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Brain PPAR-γ promotes obesity and is required for the insulin–sensitizing effect of thiazolidinediones

Nature Medicine volume 17, pages 618–622 (2011)Cite this article

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Abstract

In adipose tissue, muscle, liver and macrophages, signaling by the nuclear receptor peroxisome proliferator–activated receptor-γ (PPAR-γ) is a determinant of insulin sensitivity and this receptor mediates the insulin–sensitizing effects of thiazolidinediones (TZDs)1,2,3,4. As PPAR-γ is also expressed in neurons5, we generated mice with neuron-specific Pparg knockout (Pparg brain knockout (BKO)) to determine whether neuronal PPAR-γ signaling contributes to either weight gain or insulin sensitivity. During high-fat diet (HFD) feeding, food intake was reduced and energy expenditure increased in Pparg-BKO mice compared to Ppargf/f mice, resulting in reduced weight gain. Pparg-BKO mice also responded better to leptin administration than Ppargf/f mice. When treated with the TZD rosiglitazone, Pparg-BKO mice were resistant to rosiglitazone-induced hyperphagia and weight gain and, relative to rosiglitazone-treated Ppargf/f mice, experienced only a marginal improvement in glucose metabolism. Hyperinsulinemic euglycemic clamp studies showed that the increase in hepatic insulin sensitivity induced by rosiglitazone treatment during HFD feeding was completely abolished in Pparg-BKO mice, an effect associated with the failure of rosiglitazone to improve liver insulin receptor signal transduction. We conclude that excess weight gain induced by HFD feeding depends in part on the effect of neuronal PPAR-γ signaling to limit thermogenesis and increase food intake. Neuronal PPAR-γ signaling is also required for the hepatic insulin sensitizing effects of TZDs.

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Figure 1: Neuronal deletion of Pparg in brains of mice.
Figure 2: Energy balance parameters in Pparg-BKO mice.
Figure 3: Effect of rosiglitazone on weight gain and food intake in control and Pparg-BKO mice.
Figure 4: Neuronal PPAR-γ is required for the full insulin-sensitizing effect of TZD treatment.

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Acknowledgements

We thank the P. Mellon lab at UCSD for providing Syn1-Cre mice. We thank J. Pimentel, A. Amidi, B. Scott, J. Meadows and J. Ficsher for technical support. We thank D. Oh, J. Xu, E. Bae, O. Osborne, A. Chen and D. Sears for helpful discussions. We thank the Histology and Immunohistochemistry Resource (L. Gapuz and N. Varki) at the Rebecca & John Moores UCSD Cancer Center. This work was supported by US National Institutes of Health (NIH) grants DK033651, DK063491, DK074868 and DK09062 (to J.M.O.) and by the Eunice Kennedy Shriver National Institutes of Child Health and Human Development/NIH through cooperative agreement of U54 HD012303-25 as part of the specialized Cooperative Centers Program in Reproduction and Infertility Research. This work was also supported by NIH grants DK068384, DK083042 and DK052989 (to M.W.S.), by Ruth L. Kirschstein National Research Service Award fellowship F32DK080604–01 (to D.A.S.), and by the Nutrition Obesity Research Center grant DK035816 and the Mouse Metabolic Phenotyping Center (U24 DK076126) at the University of Washington. UCSD Cancer Center microscopy core is supported by the UCSD Cancer Center Specialized Support Grant P30 CA23100. Body composition and energy expenditure analyses were performed with support from the NIH-funded Mouse Metabolic Phenotyping Center at the University of Washington. Calorimetry was performed by K. Ogimoto and expert assistance in analyses of these data was provided by K. Kaiyala.

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Authors and Affiliations

  1. Department of Medicine, University of California–San Diego (UCSD), San Diego, California, USA

    Min Lu, Saswata Talukdar, Shweta Sharma, Pingping Li, Gautam Bandyopadhyay, Sarah Nalbandian, WuQiang Fan, Jiaur R Gayen, Sushil K Mahata, Nicholas J Webster & Jerrold M Olefsky

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

    David A Sarruf & Michael W Schwartz

  3. Medical Research Service, Veterans Affairs San Diego Healthcare System, San Diego, California, USA

    Shweta Sharma, Jiaur R Gayen, Sushil K Mahata & Nicholas J Webster

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  1. Min Lu
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Contributions

J.M.O., M.L. and M.W.S. designed the study and co-wrote the manuscript. M.L. performed most of the experiments. D.A.S. was responsible for body composition, locomotor activity, indirect calorimetry and leptin sensitivity assays. S.T. conducted most of the qPCR and performed acute insulin stimulation in mice. S.S. and N.J.W. were involved in mouse breeding and performed immunohistochemistry. P.L. was involved in hyperinsulinemic euglycemic clamp and western blotting studies. G.B. measured tissue lipid content. S.N. was involved in metabolic studies in mice. W.F. contributed to western blotting. J.R.G. and S.K.M. were responsible for measurement of cardiac function and catecholamine concentrations.

Corresponding authors

Correspondence to Michael W Schwartz or Jerrold M Olefsky.

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The authors declare no competing financial interests.

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Lu, M., Sarruf, D., Talukdar, S. et al. Brain PPAR-γ promotes obesity and is required for the insulin–sensitizing effect of thiazolidinediones. Nat Med 17, 618–622 (2011). https://doi.org/10.1038/nm.2332

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