Galanin-like peptide (GALP) is expressed in the hypothalamic arcuate nucleus and is regulated by leptin and insulin. Centrally administered GALP stimulates gonadotropin secretion and sexual behavior in the rat. Type 1 diabetes is associated with reduced expression of GALP, as well as an overall decline in reproductive function. We postulated that tonic activity of GALP in the brain is required to sustain normal reproductive activity. To test this hypothesis, we examined whether central (intracerebroventricular) immunoblockade of GALP would reduce sexual behaviors and serum levels of luteinizing hormone (LH) in normal adult male rats. We found that GALP antibody reversibly reduced serum levels of LH and abolished male sexual behaviors (P < 0.05 and 0.001, respectively). Second, we tested whether intracerebroventricular GALP could restore normal plasma LH levels and sexual behavior in diabetic animals. We compared groups of diabetic rats that received intracerebroventricular GALP or vehicle and found that GALP increased serum levels of LH and sexual behavior. Third, we examined whether intracerebroventricular administration of affinity-purified GALP antibody could block the effect of insulin and leptin in reversing the effects of diabetes on LH and sexual behavior. We found that treatment of diabetic animals with insulin and leptin nearly normalized LH levels and sexual behaviors; however, this effect was attenuated by intracerebroventricular administration of GALP antibody (P < 0.05). These observations demonstrate that endogenous GALP provides trophic support to the neuroendocrine reproductive axis, including sexual behavior. Diabetes 54:2471-2476, 2005 D eviations of normal metabolism and nutrition can disrupt reproduction. The activity of the reproductive axis may be altered by changes in circulating levels of metabolic hormones such as leptin and insulin, whose blood levels typically reflect an animal's metabolic status and fuel reserves (1). Reproductive dysfunction is common in metabolic diseases, such as type 1 and type 2 diabetes (2,3; rev. in 4). Sexual dysfunction in diabetes is thought to be attributable to a central neuropathy (5); however, the cellular and molecular etiology of this phenomenon is unknown. It seems plausible that the reproductive dysfunction associated with diabetes is caused by a disruption in the cellular and molecular targets in the brain for insulin and other metabolic factors that may be altered in diabetes. Neurons that produce galanin-like peptide (GALP) are prime candidates for mediating this phenomenon.GALP is a neuropeptide that is expressed in the arcuate nucleus of the hypothalamus and has been implicated in the regulation of gonadotropin-releasing hormone. Central infusions of GALP stimulate the secretion of gonadotropin-releasing hormone as well as luteinizing hormone (LH) and induce all aspects of sexual behavior in the male rat (6 -9). GALP has also been implicated in the neuroendocrine regulation of feeding and body weight (7,10 -12). Fasting and uncontrolled diabetes...