Endoplasmic Reticulum Stress Regulates Adipocyte Resistin Expression
- Martina I. Lefterova,
- Shannon E. Mullican,
- Takuya Tomaru,
- Mohammed Qatanani,
- Michael Schupp and
- Mitchell A. Lazar
- From the Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine and Department of Genetics, and The Institute for Diabetes, Obesity, and Metabolism, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania.
- Corresponding author: Mitchell A. Lazar, lazar{at}mail.med.upenn.edu.
Abstract
OBJECTIVE Resistin is a secreted polypeptide that impairs glucose metabolism and, in rodents, is derived exclusively from adipocytes. In murine obesity, resistin circulates at elevated levels but its gene expression in adipose tissue is paradoxically reduced. The mechanism behind the downregulation of resistin mRNA is poorly understood. We investigated whether endoplasmic reticulum (ER) stress, which is characteristic of obese adipose tissue, regulates resistin expression in cultured mouse adipocytes.
RESEARCH DESIGN AND METHODS The effects of endoplasmic stress inducers on resistin mRNA and secreted protein levels were examined in differentiated 3T3-L1 adipocytes, focusing on the expression and genomic binding of transcriptional regulators of resistin. The association between downregulated resistin mRNA and induction of ER stress was also investigated in the adipose tissue of mice fed a high-fat diet.
RESULTS ER stress reduced resistin mRNA in 3T3-L1 adipocytes in a time- and dose-dependent manner. The effects of ER stress were transcriptional because of downregulation of CAAT/enhancer binding protein-α and peroxisome proliferator–activated receptor-γ transcriptional activators and upregulation of the transcriptional repressor CAAT/enhancer binding protein homologous protein-10 (CHOP10). Resistin protein was also substantially downregulated, showing a close correspondence with mRNA levels in 3T3-L1 adipocytes as well as in the fat pads of obese mice.
CONCLUSIONS ER stress is a potent regulator of resistin, suggesting that ER stress may underlie the local downregulation of resistin mRNA and protein in fat in murine obesity. The paradoxical increase in plasma may be because of various systemic abnormalities associated with obesity and insulin resistance.
Footnotes
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- Received December 8, 2008.
- Accepted May 8, 2009.
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- © 2009 by the American Diabetes Association.
