Reed JA, Benoit SC, Pfluger PT, Tschö p MH, D'Alessio DA, Seeley RJ. Mice with chronically increased circulating ghrelin develop age-related glucose intolerance. Am J Physiol Endocrinol Metab 294: E752-E760, 2008. First published February 12, 2008 doi:10.1152/ajpendo.00463.2007.-Ghrelin is a gut peptide that stimulates food intake and increases body fat mass when administered centrally or peripherally. In this study, ghrelin was overexpressed in neurons using the neuron-specific enolase (NSE) promoter sequences and mouse ghrelin cDNA (NSE-Ghr). Ghrelin expression in NSE-Ghr brain tissues was increased compared with wild-type mice. Ghrelin expression was also increased to a much smaller extent in liver of these mice, but mRNA levels in stomach or duodenum did not differ from wild-type mice. Body weight and composition was analyzed in two lines of NSE-Ghr mice, one line with increased circulating bioactive ghrelin (L43) and one line without (L73). No increases in body weight, food intake, or fat mass were found. Energy expenditure was measured in L43 mice and did not differ from wild-type controls, whereas locomotor activity was increased in NSE-Ghr mice. Young NSE-Ghr mice had normal glucose tolerance; however, L43 NSE-Ghr mice, but not L73 mice, developed glucose intolerance at 32 wk of age. Despite the impaired glucose tolerance in L43 mice, insulin levels did not differ from those of wild-type mice. These findings suggest a role for ghrelin in age-associated impairments of glucose homeostasis. food intake; adipose; obesity GHRELIN IS A 28 AMINO-ACID PEPTIDE with a unique eight-carbon octanoyl group modification to the NH 2 -terminal third amino acid (17). Important roles for ghrelin include increasing food intake and body fat mass as well as stimulating growth hormone release and gastric motility (8,16,26). Other studies (2) have demonstrated a role for ghrelin in ACTH, cortisol, and prolactin release. Since the octanoyl modification appears to be required for all biological functions of ghrelin in vivo, the nonoctanoylated form, des-octanoyl ghrelin, has been thought (13) to be biologically inactive.Ghrelin was originally isolated from the stomach, and this tissue has the highest levels of ghrelin expression (16). However, ghrelin is also expressed at lower levels in the small intestine and has been detected (17) at very low levels in many other tissues, including large intestine, pituitary, lung, placenta, ovary, testis, kidney, hypothalamus, and various endocrine tumors. The only known receptor for ghrelin is the growth hormone secretagogue receptor (GHS-R), which is expressed in several parts of the central nervous system [CNS; ventral tegmentum, substantia nigra, raphe nucleus, hippocampus, brainstem, and several hypothalamic nuclei, including the arcuate nucleus (ARC), paraventricular nucleus (PVN), ventromedial hypothalamic nucleus (VMN), anteroventral preoptic nucleus, anterior hypothalamic area, suprachiasmatic nucleus, anterolateral hypothalamic nucleus, and tuberomamillary nucleus (4, 10, 31)]. Amo...