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Inhibition of RXR and PPARgamma ameliorates diet-induced obesity and type 2 diabetes

T Yamauchi1, H Waki, J Kamon

  • 1Department of Internal Medicine, Graduate School of Medicine, University of Tokyo, Tokyo, Japan.

The Journal of Clinical Investigation
|October 3, 2001
PubMed

Insights

Functional antagonism of PPARgamma/RXR may treat obesity and type 2 diabetes. Inhibitors reduced fat and improved insulin sensitivity, but paradoxically worsened outcomes in deficient mice, suggesting careful modulation is key.

Area of Science:

  • Metabolism and Endocrinology
  • Molecular Biology
  • Pharmacology

Background:

  • Peroxisome proliferator-activated receptor gamma (PPARgamma) is a nuclear receptor crucial for metabolic regulation.
  • PPARgamma agonists treat type 2 diabetes but cause weight gain.
  • Reduced PPARgamma activity can protect against diet-induced obesity and insulin resistance.

Purpose of the Study:

  • To investigate the therapeutic potential of PPARgamma/RXR functional antagonism for obesity and type 2 diabetes.
  • To determine the effects of RXR and PPARgamma antagonists on metabolic parameters.

Main Methods:

  • Administration of RXR and PPARgamma antagonists in diet-induced obesity and insulin resistance models.
  • Assessment of triglyceride content, leptin levels, fatty acid oxidation, and energy expenditure.
  • Evaluation in heterozygous PPARgamma-deficient mice.

Main Results:

  • RXR and PPARgamma antagonists decreased triglyceride accumulation in adipose tissue, muscle, and liver.
  • Inhibitors enhanced leptin sensitivity, increased fatty acid combustion, and improved energy dissipation.
  • Paradoxically, antagonists worsened metabolic outcomes in PPARgamma-deficient mice, increasing fat deposition and insulin resistance.

Conclusions:

  • Targeted functional antagonism of the PPARgamma/RXR pathway shows promise for treating obesity and type 2 diabetes.
  • The therapeutic effect is dependent on the level of PPARgamma activity.
  • Careful modulation of PPARgamma/RXR signaling is essential for effective treatment.

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