Heparin-binding EGF-like growth factor (HB-EGF) mediates 5-HT-induced insulin resistance through activation of EGF receptor-ERK1/2-mTOR pathway.
Although an inverse correlation between insulin sensitivity and the level of Gq/11-coupled receptor agonists, such as endothelin-1, thrombin, and 5-hydroxytryptamine (5-HT), has been reported, its precise mechanism remains unclear. In this report, we provide evidence that 5-HT induced production of heparin-binding epidermal growth factor-like growth factor (HB-EGF) and caused insulin resistance in 3T3-L1 adipocytes, primary adipocytes, and C2C12 myotubes. In 3T3-L1 adipocytes, 5-HT stimulated HB-EGF production by promoting metalloproteinase-dependent shedding of transmembrane protein pro-HB-EGF. HB-EGF then bound and tyrosine-phosphorylated EGF receptors, which activated the mammalian target of rapamycin pathway through ERK1/2 phosphorylation. Mammalian target of rapamycin activation caused serine phosphorylation of insulin receptor substrate-1, which attenuated insulin-stimulated tyrosine phosphorylation of insulin receptor substrate-1 and glucose uptake. Pharmacological inhibition of either Gq/11-coupled receptors or metalloproteinases, as well as either inhibition or knockdown of HB-EGF or Gαq/11, restored insulin signal transduction impaired by 5-HT. Inhibition of metalloproteinase activity also abolished HB-EGF production and subsequent EGF receptor activation by other Gq/11-coupled receptor agonists known to cause insulin resistance, such as endothelin-1 and thrombin. These results suggest that transactivation of the EGF receptor through HB-EGF processing plays a pivotal role in 5-HT-induced insulin resistance.
The Clinical Research Center for Diabetes, Tokushima University Hospital, 2-50-1 Kuramoto-cho, Tokushima 770-8503, Japan.
Qinkai
Q
Li
Toshio
T
Hosaka
Yosuke
Y
Shikama
Yukiko
Y
Bando
Chisato
C
Kosugi
Nanako
N
Kataoka
Yutaka
Y
Nakaya
Makoto
M
Funaki
D041721:3T3-L1 Cells; D017667:Adipocytes / Q000187:drug effects / Q000378:metabolism; D000818:Animals; D002460:Cell Line; D002478:Cells, Cultured; D019332:Endothelin-1 / Q000494:pharmacology; D066246:ErbB Receptors / Q000235:genetics / Q000378:metabolism; D043802:GTP-Binding Protein alpha Subunits, Gq-G11 / Q000378:metabolism; D005947:Glucose / Q000378:metabolism; D066257:Heparin-binding EGF-like Growth Factor; D007328:Insulin / Q000494:pharmacology; D055504:Insulin Receptor Substrate Proteins / Q000378:metabolism; D007333:Insulin Resistance / Q000502:physiology*; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism*; D020935:MAP Kinase Signaling System / Q000187:drug effects / Q000502:physiology; D051379:Mice; D018485:Muscle Fibers, Skeletal / Q000187:drug effects / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D012701:Serotonin / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism; D013917:Thrombin / Q000494:pharmacology; D015533:Transcriptional Activation / Q000187:drug effects
D019332:Endothelin-1; C587884:Hbegf protein, mouse; D066257:Heparin-binding EGF-like Growth Factor; D007328:Insulin; D055504:Insulin Receptor Substrate Proteins; D036341:Intercellular Signaling Peptides and Proteins; C526295:Irs1 protein, mouse; D012701:Serotonin; C546843:mTOR protein, mouse; D066246:ErbB Receptors; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases; D013917:Thrombin; D043802:GTP-Binding Protein alpha Subunits, Gq-G11; D005947:Glucose