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JNK and IKKβ phosphorylation is reduced by glucocorticoids in adipose tissue from insulin-resistant rats

Katia Motta¹, Amanda Marreiro Barbosa², Franciane Bobinski³

¹Multicenter Graduate Program in Physiological Sciences, Center of Biological Sciences, Federal University of Santa Catarina (UFSC), Florianópolis, Brazil.

The Journal of Steroid Biochemistry and Molecular Biology

|October 1, 2014

Abstract

Objectives:

Peripheral insulin resistance (IR) is one of the main side effects caused by glucocorticoid (GC)-based therapies, and the molecular mechanisms of GC-induced IR are not yet fully elucidated. Thus, we aimed to investigate the effects of dexamethasone treatment on the main components of insulin and inflammatory signaling in the adipose tissue of rats.

Materials/Methods:

Male Wistar rats received daily injections of dexamethasone (1mg/kg body weight (b.w.), intraperitoneally (i.p.)) for 5 days (DEX), whereas control rats received saline (CTL). The metabolic status was investigated, and the epididymal fat fragments were collected for lipolysis and western blot analyses.

Results:

The DEX rats became hyperglycemic, hyperinsulinemic, insulin resistant and glucose intolerant, compared with the CTL rats (P<0.05). The basal glycerol release in the fat fragments was 1.5-fold higher in the DEX rats (P<0.05). The phosphorylation of protein kinase B (PKB) at ser(473) decreased by 44%, whereas, the phosphorylation of insulin receptor substrate (IRS)-1 at ser(307) increased by 93% in the adipose tissue of the DEX rats after an oral bolus of glucose (P<0.05). The basal phosphorylation of c-jun-N-terminal kinase (JNK) and inhibitor of nuclear factor kappa-B (IKKβ) proteins was reduced by 46% and 58%, respectively, in the adipose tissue of the DEX rats (P<0.05). This was paralleled with a significant reduction (47%) in the glucocorticoid receptor (GR) protein content in the adipose tissue of the DEX rats (P<0.05).

Conclusion:

The insulin-resistant status of rats induced by dexamethasone administration have PKB and IRS-1 activity attenuated in epididymal fat without increases in the phosphorylation of the proinflammatory signals JNK and IKKβ.

Insights

Dexamethasone treatment induced insulin resistance in rats, characterized by impaired protein kinase B (PKB) and insulin receptor substrate-1 (IRS-1) activity in adipose tissue. This occurred without increasing pro-inflammatory signaling pathways.

Area of Science:

Endocrinology
Metabolic Research
Molecular Biology

Background:

Peripheral insulin resistance (IR) is a significant side effect of glucocorticoid (GC) therapies.
The precise molecular mechanisms underlying GC-induced IR remain incompletely understood.

Purpose of the Study:

To investigate the impact of dexamethasone administration on key insulin and inflammatory signaling components within rat adipose tissue.
To elucidate the molecular pathways contributing to dexamethasone-induced insulin resistance.

Main Methods:

Male Wistar rats were administered daily intraperitoneal injections of dexamethasone (1mg/kg b.w.) or saline for 5 days.
Metabolic status was assessed, and epididymal fat tissue was collected for lipolysis and Western blot analyses to examine protein phosphorylation and content.

Main Results:

Dexamethasone-treated rats exhibited hyperglycemia, hyperinsulinemia, insulin resistance, and glucose intolerance compared to controls.
Adipose tissue showed decreased protein kinase B (PKB) phosphorylation and increased insulin receptor substrate-1 (IRS-1) phosphorylation at inhibitory sites.
Despite IR, basal phosphorylation of pro-inflammatory markers c-jun-N-terminal kinase (JNK) and inhibitor of nuclear factor kappa-B (IKKβ) was reduced, alongside decreased glucocorticoid receptor (GR) protein content.

Conclusions:

Dexamethasone-induced insulin resistance in rats involves attenuated PKB and IRS-1 activity in epididymal fat.
The development of insulin resistance under these conditions did not involve increased phosphorylation of pro-inflammatory JNK and IKKβ signaling pathways.

Read full analysis

Keywords:

Dexamethasone Glucocorticoid Glucocorticoid receptor Inflammatory signaling Insulin resistance Insulin signaling

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