TY - JOUR
T1 - Metabolic regulation of ghrelin O-acyl transferase (GOAT) expression in the mouse hypothalamus, pituitary, and stomach
AU - Gahete, Manuel D.
AU - Córdoba-Chacón, Jose
AU - Salvatori, Roberto
AU - Castaño, Justo P.
AU - Kineman, Rhonda D.
AU - Luque, Raul M.
N1 - Funding Information:
Funding: This work is supported in part by grants from Programa Nacional de becas de FPU ( FPU-AP20052473 , to MDG) and Programa Ramon y Cajal del Ministerio de Educación y Ciencia, Spain ( RYC-2007-00186 , to RML); Ayudas predoctorales de formacion en investigacion en salud del Fondo de Investigación sanitaria del Instituto de Salud Carlos III ( FI06/00804 ; to JCC) and by grants from Junta de Andalucía BIO-0139 and CTS-01705 and Ministerio de Ciencia e Innovacion/FEDER BFU2007-60180/BFI, BFU2008-01136/BFISpain, and NIDDK 30677 and the Department of Veterans Affairs, Veterans Health Administration, Office of Research and Development Merit Award (to RDK). CIBER is an initiative of Instituto de Salud Carlos III (Ministerio de Sanidad, Ministerio de Ciencia e Innovación, Spain).
PY - 2010/4/12
Y1 - 2010/4/12
N2 - Ghrelin acts as an endocrine link connecting physiological processes regulating food intake, body composition, growth, and energy balance. Ghrelin is the only peptide known to undergo octanoylation. The enzyme mediating this process, ghrelin O-acyltransferase (GOAT), is expressed in the gastrointestinal tract (GI; primary source of circulating ghrelin) as well as other tissues. The present study demonstrates that stomach GOAT mRNA levels correlate with circulating acylated-ghrelin levels in fasted and diet-induced obese mice. In addition, GOAT was found to be expressed in both the pituitary and hypothalamus (two target tissues of ghrelin's actions), and regulated in response to metabolic status. Using primary pituitary cell cultures as a model system to study the regulation of GOAT expression, we found that acylated-ghrelin, but not desacyl-ghrelin, increased GOAT expression. In addition, growth-hormone-releasing hormone (GHRH) and leptin increased, while somatostatin (SST) decreased GOAT expression. The physiologic relevance of these later results is supported by the observation that pituitary GOAT expression in mice lacking GHRH, SST and leptin showed opposite changes to those observed after in vitro treatment with the corresponding peptides. Therefore, it seems plausible that these hormones directly contribute to the regulation of pituitary GOAT. Interestingly, in all the models studied, pituitary GOAT expression paralleled changes in the expression of a dominant spliced-variant of ghrelin (In2-ghrelin) and therefore this transcript may be a primary substrate for pituitary GOAT. Collectively, these observations support the notion that the GI tract is not the only source of acylated-ghrelin, but in fact locally produced des-acylated-ghrelin could be converted to acylated-ghrelin within target tissues by locally active GOAT, to mediate its tissue-specific effects.
AB - Ghrelin acts as an endocrine link connecting physiological processes regulating food intake, body composition, growth, and energy balance. Ghrelin is the only peptide known to undergo octanoylation. The enzyme mediating this process, ghrelin O-acyltransferase (GOAT), is expressed in the gastrointestinal tract (GI; primary source of circulating ghrelin) as well as other tissues. The present study demonstrates that stomach GOAT mRNA levels correlate with circulating acylated-ghrelin levels in fasted and diet-induced obese mice. In addition, GOAT was found to be expressed in both the pituitary and hypothalamus (two target tissues of ghrelin's actions), and regulated in response to metabolic status. Using primary pituitary cell cultures as a model system to study the regulation of GOAT expression, we found that acylated-ghrelin, but not desacyl-ghrelin, increased GOAT expression. In addition, growth-hormone-releasing hormone (GHRH) and leptin increased, while somatostatin (SST) decreased GOAT expression. The physiologic relevance of these later results is supported by the observation that pituitary GOAT expression in mice lacking GHRH, SST and leptin showed opposite changes to those observed after in vitro treatment with the corresponding peptides. Therefore, it seems plausible that these hormones directly contribute to the regulation of pituitary GOAT. Interestingly, in all the models studied, pituitary GOAT expression paralleled changes in the expression of a dominant spliced-variant of ghrelin (In2-ghrelin) and therefore this transcript may be a primary substrate for pituitary GOAT. Collectively, these observations support the notion that the GI tract is not the only source of acylated-ghrelin, but in fact locally produced des-acylated-ghrelin could be converted to acylated-ghrelin within target tissues by locally active GOAT, to mediate its tissue-specific effects.
KW - Ghrelin O-acyl transferase (GOAT)
KW - Hypothalamus
KW - Mouse models (fasting, obesity, knockouts)
KW - Pituitary
KW - Stomach
UR - http://www.scopus.com/inward/record.url?scp=74749103533&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=74749103533&partnerID=8YFLogxK
U2 - 10.1016/j.mce.2009.12.023
DO - 10.1016/j.mce.2009.12.023
M3 - Article
C2 - 20035826
AN - SCOPUS:74749103533
SN - 0303-7207
VL - 317
SP - 154
EP - 160
JO - Molecular and Cellular Endocrinology
JF - Molecular and Cellular Endocrinology
IS - 1-2
ER -