Resistance to High-Fat Diet–Induced Obesity but Exacerbated Insulin Resistance in Mice Overexpressing Preadipocyte Factor-1 (Pref-1)
A New Model of Partial Lipodystrophy
- Josep A. Villena1,
- Cheol Soo Choi2,
- Yuhui Wang1,
- Sheene Kim2,
- Yu-Jin Hwang2,
- Young-Bum Kim4,
- Gary Cline2,
- Gerald I. Shulman235 and
- Hei Sook Sul1
- 1Department of Nutritional Science and Toxicology, University of California, Berkeley, California
- 2Department of Internal Medicine, Howard Hughes Medical Institute, Yale University School of Medicine, New Haven, Connecticut
- 3Department of Cellular and Molecular Physiology, Howard Hughes Medical Institute, Yale University School of Medicine, New Haven, Connecticut
- 4Department of Medicine, Beth Israel Deaconess Medical Center, Boston, Massachusetts
- 5Howard Hughes Medical Institute, Yale University School of Medicine, New Haven, Connecticut
- Corresponding author: Hei Sook Sul, hsul{at}nature.berkeley.edu
Abstract
OBJECTIVE—White adipose tissue is a critical regulator of whole-body glucose metabolism. Preadipocyte factor-1 (Pref-1) is a secreted protein that inhibits adipocyte differentiation, both in vitro and in vivo. In this study, we have investigated the effects of Pref-1 overexpression on whole-body glucose homeostasis and its contribution to the development of insulin resistance.
RESEARCH DESIGN AND METHODS—To gain insight into the role of Pref-1 on the onset of insulin resistance and type 2 diabetes, we measured body composition and whole-body insulin-stimulated glucose metabolism during a hyperinsulinemic-euglycemic clamp in Pref-1 transgenic and wild-type control mice fed a high-fat diet.
RESULTS—Mice overexpressing Pref-1 were resistant to high-fat diet–induced obesity, as reflected by a marked reduction in adipose tissue mass. However, Pref-1–overexpressing mice were severely insulin resistant, mainly because of a reduction in insulin-stimulated glucose uptake in skeletal muscle and adipose tissue. The aggravated insulin resistance was associated with impaired insulin signaling and increased diacylglycerol content in skeletal muscle.
CONCLUSIONS—Mice overexpressing Pref-1 are insulin resistant despite being protected from diet-induced obesity and may provide a new rodent model for the study of lipodystrophic disorders.
Footnotes
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Published ahead of print at http://diabetes.diabetesjournals.org on 3 October 2008.
J.A.V., C.S.C., and Y.W. contributed equally to this work.
J.A.V. is currently affiliated with the Metabolism and Obesity Group, Hospital Universitari Vall d’Hebron Research Institute, Barcelona, Spain. C.S.C. is currently affiliated with the Laboratory of Cellular and Molecular Physiology and Metabolism, Lee Gil Ya Cancer and Diabetes Institute, Gachon University of Medicine and Science, Incheon, Korea.
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- Accepted September 17, 2008.
- Received December 12, 2007.
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