Galanin-like peptide: a molecular link between energy homeostasis and reproduction

Thesis (Ph. D.)--University of Washington, 2004Galanin-like peptide (GALP) shares partial sequence identity with galanin and exhibits agonistic activity at galanin receptors (GALR1 and GALR2) in vitro. GALP neurons almost exclusively reside within the arcuate nucleus, a region of the hypothalamus that plays a pivotal role in the control of body weight and reproduction. GALP gene expression is highly induced by leptin, which implicates GALP neurons as potential downstream effectors of leptin's actions within the brain. To determine whether GALP mimics leptin's suppressive effect on body weight and/or its stimulatory effect on gonadotropin secretion, I administered intracerebroventricular (ICV) GALP injections to wild-type and mutant mice. I observed that ICV GALP elicits rapid but transient reductions in feeding and body weight in wild-type mice. However, acute ICV GALP treatment also reduces locomotor activity and elicits the formation of a conditioned taste aversion, which raises the possibility that GALP's anorectic effect does not reflect a homeostatic regulation of energy balance. I also observed that ICV GALP treatment robustly stimulates luteinizing hormone (LH) and testosterone secretion in wild-type mice. In contrast to GALP's transitory effect on body weight in wild-type mice, leptin-deficient ob/ob mice exhibit a sustained reduction in body weight during chronic GALP treatment as a consequence of reduced feeding and increased thermogenesis. Although male ob/ob mice release LH in response to acute GALP treatment, long-term GALP administration does not significantly improve reproductive function in these infertile animals. Finally, I investigated whether GALP's actions in the brain are mediated by galanin receptor signaling. I found that GALR1 knockout and GALR2 knockout mice exhibit normal responses to ICV GALP treatment with respect to feeding, body weight, and LH secretion. Furthermore, a truncated GALP fragment containing the galanin-homologous sequence of the GALP molecule does not mimic the effects of full-length GALP on any of these parameters in wild-type mice. Collectively, these observations implicate GALP neurons as likely components of the neural circuitry that regulates and integrates energy homeostasis and reproduction. These findings do not support the hypothesis that GALP signals solely through galanin receptors in vivo, and instead hint at the existence of a yet-to-be-identified GALP-specific receptor