Obesity Alters POMC and Kisspeptin Neuron Cross Talk Leading to Reduced Luteinizing Hormone in Male Mice

Abstract

Obesity is associated with hypogonadism in males, characterized by low testosterone and sperm number. Previous studies determined that these stem from dysregulation of hypothalamic circuitry that regulates reproduction, by unknown mechanisms. Herein, we used mice fed chronic high-fat diet, that mimics human obesity, to determine mechanisms of impairment at the level of the hypothalamus, in particular gonadotropin-releasing hormone (GnRH) neurons that regulate luteinizing hormone (LH), which then regulates testosterone. Consistent with obese humans, we demonstrated lower LH, and lower pulse frequency of LH secretion, but unchanged pituitary responsiveness to GnRH. LH pulse frequency is regulated by pulsatile GnRH secretion, which is controlled by kisspeptin. Peripheral and central kisspeptin injections, and DREADD-mediated activation of kisspeptin neurons, demonstrated that kisspeptin neurons were suppressed in obese mice. Thus, we investigated regulators of kisspeptin secretion. We determined that the LH response to NMDA was lower in obese mice, corresponding to fewer glutamate receptors in kisspeptin neurons, which may be critical for kisspeptin synchronization. Given that kisspeptin neurons also interact with POMC neurons, which regulate satiety and are affected by obesity, we examined their crosstalk, and determined that the LH response to either DREADD-mediated activation of POMC neurons or central injection of αMSH, a product of POMC, is abolished in obese mice. This was accompanied by diminished levels of αMSH receptor, MC4R, in kisspeptin neurons. Together, our studies determined that obesity leads to the downregulation of receptors that regulate kisspeptin neurons, which is associated with lower LH pulse frequency, leading to lower LH and hypogonadism.Significance StatementObesity presents a significant health concern, with multiple comorbidities, including impaired reproduction. However, mechanisms are not clear, and studies are confounded by the chronic nature of this condition that leads to synaptic changes and alterations in neuron responsiveness to stimuli. Here, we demonstrate that the interaction between feeding circuitry and reproductive circuitry is altered by chronic obesity. The reason may be that chronically higher activity of POMC neurons in response to higher leptin in obesity, downregulates αMSH receptors on target neurons, including kisspeptin. This may lead to the suppression of kisspeptin neurons, and their inability to regulate pulsatile secretion of GnRH, which then lowers LH pulse frequency, leading to lower LH in the circulation, lower testosterone, and lower sperm count.

Astrocytes: a star emerges in the control of reproductive hormones

“…Obesity suppresses activity of ARC kisspeptin neurons leading to obesity-induced hypogonadism ( 13 ). In obese male mice, kisspeptin neurons have fewer glutamate and melanocortin 4 receptors ( 14 ). Although a high-fat diet (HFD) advanced initiation of puberty in female mice (albeit not in male mice), Torres and colleagues did not find this effect in G-KiR-KO mice ( 10 ).…”

POMC neurons control fertility through differential signaling of MC4R in Kisspeptin neurons

“…In rodents, compelling evidence indicates a close interaction between Kiss1 neurons and the melanocortin system: 1) fibers from POMC neurons in the arcuate nucleus (POMC ARH ) project to and juxtapose Kiss1 ARH neurons 13 ; 2) the melanocortin signaling through MC4R contributes to the permissive role of leptin on puberty onset 13,15,16 ; and 3) MC4R expression on both Kiss1 ARH 17–19 and Kiss1 AVPV/PeN 17,20 . Altogether, this evidence suggests a clear role for MC4R in Kiss1 neurons, in the control of reproductive maturation and fertility.…”