Heparin-Binding EGF-Like Growth Factor (HB-EGF) Mediates 5-HT-Induced Insulin Resistance Through Activation of EGF Receptor-ERK1/2-mTOR Pathway

Abstract

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.

Activation of Akt through 5-HT2A receptor ameliorates serotonin-induced degradation of insulin receptor substrate-1 in adipocytes

“…5-HT2A/2B/2C in 5-HT receptors (Saxena, 1995). It was previously reported that Akt can be activated by 5-HT through 5-HT2A receptor in smooth muscle cells, and recently, functional 5-HT2A receptor was also found in 3T3-L1 adipocytes (Liu and Fanburg, 2006;Li et al, 2012). Consistent with these reports, we found that activation of Akt by 5-HT could be blocked by 10 nmol/l ketanserin, the highly specific antagonist of 5-HT2A receptor under current dose we used in 3T3-L1 adipocytes (Fig.…”

“…In one study, acute treatment of either L6 myotubes or isolated rat skeletal muscle with 50 folds of physiological concentration of 5-HT (50 lmol/l) stimulates glucose uptake through activation of 5-HT2A receptor, implying an insulin mimetic effect of 5-HT in muscle cells (Hajduch et al, 1999). Our previous work also discovered that 5-HT induces insulin resistance by activating extracellular-regulated kinase (Erk) and mammalian target of rapamycin (mTOR) signals via the transactivation of epidermal growth factor (EGF) receptor (Li et al, 2012). In this study, we attempted to have a further assessment on how 5-HT modifies insulin signaling in adipocytes.…”

Important role of 5‐hydroxytryptamine in glucocorticoid‐induced insulin resistance in liver and intra‐abdominal adipose tissue of rats

“…5‐HT can also induce IR in cultured 3T3‐L1 adipocytes, mouse primary adipocytes and C2C12 myotubes12. It is widely believed that the majority of 5‐HT in the periphery is synthesized by enterochromaffin cells, a type of epithelial cell in the gastrointestinal tract, and exported to peripheral organs through circulation13.…”

Central Role of the EGF Receptor in Neurometabolic Aging

“…In addition to this functional system bridge between neuronal and metabolic systems, ligands of G α q/11-coupled GPCRs that are associated with insulin resistance, such as serotonin, endothelin-1, and thrombin, may also stimulate HB-EGF production and transactivate EGFR in 3T3-L1 adipocytes. Serotonin has been shown to additionally have this effect in primary adipocytes and myotubes [33]. Not only can serotonin induce activation of the EGFR but it also appears to be able to regulate the posttranslational activity, via serine phosphorylation and the mTOR pathway, of the insulin/IGF-1 receptor-associated protein, IRS-1 [33].…”

“…Serotonin has been shown to additionally have this effect in primary adipocytes and myotubes [33]. Not only can serotonin induce activation of the EGFR but it also appears to be able to regulate the posttranslational activity, via serine phosphorylation and the mTOR pathway, of the insulin/IGF-1 receptor-associated protein, IRS-1 [33]. IRS-1 and -2 are insulin receptor-associated scaffold proteins essential for effective glucose metabolism in multiple energy-regulatory tissues such as the liver [34].…”