|
(M341) GALANIN-LIKE PEPTIDE: A POTENTIAL MEDIATOR OF LEPTIN'S EFFECTS ON REPRODUCTION. Clifton, Donald1, Jureus, Anders2, Cunningham, Matthew3, Krasnow, Stephanie2, McClain, Molly3, Scarlett, Jarrad1, Teklemichael, Dawit1, Li, Dorothy2, Leilibadi, Soly2, Acohido, Blake2, Fraley, Greg2, Steiner, Robert1,2,4, 1 Department of Obstetrics and Gynecology, Seattle, WA2 Department of Physiology and Biophysics, Seattle, WA3 Neurobiology and Behavior Program, Seattle, WA4 Department of Zoology, Seattle, WA ABSTRACT- Successful reproduction depends on adequate energy reserves. Although there are a number of metabolic factors that signal energy status to the reproductive system, recent attention has focused on leptin, a peptide hormone secreted by adipocytes. Mice lacking endogenous leptin (ob/ob mice) are infertile, and treatment of these animals with leptin stimulates the activity of the reproductive endocrine system and induces fertility. Furthermore, severe food restriction in normal animals causes leptin levels to fall and leads to reproductive deficits that can be reversed by leptin treatment. Adequate leptin levels also appear to be prerequisite for normal pubertal progression (at least in rodent species) and leptin treatment can reverse the delay in sexual maturation caused by modest food restriction. While leptin may act at multiple sites throughout the reproductive system to regulate fertility, one of the most important targets for leptin is the brain. Within the brain, leptin acts on receptors expressed by neurons that are involved in the regulation of food intake, body weight, metabolism and reproduction. The specific neurons responsible for mediating the effects of leptin on reproduction have not been determined, but GnRH neurons themselves do not appear to express leptin receptors. Nevertheless, some neurons thought to be involved in regulating gonadotropin secretion (as well as food intake and body weight) have been shown to express leptin receptors, including some of the neurons that express neuropeptide Y (NPY), proopiomelanocortin (POMC) and serotonin. Recently, a neuropeptide called galanin-like peptide (GALP) was identified from porcine hypothalamus and shown to be expressed in the brain by cells located within the hypothalamic arcuate nucleus and median eminence. The expression of GALP mRNA is dramatically reduced by fasting and this effect can be reversed by leptin treatment. Essentially all GALP neurons in the arcuate nucleus express leptin receptor mRNA. Furthermore, these same GALP neurons express receptors for other neurotransmitters that are regulated by leptin, such as NPY (Y1) and serotonin (5-HT2c) receptors. The fact that GALP neurons are located in the heart of the arcuate nucleus and are sensitive to circulating leptin levels make them ideal candidates for mediating the effects of leptin on a variety of neuroendocrine systems. Are GALP neurons involved in relaying information about metabolic status, as reflected by blood leptin concentrations, to the reproductive neuroendocrine system? Although this question is still in the early stages of investigation, initial evidence suggests this might be the case. GALP, when injected into the cerebral ventricles, induces the release of LH in rats, mice and monkeys. In rats the effect of exogenous GALP on LH secretion appears to involve the release of GnRH, since it is accompanied by the induction of FOS in GnRH neurons and is blunted by pretreatment with a GnRH antagonist. In addition, GALP fibers project to the medial preoptic area where they come in close proximity to GnRH neurons. These observations implicate GALP as a potential mediator of leptin's action in the reproductive system, thus opening the possibility that the effects of other metabolic signals—in addition to leptin—are mediated by GALP neurons and providing a strong rationale for further investigations of this molecule. KEY WORDS: GALP, galanin-like peptide, leptin, metabolism |
