PPARα and Sirt1 Mediate Erythropoietin Action in Increasing Metabolic Activity and Browning of White Adipocytes to Protect Against Obesity and Metabolic Disorders
- Li Wang1,2,
- Ruifeng Teng1,3,
- Lijun Di2,
- Heather Rogers1,
- Hong Wu4,
- Jeffrey B. Kopp5 and
- Constance Tom Noguchi1⇑
- 1Molecular Medicine Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland
- 2Faculty of Health Sciences, University of Macau, Macau, China
- 3Mouse Metabolism Core Laboratory, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland
- 4Molecular Biology Institute, University of California at Los Angeles, Los Angeles, California
- 5Kidney Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland
- Corresponding author: Constance Tom Noguchi, .
Erythropoietin (EPO) has shown beneficial effects in the regulation of obesity and metabolic syndrome; however, the detailed mechanism is still largely unknown. Here, we created mice with adipocyte-specific deletion of EPO receptor. These mice exhibited obesity and decreased glucose tolerance and insulin sensitivity, especially when fed a high-fat diet. Moreover, EPO increased oxidative metabolism, fatty acid oxidation, and key metabolic genes in adipocytes and in white adipose tissue from diet-induced obese wild-type mice. Increased metabolic activity by EPO is associated with induction of brown fat–like features in white adipocytes, as demonstrated by increases in brown fat gene expression, mitochondrial content, and uncoupled respiration. Peroxisome proliferator–activated receptor (PPAR)α was found to mediate EPO activity because a PPARα antagonist impaired EPO-mediated induction of brown fat–like gene expression and uncoupled respiration. PPARα also cooperates with Sirt1 activated by EPO through modulating the NAD+ level to regulate metabolic activity. PPARα targets, including PPARγ coactivator 1α, uncoupling protein 1, and carnitine palmitoyltransferase 1α, were increased by EPO but impaired by Sirt1 knockdown. Sirt1 knockdown also attenuated adipose response to EPO. Collectively, EPO, as a novel regulator of adipose energy homeostasis via these metabolism coregulators, provides a potential therapeutic strategy to protect against obesity and metabolic disorders.
This article contains Supplementary Data online at http://diabetes.diabetesjournals.org/lookup/suppl/doi:10.2337/db13-0518/-/DC1.
- Received April 5, 2013.
- Accepted August 22, 2013.
- © 2013 by the American Diabetes Association.
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