ABSTRACT
Adipose tissue is a dynamic organ that makes critical contributions to whole-body metabolic homeostasis. Although recent studies have revealed that different fat depots have distinct molecular signatures, metabolic functions and adipogenic mechanisms, peroxisome proliferator-activated receptor γ (PPARγ) is still widely viewed as the master regulator of adipogenesis and critical for maintaining mature adipocyte function. Using an inducible, adipocyte-specific knockout system, we explored the role of PPARγ in mature adipocytes in vivo. Short-term PPARγ deficiency in adipocytes reduces whole-body insulin sensitivity, but adipocytes are viable both in vitro and in vivo. However, after exposure to a high-fat diet, even short-term PPARγ deficiency leads to rapid adipocyte death. When mature adipocytes are depleted of both PPARγ and CCAAT-enhancer-binding protein α (C/EBPα), they are rapidly depleted of lipids and undergo adipocyte death, both in vitro and in vivo. Surprisingly, although thiazolidinediones (TZDs; PPARγ agonists) are thought to act mainly on PPARγ, PPARγ in adipocytes is not required for the whole-body insulin-sensitizing effect of TZDs. This offers new mechanistic aspects of PPARγ/TZD action and its effect on whole-body metabolic homeostasis.
SUPPLEMENTAL MATERIAL
Supplemental material for this article may be found at https://doi.org/10.1128/MCB.00677-17.
ACKNOWLEDGMENTS
We thank the UT Southwestern Histology Core for assistance in embedding and processing of tissue samples.
This study was supported by U.S. National Institutes of Health (NIH) grants R01-DK55758, P01-DK088761, and R01-DK099110 (P.E.S.). Q.A.W. is supported by NIH grant K01-DK107788. R.K.G. is supported by NIH grant R01-DK104789.
Q.A.W., R.K.G., and P.E.S. designed the experiments and wrote the manuscript. Q.A.W., F.Z., L.J., M.S., Y.A., R.Y., and C.T. performed experiments and analyzed data.