Food Restriction-Induced Changes in Gonadotropin-Inhibiting Hormone Cells are Associated with Changes in Sexual Motivation and Food Hoarding, but not Sexual Performance and Food Intake

The neuropeptide control of gonadotropin secretion at the level of the anterior pituitary gland is primarily through the stimulatory action of the hypothalamic decapeptide, gonadotropin-releasing hormone (GnRH), which was originally isolated from mammals and subsequently from non-mammals. To date, however, an inhibitory peptide of gonadotropin release is unknown in vertebrates. Here we show, in a bird, that the hypothalamus also contains a novel peptide which inhibits gonadotropin release. Acetic acid extracts of quail brains were passed through C-18 reversed-phase cartridges, and then the retained material was subjected to the reversed-phase and cation-exchange high-performance liquid chromatography (HPLC). The peptide was isolated from avian brain and shown to have the sequence Ser-Ile-Lys-Pro-Ser-Ala-Tyr-Leu-Pro-Leu-Arg-Phe-NH(2). Cell bodies and terminals containing this peptide were localized immunohistochemically in the paraventricular nucleus and median eminence, respectively. This peptide inhibited, in a dose-related way, gonadotropin release from cultured quail anterior pituitaries. This is the first hypothalamic peptide inhibiting gonadotropin release reported in a vertebrate. We therefore term it gonadotropin-inhibitory hormone (GnIH). Copyright 2000 Academic Press.

Successful reproduction requires maintenance of the reproductive axis within fine operating limits through negative feedback actions of sex steroids. Despite the importance of this homeostatic process, our understanding of the neural loci, pathways, and neurochemicals responsible remain incomplete. Here, we reveal a neuropeptidergic pathway that directly links gonadal steroid actions to regulation of the reproductive system. An RFamide (Arg-Phe-NH2) peptide that inhibits gonadotropin release from quail pituitary was recently identified and named gonadotropin-inhibitory hormone (GnIH). Birds are known to have specialized adaptations associated with gonadotropin-releasing hormone (GnRH) regulation to optimize reproduction (e.g., encephalic photoreceptors), and the existence of a hypothalamic peptide inhibiting gonadotropins may or may not be another such specialization. To determine whether GnIH serves as a signaling pathway for sex steroid regulation of the reproductive axis, we used immunohistochemistry and in situ hybridization to characterize the distribution and functional role of this peptide in hamsters, rats, and mice. GnIH-immunoreactive (GnIH-ir) cell bodies are clustered in the mediobasal hypothalamus with pronounced projections and terminals throughout the CNS. In vivo GnIH administration rapidly inhibits luteinizing hormone secretion. Additionally, GnIH-ir neurons form close appositions with GnRH cells, suggesting a direct means of GnRH modulation. Finally, GnIH-ir cells express estrogen receptor-alpha and exhibit robust immediate early gene expression after gonadal hormone stimulation. Taken together, the distribution of GnIH efferents to neural sites regulating reproductive behavior and neuroendocrine secretions, expression of steroid receptors in GnIH-ir nuclei, and GnIH inhibition of luteinizing hormone secretion indicate the discovery of a system regulating the mammalian reproductive axis.

The physiological mechanisms that control energy balance are reciprocally linked to those that control reproduction, and together, these mechanisms optimize reproductive success under fluctuating metabolic conditions. Thus, it is difficult to understand the physiology of energy balance without understanding its link to reproductive success. The metabolic sensory stimuli, hormonal mediators and modulators, and central neuropeptides that control reproduction also influence energy balance. In general, those that increase ingestive behavior inhibit reproductive processes, with a few exceptions. Reproductive processes, including the hypothalamic-pituitary-gonadal (HPG) system and the mechanisms that control sex behavior are most proximally sensitive to the availability of oxidizable metabolic fuels. The role of hormones, such as insulin and leptin, are not understood, but there are two possible ways they might control food intake and reproduction. They either mediate the effects of energy metabolism on reproduction or they modulate the availability of metabolic fuels in the brain or periphery. This review examines the neural pathways from fuel detectors to the central effector system emphasizing the following points: first, metabolic stimuli can directly influence the effector systems independently from the hormones that bind to these central effector systems. For example, in some cases, excess energy storage in adipose tissue causes deficits in the pool of oxidizable fuels available for the reproductive system. Thus, in such cases, reproduction is inhibited despite a high body fat content and high plasma concentrations of hormones that are thought to stimulate reproductive processes. The deficit in fuels creates a primary sensory stimulus that is inhibitory to the reproductive system, despite high concentrations of hormones, such as insulin and leptin. Second, hormones might influence the central effector systems [including gonadotropin-releasing hormone (GnRH) secretion and sex behavior] indirectly by modulating the metabolic stimulus. Third, the critical neural circuitry involves extrahypothalamic sites, such as the caudal brain stem, and projections from the brain stem to the forebrain. Catecholamines, neuropeptide Y (NPY) and corticotropin-releasing hormone (CRH) are probably involved. Fourth, the metabolic stimuli and chemical messengers affect the motivation to engage in ingestive and sex behaviors instead of, or in addition to, affecting the ability to perform these behaviors. Finally, it is important to study these metabolic events and chemical messengers in a wider variety of species under natural or seminatural circumstances. Copyright 2004 Elsevier Inc.