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Dexamethasone induction of hypertension and diabetes is PPAR-alpha dependent in LDL receptor-null mice

  • 0Department of Medicine, Washington University School of Medicine, St. Louis, Missouri 63110 USA.
Nature Medicine +

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July 9, 2003

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July 9, 2003

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Summary

This summary is machine-generated.

Glucocorticoid treatment can cause diabetes and hypertension. This study shows that activating PPAR-alpha in the liver drives these side effects by increasing glucose production and impairing insulin sensitivity.

Area Of Science

  • Endocrinology
  • Metabolic Research
  • Molecular Biology

Background

  • Glucocorticoids are widely used medications with known side effects including hypertension and diabetes.
  • The precise molecular mechanisms linking glucocorticoid treatment to these metabolic disturbances are not fully understood.

Purpose Of The Study

  • To investigate the role of peroxisome proliferator-activated receptor-alpha (PPAR-alpha) in mediating glucocorticoid-induced insulin resistance, hyperglycemia, and hypertension.
  • To elucidate the impact of PPAR-alpha activation on hepatic glucose metabolism and blood pressure regulation.

Main Methods

  • Mice lacking low-density lipoprotein receptors (Ldlr-/-), with or without PPAR-alpha (Ppara+/+ and Ppara-/-), were treated with dexamethasone.
  • Gene expression analysis of hepatic gluconeogenic enzymes was performed.
  • Adenoviral vectors were used to reconstitute PPAR-alpha in Ppara-/- mice.
  • Human hepatocytes were treated with dexamethasone and a PPAR-alpha agonist.

Main Results

  • Dexamethasone treatment induced hyperglycemia, hyperinsulinemia, and hypertension in Ppara+/+ mice but not in Ppara-/- mice.
  • PPAR-alpha activation in Ppara+/+ mice led to increased hepatic gluconeogenic gene expression and impaired insulin suppression of glucose production.
  • Reconstitution of PPAR-alpha in Ppara-/- mice mimicked the adverse metabolic and hypertensive effects.
  • PPAR-alpha and gluconeogenic gene expression were upregulated in human hepatocytes treated with dexamethasone and a PPAR-alpha agonist.

Conclusions

  • Hepatic activation of PPAR-alpha is a key mechanism underlying glucocorticoid-induced insulin resistance and hyperglycemia.
  • PPAR-alpha mediates increased gluconeogenesis, impaired insulin action, and contributes to hypertension through effects on the renin-angiotensin system and sympathetic nervous activity.
  • Targeting PPAR-alpha may offer a strategy to mitigate the adverse metabolic consequences of glucocorticoid therapy.

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