Insulin regulation of reproductive brain: rodent and human studies
Insulin has been shown to participate in the long-term regulation of satiety, and it is emerging as a peripheral modulator of the activity of the neuroendocrine reproductive axis as well. Following the observation that mice lacking the expression of brain insulin receptors exhibit central hypogonadism and infertility, we could show that peripheral insulin can stimulate LH secretion in rodents. This effect is likely mediated at the level of the hypothalamus, as suggested by the increases in GnRH expression and secretion resulting from direct insulin stimulation of primary hypothalamic neurons in culture. We were then able in further studies to confirm that insulin accelerates LH pulsatile secretion in normal humans as well. Our finding that the GnRH-expressing GnV-3 cells do express a functional insulin receptor is suggestive of a direct modulation of hypothalamic GnRH neurons, although neuropeptide Y-ergic or GABA-ergic cells are also likely involved. Together, these data establish insulin as a metabolic signal to the neuroendocrine reproductive axis, involved in subtle but potentially important regulations of the hypothalamic GnRH pulse generator. Given the increasingly recognized importance that metabolic changes play in the relationships between the periphery and the central nervous system, we hypothesize that other gastro-intestinal hormones may participate in these modulations. All these signals are then integrated by a network of first and second order neurons, including GnRH cells, at the level of the hypothalamus.