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

Abstract

Both glucocorticoids and 5-hydroxytryptamine (5-HT) have been shown to induce insulin resistance (IR) in hepatocytes and adipocytes. Here, we explore whether there is a correlation between them. Except for the control group, male rats were exposed to dexamethasone treated with or without para-chlorophenylalanine (pCPA), or carbidopa for 20 days. Except for the control group, buffalo rat liver 3A (BRL-3A) cells were exposed to dexamethasone for 24 h, treated with or without pCPA, carbidopa, or clorgiline for 48 h, or exposed to 5-HT treated with or without fluoxetine for 48 h. Whole-body IR was determined by both glucose tolerance test and measurement of fasting blood glucose and insulin, whereas hepatocytes or adipocytes IR was determined by examining either hepatic gluconeogenesis, steatosis and glucose transporter 2 expression or lipolysis. Dexamethasone-induced whole-body IR, liver and intraabdominal adipose IR were accompanied by upregulated expressions of tryptophan hydroxylase-1 and aromatic amino acid decarboxylase with increased 5-HT level in both tissues, which were attenuated significantly by pCPA, inhibiting tryptophan hydroxylase-1, or carbidopa, inhibiting aromatic amino acid decarboxylase. [Correction added on 22 September 2015, after first online publication: 'inhibiting aromatic amino acid decarboxylase' was duplicated and has been replaced by 'tryptophan hydroxylase-1'.] In the BRL-3A cells, dexamethasone-induced IR was also accompanied by upregulated 5-HT synthesis in dose- and time-dependent manners, and was attenuated by pCPA or carbidopa, but exacerbated by clorgiline, inhibiting monoamine oxidase-A to further increase 5-HT level. Dexamethasone also enhanced 5-HT 2A and 2B receptor expressions in both tissues and BRL-3A cells. Additionally, blocking 5-HT transporter with fluoxetine significantly suppressed 5-HT-induced IR in BRL-3A cells. Enhancement of 5-HT synthesis in liver and intra-abdominal adipose is an important reason for glucocorticoids-induced IR.