Reduction of Hepatic and Adipose Tissue Glucocorticoid Receptor Expression With Antisense Oligonucleotides Improves Hyperglycemia and Hyperlipidemia in Diabetic Rodents Without Causing Systemic Glucocorticoid Antagonism

  1. Lynnetta M. Watts1,
  2. Vara Prasad Manchem1,
  3. Thomas A. Leedom1,
  4. Amber L. Rivard1,
  5. Robert A. McKay1,
  6. Dingjiu Bao1,
  7. Teri Neroladakis1,
  8. Brett P. Monia1,
  9. Diane M. Bodenmiller2,
  10. Julia Xiao-Chun Cao2,
  11. Hong Yan Zhang2,
  12. Amy L. Cox2,
  13. Steven J. Jacobs2,
  14. M. Dodson Michael2,
  15. Kyle W. Sloop2 and
  16. Sanjay Bhanot1
  1. 1Isis Pharmaceuticals, Carlsbad, California
  2. 2Endocrine Discovery, Lilly Research Laboratories, Indianapolis, Indiana
  1. Address correspondence and reprint requests to Sanjay Bhanot, MD, PhD, Executive Director, Antisense Drug Discovery, Isis Pharmaceuticals, 2292, Faraday Ave., Carlsbad, CA 92008. E-mail: sbhanot{at}isisph.com

Abstract

Glucocorticoids (GCs) increase hepatic gluconeogenesis and play an important role in the regulation of hepatic glucose output. Whereas systemic GC inhibition can alleviate hyperglycemia in rodents and humans, it results in adrenal insufficiency and stimulation of the hypothalamic-pituitary-adrenal axis. In the present study, we used optimized antisense oligonucleotides (ASOs) to cause selective reduction of the glucocorticoid receptor (GCCR) in liver and white adipose tissue (WAT) and evaluated the resultant changes in glucose and lipid metabolism in several rodent models of diabetes. Treatment of ob/ob mice with GCCR ASOs for 4 weeks resulted in ∼75 and ∼40% reduction in GCCR mRNA expression in liver and WAT, respectively. This was accompanied by ∼65% decrease in fed and ∼30% decrease in fasted glucose levels, a 60% decrease in plasma insulin concentration, and ∼20 and 35% decrease in plasma resistin and tumor necrosis factor-α levels, respectively. Furthermore, GCCR ASO reduced hepatic glucose production and inhibited hepatic gluconeogenesis in liver slices from basal and dexamethasone-treated animals. In db/db mice, a similar reduction in GCCR expression caused ∼40% decrease in fed and fasted glucose levels and ∼50% reduction in plasma triglycerides. In ZDF and high-fat diet–fed streptozotocin-treated (HFD-STZ) rats, GCCR ASO treatment caused ∼60% reduction in GCCR expression in the liver and WAT, which was accompanied by a 40–70% decrease in fasted glucose levels and a robust reduction in plasma triglyceride, cholesterol, and free fatty acids. No change in circulating corticosterone levels was seen in any model after GCCR ASO treatment. To further demonstrate that GCCR ASO does not cause systemic GC antagonism, normal Sprague-Dawley rats were challenged with dexamethasone after treating with GCCR ASO. Dexamethasone increased the expression of GC-responsive genes such as PEPCK in the liver and decreased circulating lymphocytes. GCCR ASO treatment completely inhibited the increase in dexamethasone-induced PEPCK expression in the liver without causing any change in the dexamethasone-induced lymphopenia. These studies demonstrate that tissue-selective GCCR antagonism with ASOs may be a viable therapeutic strategy for the treatment of the metabolic syndrome.

Footnotes

  • The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

    • Accepted March 10, 2005.
    • Received July 23, 2004.
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