Resistin regulates pituitary somatotrope cell function through the activation of multiple signaling pathways.
The adipokine resistin is an insulin-antagonizing factor that also plays a regulatory role in inflammation, immunity, food intake, and gonadal function. Although adipose tissue is the primary source of resistin, it is also expressed in other tissues and organs, including the pituitary. However, there is no information on whether resistin, as described previously for other adipokines such as leptin and adiponectin, could regulate this gland. Likewise, the molecular basis of resistin actions remains largely unexplored. Here we show that administration of resistin to dispersed rat anterior pituitary cells increased GH release in both the short (4 h) and long (24 h) term, decreased mRNA levels of the receptor of the somatotrope regulator ghrelin, and increased free cytosolic Ca(2+) concentration in single somatotropes. By means of a pharmacological approach, we found that the stimulatory action of resistin occurs through a Gs protein-dependent mechanism and that the adenylate cyclase/cAMP/protein kinase A pathway, the phosphatidylinositol 3-kinase/Akt pathway, protein kinase C, and extracellular Ca(2+) entry through L-type voltage-sensitive Ca(2+) channels are essential players in mediating the effects of resistin on somatotropes. Taken together, our results demonstrate for the first time a regulatory role for resistin on somatotrope function and provide novel insights on the intracellular mechanisms activated by this protein.
Rodríguez-Pacheco
Francisca
F
Department of Cell Biology, Edificio Severo Ochoa, University of Córdoba, E-14014 Córdoba, Spain.
Vázquez-Martínez
Rafael
R
Martínez-Fuentes
Antonio J
AJ
Pulido
Marina R
MR
Gahete
Manuel D
MD
Vaudry
Hubert
H
Gracia-Navarro
Francisco
F
Diéguez
Carlos
C
Castaño
Justo P
JP
Malagón
Maria M
MM
D000262:Adenylyl Cyclases / Q000378:metabolism; D000818:Animals; D002118:Calcium / Q000378:metabolism; D002478:Cells, Cultured; D000242:Cyclic AMP / Q000378:metabolism; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D013006:Growth Hormone / Q000378:metabolism*; D008297:Male; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D054799:Phospholipase C beta / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D054440:Receptors, Ghrelin / Q000378:metabolism*; D018013:Receptors, Neuropeptide / Q000378:metabolism*; D018017:Receptors, Pituitary Hormone-Regulating Hormone / Q000378:metabolism*; D052243:Resistin / Q000378:metabolism*; D015398:Signal Transduction; D052683:Somatotrophs / Q000378:metabolism*
D054440:Receptors, Ghrelin; D018013:Receptors, Neuropeptide; D018017:Receptors, Pituitary Hormone-Regulating Hormone; D052243:Resistin; D013006:Growth Hormone; D000242:Cyclic AMP; D019869:Phosphatidylinositol 3-Kinases; D017868:Cyclic AMP-Dependent Protein Kinases; D054799:Phospholipase C beta; D000262:Adenylyl Cyclases; C048250:somatotropin releasing hormone receptor; D002118:Calcium