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

Li, Qinkai; Hosaka, Toshio; Harada, Nagakatsu; Nakaya, Yutaka; Funaki, Makoto

doi:10.1016/j.mce.2012.08.022

Cited by 20 publications

(11 citation statements)

References 48 publications

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“…More importantly, the aforementioned liver‐IR markers induced by Dex could be abolished significantly by inhibition of 5‐HT 2A R and 5‐HT 2B R with Sar or 5‐HT synthesis with CDP, and were more effectively abolished by the combination of Sar and CDP, suggesting that GC‐induced hepatic IR is closely involved in increased hepatic 5‐HT synthesis and 5‐HT 2 R. In addition, the present study also suggested that Dex‐stimulated lipolysis in the visceral adipose tissue resulted in increased serum FFA level, and downregulation of plasmalemmal GLUT4 expression in the visceral adipose and skeletal muscle tissue, and might very likely be involved in adipose‐specific upregulation in 5‐HT synthesis and 5‐HT 2 R expression, and muscle‐specific upregulation in 5‐HT 2 R expression. We also found that it is both 5‐HT 2A R and 5‐HT 2B R instead of 5‐HT 2A R alone that mediate 5‐HT‐stimulated IR in the three tissues, both of which were upregulated by Dex. The precise mechanisms need to be studied further.…”

Section: Discussionsupporting

confidence: 50%

“…However, both our previous study 22 and present study found that 5-HT is also synthesized in the liver and visceral adipose tissues, which were upregulated by Dex with upregulated expressions of both Tph1 and AADC, and that increased 5-HT levels by Dex in both tissues came from tissue itself rather than the blood. 5-HT by acting on 5-HT 2A R mediates hepatic steatosis and IR has been shown in several studies 24,52 , whereas activation of the mTOR-S6K pathway has been shown to be the mechanism of 5-HT action in the liver 53 , and in the adipocytes and C2C12 myotubes by inhibition of insulin-stimulated activation of the IRS-1-AKT signaling pathway with glucose uptake 54 . The present study showed that Dex-induced activations of mTOR Ser 2448 and S6K Thr 389/412 phosphorylation in the liver tissue were accompanied by upregulations of hepatic 5-HT synthesis, and 5-HT 2A R and 5-HT 2B R expression, followed by hepatic IR, such as increased gluconeogenesis, downregulation of GLUT2 expression on the cell membrane, and increased TG and VLDL synthesis with steatosis in the liver tissue.…”

Section: Discussionmentioning

confidence: 99%

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Effective treatment with combination of peripheral 5‐hydroxytryptamine synthetic inhibitor and 5‐hydroxytryptamine 2 receptor antagonist on glucocorticoid‐induced whole‐body insulin resistance with hyperglycemia

Guo

et al. 2016

J of Diabetes Invest

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Aims/IntroductionOur previous study found that dexamethasone‐induced insulin resistance (IR) was involved in 5‐hydroxytryptamine (5‐HT) synthesis and 5‐hydroxytryptamine 2 receptor (5‐HT 2R) in the periphery. The present study examined the effects of inhibitions of both peripheral 5‐HT synthesis and 5‐HT 2R on dexamethasone‐induced IR.Materials and MethodsMale rats were exposed to dexamethasone for 10 days, then treated with or without a 5‐HT 2R antagonist, sarpogrelate, a 5‐HT synthetic inhibitor, carbidopa, alone or in combination for 20 days.ResultsDexamethasone‐induced whole‐body IR, with glucose intolerance, decreased insulin sensitivity, hyperglycemia, hyperinsulinemia and dyslipidemia, could be effectively abolished by sarpogrelate or/and carbidopa, whereas IR‐related actions of dexamethasone in tissues were accompanied by increased 5‐HT synthesis in the liver and visceral adipose, and upregulated 5‐HT 2R (5‐HT 2 AR and 5‐HT 2 BR) expression in these two tissues as well as in skeletal muscle. Sarpogrelate or/and carbidopa treatment significantly abolished dexamethasone‐caused tissue‐specific IR. In the liver, increased gluconeogenesis, triglycerides and very low‐density lipoprotein syntheses with steatosis, and downregulated expression of plasmalemmal glucose transporter‐2 were markedly reversed. In the visceral adipose and skeletal muscle, downregulated expression of plasmalemmal glucose transporter‐4 was significantly reversed, and increased lipolysis was also reversed in the visceral adipose. Dexamethasone‐induced activations of hepatic mammalian target of rapamycin serine2448, and S6K threonine389/412 phosphorylation were also abolished markedly by sarpogrelate or/and carbidopa. Co‐treatment with sarpogrelate and carbidopa showed a synergistic effect on suppressing dexamethasone actions.ConclusionInhibitions of both peripheral 5‐HT synthesis and 5‐HT 2R are expected to be a dependable target for treatment of steroid‐induced diabetes.

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Section: Discussionsupporting

confidence: 50%

Section: Discussionmentioning

confidence: 99%

Effective treatment with combination of peripheral 5‐hydroxytryptamine synthetic inhibitor and 5‐hydroxytryptamine 2 receptor antagonist on glucocorticoid‐induced whole‐body insulin resistance with hyperglycemia

Guo

et al. 2016

J of Diabetes Invest

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“…'5-HT by acting on its multiple receptors exerts its effects to cells' is widely accepted. 5-HT 2 receptors in the hepatocyte and adipocyte are recognized as major receptors in 5-HT-induced IR 12,22,23 . Indeed, we also detected upregulated expression of 5-HT 2A R and 5-HT 2B R induced by Dex in the live, intra-abdominal adipose and BRL-3A cells (data in Figures S1 and S2).…”

Section: Discussionmentioning

confidence: 99%

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

Li¹,

Guo²,

Qu³

et al. 2015

J of Diabetes Invest

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Aim/IntroductionBoth 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.Materials and MethodsExcept 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.ResultsDexamethasone‐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.ConclusionEnhancement of 5‐HT synthesis in liver and intra‐abdominal adipose is an important reason for glucocorticoids‐induced IR.

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“…Additionally, stimulation of Htr2b receptor by GDS might also suppress lipogenesis, as another research group showed that ablation of Htr2b signaling during differentiation of adipocytes in vitro results in triglyceride accumulation in these cells [37]. Moreover, serotonin stimulation of white adipocytes results in impaired insulin action, degradation of insulin receptor substrate-1 (IRS-1), and reduced glucose uptake [38]. Although Htr2b seems to be required for proper lipid handling by white adipocytes, Htr2a and Htr2c receptors are also expressed in these cells.…”

Section: Serotonin -A New Hormone Regulating Adipose Tissue Functionsmentioning

confidence: 99%

The roles of peripheral serotonin in metabolic homeostasis

et al. 2015

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a b s t r a c tMetabolic homeostasis in the organism is assured both by the nervous system and by hormones. Among a plethora of hormones regulating metabolism, serotonin presents a number of unique features. Unlike classical hormones serotonin is produced in different anatomical locations. In brain it acts as a neurotransmitter and in the periphery it can act as a hormone, auto-and/or paracrine factor, or intracellular signaling molecule. Serotonin does not cross the blood-brain barrier; therefore the two major pools of this bioamine remain separated. Although 95% of serotonin is produced in the periphery, its functions have been ignored until recently. Here we review the impact of the peripheral serotonin on the regulation of function of the organs involved in glucose and lipid homeostasis.

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

Cited by 20 publications

References 48 publications

Effective treatment with combination of peripheral 5‐hydroxytryptamine synthetic inhibitor and 5‐hydroxytryptamine 2 receptor antagonist on glucocorticoid‐induced whole‐body insulin resistance with hyperglycemia

Effective treatment with combination of peripheral 5‐hydroxytryptamine synthetic inhibitor and 5‐hydroxytryptamine 2 receptor antagonist on glucocorticoid‐induced whole‐body insulin resistance with hyperglycemia

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

The roles of peripheral serotonin in metabolic homeostasis

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