Neuroendocrine integration of nutritional signals on reproduction

Abstract

Reproductive function in mammals is energetically costly and therefore tightly regulated by nutritional status. To enable this integration of metabolic and reproductive function, information regarding peripheral nutritional status must be relayed centrally to the gonadotropin-releasing hormone (GNRH) neurons that drive reproductive function. The metabolically relevant hormones leptin, insulin and ghrelin have been identified as key mediators of this 'metabolic control of fertility'. However, the neural circuitry through which they act to exert their control over GNRH drive remains incompletely understood. With the advent of Cre-LoxP technology, it has become possible to perform targeted gene-deletion and gene-rescue experiments and thus test the functional requirement and sufficiency, respectively, of discrete hormone-neuron signaling pathways in the metabolic control of reproductive function. This review discusses the findings from these investigations, and attempts to put them in context with what is known from clinical situations and wild-type animal models. What emerges from this discussion is clear evidence that the integration of nutritional signals on reproduction is complex and highly redundant, and therefore, surprisingly difficult to perturb. Consequently, the deletion of individual hormone-neuron signaling pathways often fails to cause reproductive phenotypes, despite strong evidence that the targeted pathway plays a role under normal physiological conditions. Although transgenic studies rarely reveal a critical role for discrete signaling pathways, they nevertheless prove to be a good strategy for identifying whether a targeted pathway is absolutely required, critically involved, sufficient or dispensable in the metabolic control of fertility.

Leukemia Inhibitory Factor Represses GnRH Gene Expression via cFOS during Inflammation in Male Mice

“…GnRH neuronal processes, named “dendrons,” by Herbison group [3], form an interwoven network that receives direct synaptic and neuropeptide input from upstream regulatory neurons, most notably kisspeptin [4, 5]. This GnRH network integrates other signals that impinge on reproduction, such as stress [6, 7], endocrine disruptors [8], circadian rhythms [9, 10], metabolism [11, 12], and acute inflammation during infection [13-15]. …”

Gonadotropin-releasing hormone receptor (Gnrhr) gene knock out: Normal growth and development of sensory, motor and spatial orientation behavior but altered metabolism in neonatal and prepubertal mice

“…Other factors in addition to sex steroids could affect the inguinal fat pad as there is a clear link between adipocyte metabolism and reproduction [62, 63]. For example, reproduction is sensitive to leptin feedback as a signal of the nutritional status and level of fat accumulation in the body.…”

“…In fact, all nutritional signals (e.g. adiponectin, insulin and ghrelin) with receptors on the GnRH neurons or their afferent neurons [63] would be ineffective due to the impaired GnRH receptor. However, these nutritional hormones also have peripheral effects.…”

Mammalian Reproduction Overview

“…However, it is worth mentioning the relatively recent discovery that the production of leptin, a peptide hormone produced by adipose tissues and also by the placenta, is now seen as an important modulator of diet, body condition and the neural control of reproduction (Barb et al, 2005;Daniel et al2013;Evans and Anderson, 2017). Extremes of body condition such as obesity or malnutrition are known to impact the success of reproduction in humans and other species (Hausman et al, 2012;Perez-Perez et al, 2015;Walzem and Chen, 2014).…”