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PPARγ signaling and metabolism: the good, the bad and the future

Abstract

Thiazolidinediones (TZDs) are potent insulin sensitizers that act through the nuclear receptor peroxisome proliferator-activated receptor-γ (PPARγ) and are highly effective oral medications for type 2 diabetes. However, their unique benefits are shadowed by the risk for fluid retention, weight gain, bone loss and congestive heart failure. This raises the question as to whether it is possible to build a safer generation of PPARγ-specific drugs that evoke fewer side effects while preserving insulin-sensitizing potential. Recent studies that have supported the continuing physiologic and therapeutic relevance of the PPARγ pathway also provide opportunities to develop newer classes of molecules that reduce or eliminate adverse effects. This review highlights key advances in understanding PPARγ signaling in energy homeostasis and metabolic disease and also provides new explanations for adverse events linked to TZD-based therapy.

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Figure 1: PPARγ has multiple roles in adipose tissue.
Figure 2: Known effects of PPARγ activation.
Figure 3: Post-translational modifications of PPARγ.

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Acknowledgements

We thank R. Yu, C.D. De Magalhaes Filho and S. Sarshar for useful discussions and L. Ong and C. Brondos for administrative assistance. R.M.E. is an Investigator of the Howard Hughes Medical Institute at the Salk Institute and March of Dimes Chair in Molecular and Developmental Biology. This work was supported by US National Institutes of Health grants to R.M.E. (DK057978, DK090962, HL088093, HL105278 and ES010337), the Glenn Foundation for Medical Research, the Leona M. and Harry B. Helmsley Charitable Trust, Ipsen/Biomeasure, The Ellison Medical Foundation and the Howard Hughes Medical Institute. C.L. and M.D. are funded by grants from the National Health and Medical Research Council of Australia Project Grants 512354, 632886 and 1043199. M.A. is supported by an F32 Ruth L. Kirschstein National Research Service Award (National Institute of Diabetes and Digestive and Kidney Diseases). N.H. is supported by the Pioneer Fund. We apologize for those references we could not include due to space limitations.

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Ahmadian, M., Suh, J., Hah, N. et al. PPARγ signaling and metabolism: the good, the bad and the future. Nat Med 19, 557–566 (2013). https://doi.org/10.1038/nm.3159

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