title: Signaling pathway for adiponectin expression in adipocytes by osteocalcin.
abstract: In addition to providing skeletal support, the bone is an endocrine organ that produces osteocalcin, whose uncarboxylated form (GluOC) increases insulin secretion either directly or indirectly by promoting incretin secretion. We have now investigated the signaling pathway by which GluOC increases expression of adiponectin in adipocytes. Activation of its putative receptor GPRC6A by GluOC induced the intracellular accumulation of cAMP and consequent activation of protein kinase A (PKA) in differentiated 3T3-L1 adipocytes. It also induced phosphorylation of CREB (cAMP response element binding protein), but this effect appeared to be mediated indirectly by extracellular signal-regulated kinase (ERK) rather than directly by PKA, given that it was attenuated by the ERK signaling inhibitor U0126. Activated PKA also induced activation of the tyrosine kinase Src, the small GTPase Rap1, an upstream of ERK and CREB phosphorylation. Activated CREB up-regulated the expression of peroxisome proliferator-activated receptor γ (PPARγ), which in turn led to induction of adiponectin expression. Finally, intermittent oral administration of GluOC in mice reduced the size of gonadal white adipocytes as well as increased the expression of PPARγ and adiponectin in these cells. Our results have thus revealed the signaling pathway by which GluOC induces adiponectin expression in adipocytes.
authors.affiliation: Laboratory of Molecular and Cellular Biochemistry, Faculty of Dental Science, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan; Section of Oral and Maxillofacial Surgery, Faculty of Dental Science, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan.
authors.forename: Takahito
authors.initials: T
authors.lastname: Otani
authors.affiliation: Laboratory of Molecular and Cellular Biochemistry, Faculty of Dental Science, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan.
authors.forename: Akiko
authors.initials: A
authors.lastname: Mizokami
authors.affiliation: Laboratory of Molecular and Cellular Biochemistry, Faculty of Dental Science, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan; Section of Oral and Maxillofacial Oncology, Faculty of Dental Science, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan.
authors.forename: Yoshikazu
authors.initials: Y
authors.lastname: Hayashi
authors.affiliation: Laboratory of Molecular and Cellular Biochemistry, Faculty of Dental Science, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan.
authors.forename: Jing
authors.initials: J
authors.lastname: Gao
authors.affiliation: Section of Oral and Maxillofacial Surgery, Faculty of Dental Science, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan.
authors.forename: Yoshihide
authors.initials: Y
authors.lastname: Mori
authors.affiliation: Section of Oral and Maxillofacial Oncology, Faculty of Dental Science, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan.
authors.forename: Seiji
authors.initials: S
authors.lastname: Nakamura
authors.affiliation: Division of Applied Pharmacology, Kyushu Dental University, 2-6-1 Manazuru, Kokurakita-ku, Kitakyushu 803-8580, Japan. Electronic address: r12takeuchi@fa.kyu-dent.ac.jp.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Takeuchi
authors.affiliation: Laboratory of Molecular and Cellular Biochemistry, Faculty of Dental Science, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan. Electronic address: hirata1@dent.kyushu-u.ac.jp.
authors.forename: Masato
authors.initials: M
authors.lastname: Hirata
mesh_terms: D041721:3T3-L1 Cells; D017667:Adipocytes / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D052242:Adiponectin / Q000378:metabolism; D000273:Adipose Tissue / Q000187:drug effects / Q000378:metabolism; D000818:Animals; D002070:Butadienes / Q000494:pharmacology; D000242:Cyclic AMP / Q000378:metabolism; D017362:Cyclic AMP Response Element-Binding Protein / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D017868:Cyclic AMP-Dependent Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects; D051379:Mice; D008810:Mice, Inbred C57BL; D019950:Mitogen-Activated Protein Kinase 1 / Q000037:antagonists & inhibitors / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000037:antagonists & inhibitors / Q000378:metabolism; D009570:Nitriles / Q000494:pharmacology; D015675:Osteocalcin / Q000494:pharmacology*; D047495:PPAR gamma / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D034622:RNA Interference; D043562:Receptors, G-Protein-Coupled / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*; D020827:rap1 GTP-Binding Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism
chemical_list: D052242:Adiponectin; D002070:Butadienes; C492004:Creb1 protein, mouse; D017362:Cyclic AMP Response Element-Binding Protein; C515750:GPRC6A protein, mouse; D009570:Nitriles; D047495:PPAR gamma; D043562:Receptors, G-Protein-Coupled; C113580:U 0126; D015675:Osteocalcin; D000242:Cyclic AMP; D017868:Cyclic AMP-Dependent Protein Kinases; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D020827:rap1 GTP-Binding Proteins
keywords: Adiponectin; Adipose tissue; Cell signaling; Osteoblast; Osteocalcin; PPARγ