Deletion of the α-Arrestin Protein Txnip in Mice Promotes Adiposity and Adipogenesis While Preserving Insulin Sensitivity
- William A. Chutkow1,2,
- Andreas L. Birkenfeld3,
- Jonathan D. Brown1,2,
- Hui-Young Lee3,
- David W. Frederick3,
- Jun Yoshioka1,
- Parth Patwari1,
- Romy Kursawe4,
- Samuel W. Cushman5,
- Jorge Plutzky1,
- Gerald I. Shulman6,
- Varman T. Samuel3,7 and
- Richard T. Lee1
- 1Cardiovascular Division, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Cambridge, Massachusetts;
- 2Veterans Administration Medical Center, West Roxbury, Massachusetts;
- 3Department of Internal Medicine, Yale University School of Medicine, New Haven, Connecticut;
- 4Department of Pediatrics, Yale University School of Medicine, New Haven, Connecticut;
- 5Experimental Diabetes, Metabolism, and Nutrition Section, National Institute of Diabetes and Digestive and Kidney Disease, Bethesda, Maryland;
- 6Howard Hughes Medical Institute and Departments of Internal Medicine and Cellular and Molecular Physiology, Yale University School of Medicine, New Haven, Connecticut; and
- 7Veterans Administration Medical Center, West Haven, Connecticut.
- Corresponding author: Varman T. Samuel, varman.samuel{at}yale.edu.
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V.T.S. and R.T.L. contributed equally to this study.
Abstract
OBJECTIVE Thioredoxin interacting protein (Txnip), a regulator of cellular oxidative stress, is induced by hyperglycemia and inhibits glucose uptake into fat and muscle, suggesting a role for Txnip in type 2 diabetes pathogenesis. Here, we tested the hypothesis that Txnip-null (knockout) mice are protected from insulin resistance induced by a high-fat diet.
RESEARCH DESIGN AND METHODS Txnip gene-deleted (knockout) mice and age-matched wild-type littermate control mice were maintained on a standard chow diet or subjected to 4 weeks of high-fat feeding. Mice were assessed for body composition, fat development, energy balance, and insulin responsiveness. Adipogenesis was measured from ex vivo fat preparations, and in mouse embryonic fibroblasts (MEFs) and 3T3-L1 preadipocytes after forced manipulation of Txnip expression.
RESULTS Txnip knockout mice gained significantly more adipose mass than controls due to a primary increase in both calorie consumption and adipogenesis. Despite increased fat mass, Txnip knockout mice were markedly more insulin sensitive than controls, and augmented glucose transport was identified in both adipose and skeletal muscle. RNA interference gene-silenced preadipocytes and Txnip−/− MEFs were markedly adipogenic, whereas Txnip overexpression impaired adipocyte differentiation. As increased adipogenesis and insulin sensitivity suggested aspects of augmented peroxisome proliferator–activated receptor-γ (PPARγ) response, we investigated Txnip's regulation of PPARγ function; manipulation of Txnip expression directly regulated PPARγ expression and activity.
CONCLUSIONS Txnip deletion promotes adiposity in the face of high-fat caloric excess; however, loss of this α-arrestin protein simultaneously enhances insulin responsiveness in fat and skeletal muscle, revealing Txnip as a novel mediator of insulin resistance and a regulator of adipogenesis.
Footnotes
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- Received August 14, 2009.
- Accepted March 3, 2010.
- © 2010 by the American Diabetes Association.
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