Promotion of insulin-induced glucose uptake in C2C12 myotubes by osteocalcin.
A close relationship between the bone and systemic glucose metabolism has recently been the center of attention, since the uncarboxylated form of osteocalcin (GluOC), a bone-derived protein, but not the γ-carboxylated form, is involved in glucose metabolism. However, the analysis of GluOC effect using isolated organs and related cell lines are required to understand its roles in a whole systemic metabolic status. In the present study, we examined the effect of GluOC on cell lines derived from skeletal muscle to explore the mechanisms by which GluOC regulates glucose uptake. In the differentiated C2C12 myotubes, GluOC dose-dependently induced the phosphorylation of ERK without affecting intracellular cAMP and Ca(2+) levels. This effect was inhibited by U0126, an inhibitor of ERK kinase (MEK). Additionally, U73122, an inhibitor of phospholipase C tended to inhibit it as well. Furthermore, cell treatment with GluOC for a long period promoted insulin-induced Akt phosphorylation and glucose uptake in the myotubes, which was abolished by ERK signaling inhibition. These results indicate that GluOC does not triggered Akt phosphorylation and glucose uptake by itself but promotes insulin-induced glucose uptake in myotubes, probably by up-regulating Akt signaling through ERK activation.
Division of Applied Pharmacology, Kyushu Dental University, Kitakyushu 803-8580, Japan; Department of Oral Reconstruction and Rehabilitation, Kyushu Dental University, Kitakyushu 803-8580, Japan.
Shintaro
S
Tsuka
Division of Applied Pharmacology, Kyushu Dental University, Kitakyushu 803-8580, Japan; Department of Oral Reconstruction and Rehabilitation, Kyushu Dental University, Kitakyushu 803-8580, Japan.
Fumiko
F
Aonuma
Division of Applied Pharmacology, Kyushu Dental University, Kitakyushu 803-8580, Japan.
Sen
S
Higashi
Division of Applied Pharmacology, Kyushu Dental University, Kitakyushu 803-8580, Japan.
Tomoko
T
Ohsumi
Laboratory of Molecular and Cellular Biochemistry, Faculty of Dental Science, Kyushu University, Fukuoka 812-8582, Japan.
Koki
K
Nagano
Laboratory of Molecular and Cellular Biochemistry, Faculty of Dental Science, Kyushu University, Fukuoka 812-8582, Japan.
Akiko
A
Mizokami
Laboratory of Molecular and Cellular Biochemistry, Faculty of Dental Science, Kyushu University, Fukuoka 812-8582, Japan.
Tomoyo
T
Kawakubo-Yasukochi
Department of Oral Reconstruction and Rehabilitation, Kyushu Dental University, Kitakyushu 803-8580, Japan.
Chihiro
C
Masaki
Department of Oral Reconstruction and Rehabilitation, Kyushu Dental University, Kitakyushu 803-8580, Japan.
Ryuji
R
Hosokawa
Laboratory of Molecular and Cellular Biochemistry, Faculty of Dental Science, Kyushu University, Fukuoka 812-8582, Japan.
Masato
M
Hirata
Division of Applied Pharmacology, Kyushu Dental University, Kitakyushu 803-8580, Japan. Electronic address: r12takeuchi@fa.kyu-dent.ac.jp.
Hiroshi
H
Takeuchi
D000818:Animals; D001693:Biological Transport, Active / Q000187:drug effects; D002070:Butadienes / Q000494:pharmacology; D002460:Cell Line; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004963:Estrenes / Q000494:pharmacology; D015870:Gene Expression; D005947:Glucose / Q000378:metabolism*; D007328:Insulin / Q000378:metabolism*; D020935:MAP Kinase Signaling System / Q000187:drug effects; D051379:Mice; D018485:Muscle Fibers, Skeletal / Q000187:drug effects / Q000378:metabolism*; D009570:Nitriles / Q000494:pharmacology; D015675:Osteocalcin / Q000737:chemistry / Q000378:metabolism*; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D011760:Pyrrolidinones / Q000494:pharmacology; D043562:Receptors, G-Protein-Coupled / Q000235:genetics; D015398:Signal Transduction; D010738:Type C Phospholipases / Q000037:antagonists & inhibitors
D002070:Butadienes; D004791:Enzyme Inhibitors; D004963:Estrenes; C515750:GPRC6A protein, mouse; D007328:Insulin; D009570:Nitriles; D011760:Pyrrolidinones; D043562:Receptors, G-Protein-Coupled; C113580:U 0126; D015675:Osteocalcin; C060229:1-(6-((3-methoxyestra-1,3,5(10)-trien-17-yl)amino)hexyl)-1H-pyrrole-2,5-dione; D051057:Proto-Oncogene Proteins c-akt; D010738:Type C Phospholipases; D005947:Glucose
Akt; ERK; Glucose metabolism; Insulin; Osteocalcin; Skeletal muscle