title: ERK1/2 mediates glucose-regulated POMC gene expression in hypothalamic neurons.
abstract: Hypothalamic glucose-sensing neurons regulate the expression of genes encoding feeding-related neuropetides POMC, AgRP, and NPY - the key components governing metabolic homeostasis. AMP-activated protein kinase (AMPK) is postulated to be the molecular mediator relaying glucose signals to regulate the expression of these neuropeptides. Whether other signaling mediator(s) plays a role is not clear. In this study, we investigated the role of ERK1/2 using primary hypothalamic neurons as the model system. The primary neurons were differentiated from hypothalamic progenitor cells. The differentiated neurons possessed the characteristic neuronal cell morphology and expressed neuronal post-mitotic markers as well as leptin-regulated orexigenic POMC and anorexigenic AgRP/NPY genes. Treatment of cells with glucose dose-dependently increased POMC and decreased AgRP/NPY expression with a concurrent suppression of AMPK phosphorylation. In addition, glucose treatment dose-dependently increased the ERK1/2 phosphorylation. Blockade of ERK1/2 activity with its specific inhibitor PD98059 partially (approximately 50%) abolished glucose-induced POMC expression, but had little effect on AgRP/NPY expression. Conversely, blockade of AMPK activity with its specific inhibitor produced a partial (approximately 50%) reversion of low-glucose-suppressed POMC expression, but almost completely blunted the low-glucose-induced AgRP/NPY expression. The results indicate that ERK1/2 mediated POMC but not AgRP/NPY expression. Confirming the in vitro findings, i.c.v. administration of PD98059 in rats similarly attenuated glucose-induced POMC expression in the hypothalamus, but again had little effect on AgRP/NPY expression. The results are indicative of a novel role of ERK1/2 in glucose-regulated POMC expression and offer new mechanistic insights into hypothalamic glucose sensing.
authors.affiliation: Department of PediatricsThe Second Affiliated Hospital of Shantou University Medical College, Shantou 515041, ChinaDepartment of Molecular PathologyShantou University Medical College, Shantou 515041, China.
authors.forename: Juan
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Department of PediatricsThe Second Affiliated Hospital of Shantou University Medical College, Shantou 515041, ChinaDepartment of Molecular PathologyShantou University Medical College, Shantou 515041, China.
authors.forename: Yunting
authors.initials: Y
authors.lastname: Zhou
authors.affiliation: Department of PediatricsThe Second Affiliated Hospital of Shantou University Medical College, Shantou 515041, ChinaDepartment of Molecular PathologyShantou University Medical College, Shantou 515041, China.
authors.forename: Cheng
authors.initials: C
authors.lastname: Chen
authors.affiliation: Department of PediatricsThe Second Affiliated Hospital of Shantou University Medical College, Shantou 515041, ChinaDepartment of Molecular PathologyShantou University Medical College, Shantou 515041, China.
authors.forename: Feiyuan
authors.initials: F
authors.lastname: Yu
authors.affiliation: Department of PediatricsThe Second Affiliated Hospital of Shantou University Medical College, Shantou 515041, ChinaDepartment of Molecular PathologyShantou University Medical College, Shantou 515041, China.
authors.forename: Yun
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Department of PediatricsThe Second Affiliated Hospital of Shantou University Medical College, Shantou 515041, ChinaDepartment of Molecular PathologyShantou University Medical College, Shantou 515041, China.
authors.forename: Jiang
authors.initials: J
authors.lastname: Gu
authors.affiliation: Department of PediatricsThe Second Affiliated Hospital of Shantou University Medical College, Shantou 515041, ChinaDepartment of Molecular PathologyShantou University Medical College, Shantou 515041, China.
authors.forename: Lian
authors.initials: L
authors.lastname: Ma
authors.affiliation: Department of PediatricsThe Second Affiliated Hospital of Shantou University Medical College, Shantou 515041, ChinaDepartment of Molecular PathologyShantou University Medical College, Shantou 515041, China guyuh@yahoo.com.
authors.forename: Guyu
authors.initials: G
authors.lastname: Ho
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000378:metabolism; D054369:Agouti-Related Protein / Q000235:genetics / Q000378:metabolism; D000818:Animals; D002454:Cell Differentiation; D002478:Cells, Cultured; D004789:Enzyme Activation / Q000187:drug effects; D005247:Feeding Behavior / Q000187:drug effects; D005260:Female; D005419:Flavonoids / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000187:drug effects*; D005947:Glucose / Q000494:pharmacology*; D007031:Hypothalamus / Q000166:cytology*; D007276:Injections, Intraventricular; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism*; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism*; D009474:Neurons / Q000166:cytology / Q000187:drug effects / Q000201:enzymology*; D009478:Neuropeptide Y / Q000235:genetics / Q000378:metabolism; D010766:Phosphorylation; D011333:Pro-Opiomelanocortin / Q000235:genetics* / Q000378:metabolism; D017207:Rats, Sprague-Dawley
chemical_list: D054369:Agouti-Related Protein; D005419:Flavonoids; D009478:Neuropeptide Y; D011333:Pro-Opiomelanocortin; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D055372:AMP-Activated Protein Kinases; D005947:Glucose; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one
keywords: AMPK; AgRP; ERK1/2; NPY; POMC; glucose sensing