pituitary and ovary and that retained insulin sensitivity in reproductive tissues results in elevated insulin signaling in hyperinsulinemic conditions such as obesity.
Abstract and Introduction
Abstract
Reproductive dysfunction is associated with obesity. We previously showed that female mice with diet-induced obesity (DIO) exhibit infertility and thus serve as a model of human polycystic ovary syndrome (PCOS). We postulated that differential insulin signaling of tissues leads to reproductive dysfunction; therefore, a comparison of insulin signaling in reproductive tissues and energy storage tissues was performed. Pituitary-specific insulin receptor knockout mice were used as controls. High-fat diet–induced stress, which leads to insulin resistance, was also investigated by assaying macrophage infiltration and phosphorylated Jun NH2-terminal kinase (pJNK) signaling. In lean mice, reproductive tissues exhibited reduced sensitivity to insulin compared with peripheral metabolic tissues. However, in obese mice, where metabolic tissues exhibited insulin resistance, the pituitary and ovary maintained insulin sensitivity. Pituitaries responded to insulin through insulin receptor substrate (IRS)2 but not IRS1, whereas in the ovary, both IRS1 and IRS2 were activated by insulin. Macrophage infiltration and pJNK signaling were not increased in the pituitary or ovary of lean mice relative to DIO mice. The lack of inflammation and cytokine signaling in the pituitary and ovary in DIO mice compared with lean mice may be one of the reasons that these tissues remained insulin sensitive. Retained sensitivity of the pituitary and ovary to insulin may contribute to the pathophysiology of PCOS.
Introduction
Secretion of luteinizing hormone and follicle-stimulating hormone stimulates the maturation, development, and function of the gonads and, ultimately, through regulation of gonadal steroid hormone secretion, regulates reproduction. While nutritional deprivation inhibits reproductive function, it is becoming clear that nutritional excess can also impair reproductive function. Recently, the response of the reproductive axis to nutritional excess has gained attention because of the rise in obesity and its associated diseases, such as type 2 diabetes, metabolic syndrome, and polycystic ovary syndrome (PCOS), all of which are associated with reproductive dysfunction. PCOS is defined as hyperandrogenism with oligo/amenorrhea and accounts for >75% of cases of anovulatory infertility. PCOS is marked by an increase in luteinizing hormone pulsatility, often accompanied by high baseline luteinizing hormone levels, ovarian overproduction of testosterone, polycystic ovaries, and peripheral insulin resistance. The pathophysiologic mechanisms underlying the reproductive and metabolic derangements in PCOS have yet to be delineated. We recently revealed a role for insulin signaling in the pituitary in a mouse model of obesity-induced reproductive dysfunction and hyperandrogenism.
While insulin resistance in the energy-storing tissues has been extensively studied, the effects of chronic hyperinsulinemia and obesity in tissues of the female reproductive axis have been more superficially addressed. Analysis of the insulin receptor substrate (IRS)2 knockout (KO) mouse has confirmed the importance of the IRS2 scaffolding protein for normal reproductive function; yet, the role that IRS1 and -2 play in the function of reproductive tissues in obesity has not been explored. Therefore, an analysis of the insulin-signaling pathways in the pituitary and ovary in lean and diet-induced obesity (DIO) mice was performed in this study. We demonstrate that the mechanisms that induce insulin resistance at the level of IRS2 are absent in the pituitary and ovary and that retained insulin sensitivity in reproductive tissues results in elevated insulin signaling in hyperinsulinemic conditions such as obesity.
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