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A role for central nervous system PPAR-γ in the regulation of energy balance

Nature Medicine volume 17, pages 623–626 (2011)Cite this article

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Abstract

The peroxisome proliferator–activated receptor-γ (PPAR-γ) is a nuclear receptor that is activated by lipids to induce the expression of genes involved in lipid and glucose metabolism, thereby converting nutritional signals into metabolic consequences1. PPAR-γ is the target of the thiazolidinedione (TZD) class of insulin-sensitizing drugs, which have been widely prescribed to treat type 2 diabetes mellitus. A common side effect of treatment with TZDs is weight gain2. Here we report a previously unknown role for central nervous system (CNS) PPAR-γ in the regulation of energy balance. We found that both acute and chronic activation of CNS PPAR-γ, by either TZDs or hypothalamic overexpression of a fusion protein consisting of PPAR-γ and the viral transcriptional activator VP16 (VP16–PPAR-γ), led to positive energy balance in rats. Blocking the endogenous activation of CNS PPAR-γ with pharmacological antagonists or reducing its expression with shRNA led to negative energy balance, restored leptin sensitivity in high-fat-diet (HFD)-fed rats and blocked the hyperphagic response to oral TZD treatment. These findings have implications for the widespread clinical use of TZD drugs and for understanding the etiology of diet-induced obesity.

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Figure 1: Activation of hypothalamic PPAR-γ leads to positive energy balance.
Figure 2: Activation of CNS PPAR-γ is required for the hyperphagic effect of oral rosiglitazone.
Figure 3: Blocking the activation of CNS PPAR-γ with GW9662 leads to negative energy balance.
Figure 4: Blocking the activation of CNS PPAR-γ with GW9662 leads to improved leptin sensitivity.

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Acknowledgements

This work was funded by the US National Institute of Diabetes and Digestive and Kidney Diseases (DK082173 to K.K.R., DK17844 to S.C.W. and DK056863 and DK073505 to R.J.S.). The VP16–PPAR-γ construct was generously provided by M. Lazar (University of Pennsylvania).

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Authors and Affiliations

  1. Department of Internal Medicine, Division of Endocrinology, University of Cincinnati College of Medicine, Cincinnati, Ohio, USA

    Karen K Ryan, Bailing Li, Bernadette E Grayson, Emily K Matter & Randy J Seeley

  2. Department of Psychiatry, University of Cincinnati College of Medicine, Cincinnati, Ohio, USA

    Stephen C Woods

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  1. Karen K Ryan
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  2. Bailing Li
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Contributions

K.K.R. conceptualized, designed, performed and analyzed the experiments and wrote the manuscript. B.E.G. designed and performed the immunohistochemistry experiments. B.L. and E.K.M. cloned the VP16–PPAR-γ into the lentiviral vector and designed, and performed and analyzed the in vitro and gene expression experiments. S.C.W. and R.J.S. conceptualized, designed and analyzed the experiments and edited the manuscript.

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Correspondence to Randy J Seeley.

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The authors declare no competing financial interests.

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Ryan, K., Li, B., Grayson, B. et al. A role for central nervous system PPAR-γ in the regulation of energy balance. Nat Med 17, 623–626 (2011). https://doi.org/10.1038/nm.2349

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