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Peroxisome proliferation–associated control of reactive oxygen species sets melanocortin tone and feeding in diet-induced obesity

Nature Medicine volume 17, pages 1121–1127 (2011)Cite this article

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A Corrigendum to this article was published on 11 October 2011

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Abstract

Previous studies have proposed roles for hypothalamic reactive oxygen species (ROS) in the modulation of circuit activity of the melanocortin system1,2. Here we show that suppression of ROS diminishes pro-opiomelanocortin (POMC) cell activation and promotes the activity of neuropeptide Y (NPY)- and agouti-related peptide (AgRP)-co-producing (NPY/AgRP) neurons and feeding, whereas ROS-activates POMC neurons and reduces feeding. The levels of ROS in POMC neurons were positively correlated with those of leptin in lean and ob/ob mice, a relationship that was diminished in diet-induced obese (DIO) mice. High-fat feeding resulted in proliferation of peroxisomes and elevated peroxisome proliferator–activated receptor γ (PPAR-γ) mRNA levels within the hypothalamus. The proliferation of peroxisomes in POMC neurons induced by the PPAR-γ agonist rosiglitazone decreased ROS levels and increased food intake in lean mice on high-fat diet. Conversely, the suppression of peroxisome proliferation by the PPAR antagonist GW9662 increased ROS concentrations and c-fos expression in POMC neurons. Also, it reversed high-fat feeding–triggered elevated NPY/AgRP and low POMC neuronal firing, and resulted in decreased feeding of DIO mice. Finally, central administration of ROS alone increased c-fos and phosphorylated signal transducer and activator of transcription 3 (pStat3) expression in POMC neurons and reduced feeding of DIO mice. These observations unmask a previously unknown hypothalamic cellular process associated with peroxisomes and ROS in the central regulation of energy metabolism in states of leptin resistance.

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Figure 1: Free radicals' effect on the melanocortin system.
Figure 2: Peroxisome proliferation in POMC neurons.
Figure 3: Peroxisome proliferation in POMC neurons is associated with altered feeding.
Figure 4: The effect of PPAR ligands on the melanocortin system.

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  • 16 September 2011

     In the version of this article initially published, the top electrophysiological trace of Figure 4a was inadvertently repeated as the bottom electrophysiological trace of Figure 4b. The scientific conclusions of the paper were not affected by the error. The error has been corrected in the HTML and PDF versions of the article.

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Acknowledgements

We thank J.M. Olefsky, Department of Medicine, University of California–San Diego, for generating and providing brain-specific PPAR-γ–knockout mice and B.B. Lowell, Beth Israel Deaconess Medical Center, for providing breeding pairs of UCP2-knockout mice. This work was supported by US National Institutes of Health (NIH) grants DK084065 (S.D.) and DK080000 and OD006850 (T.L.H.) and by American Diabetes Association grant 7-08-MN-25 (T.L.H.). This work was also supported by NIH grants DK089098 (X.Y.), DK072033 (C.V.M.) DK090320 and DK052989 (M.W.S.) and AR47901and P30 AR42687 (J.L.A.).

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Authors and Affiliations

  1. Program in Integrative Cell Signaling and Neurobiology of Metabolism, Yale University School of Medicine, New Haven, Connecticut, USA

    Sabrina Diano, Zhong-Wu Liu, Jin Kwon Jeong, Marcelo O Dietrich, Hai-Bin Ruan, Shigetomo Suyama, Kaitlin Kelly, Erika Gyengesi, Anton M Bennett, Marya Shanabrough, Xiaoyong Yang, Xiao-Bing Gao & Tamas L Horvath

  2. Department of Obstetrics and Gynecology, Yale University School of Medicine, New Haven, Connecticut, USA

    Sabrina Diano, Jin Kwon Jeong, Kaitlin Kelly, Erika Gyengesi, Xiao-Bing Gao & Tamas L Horvath

  3. Section of Comparative Medicine, Yale University School of Medicine, New Haven, Connecticut, USA

    Sabrina Diano, Zhong-Wu Liu, Marcelo O Dietrich, Hai-Bin Ruan, Shigetomo Suyama, Anton M Bennett, Marya Shanabrough, Xiaoyong Yang, Xiao-Bing Gao & Tamas L Horvath

  4. Department of Neurobiology, Yale University School of Medicine, New Haven, Connecticut, USA

    Sabrina Diano & Tamas L Horvath

  5. Department of Biochemistry, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil

    Marcelo O Dietrich & Charles V Mobbs

  6. Department of Neuroscience, Friedman Brain Institute, Mount Sinai School of Medicine, New York, New York, USA

    Esther Kim

  7. Department of Geriatrics, Friedman Brain Institute, Mount Sinai School of Medicine, New York, New York, USA

    Esther Kim

  8. Department of Dermatology, Emory University School of Medicine, Winship Cancer Institute, Atlanta VA Medical Center, Atlanta, Georgia, USA

    Jack L Arbiser

  9. Department of Physiology, University of Toronto and Division of Cellular and Molecular Biology, Toronto General Hospital Research Institute, University Health Network, Toronto, Ontario, Canada

    Denise D Belsham

  10. Diabetes and Obesity Center of Excellence, University of Washington, Seattle, Washington, USA

    David A Sarruf & Michael W Schwartz

  11. Department of Medicine, University of Washington, Seattle, Washington, USA

    David A Sarruf & Michael W Schwartz

  12. Department of Pharmacology, Yale University School of Medicine, New Haven, Connecticut, USA

    Anton M Bennett

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Contributions

S.D. and T.L.H. developed the conceptual framework of the study, designed the experiments, conducted studies, analyzed data and wrote the paper. Z.-W.L., J.K.J., M.O.D., H.-B.R., E.K., S.S., K.K., E.G., D.A.S. and M.S. conducted experiments. J.L.A. initiated studies with honokiol and provided reagents. C.V.M. designed and supervised in vitro cell signaling studies. M.W.S. designed studies on PPAR-γ–knockout mice. D.D.B. provided POMC and AgRP cell cultures and helped design experiments. A.M.B. provided reagents and advised on signaling aspects of the work. X.Y. and X.-B.G. supervised experiments and analyzed data.

Corresponding authors

Correspondence to Sabrina Diano or Tamas L Horvath.

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Diano, S., Liu, ZW., Jeong, J. et al. Peroxisome proliferation–associated control of reactive oxygen species sets melanocortin tone and feeding in diet-induced obesity. Nat Med 17, 1121–1127 (2011). https://doi.org/10.1038/nm.2421

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