Inflammation Is Necessary for Long-Term but Not Short-Term High-Fat Diet–Induced Insulin Resistance
- Yun Sok Lee1,2,3,
- Pingping Li3,
- Jin Young Huh1,2,
- In Jae Hwang1,2,
- Min Lu3,
- Jong In Kim1,2,
- Mira Ham1,2,
- Saswata Talukdar3,
- Ai Chen3,
- Wendell J. Lu3,
- Guatam K. Bandyopadhyay3,
- Reto Schwendener4,
- Jerrold Olefsky3 and
- Jae Bum Kim1,2,5⇓
- 1Institute of Molecular Biology and Genetics, Seoul National University, Seoul, Korea
- 2School of Biological Sciences, Seoul National University, Seoul, Korea
- 3Department of Medicine, Division of Endocrinology and Metabolism, University of California, San Diego, La Jolla, California
- 4Institute of Molecular Cancer Research, University of Zurich, Zurich, Switzerland
- 50Department of Biophysics and Chemical Biology, Seoul National University, Seoul, Korea
- Corresponding author: Jae Bum Kim, .
Y.S.L., P.L., and J.Y.H. contributed equally to this study.
OBJECTIVE Tissue inflammation is a key factor underlying insulin resistance in established obesity. Several models of immuno-compromised mice are protected from obesity-induced insulin resistance. However, it is unanswered whether inflammation triggers systemic insulin resistance or vice versa in obesity. The purpose of this study was to assess these questions.
RESEARCH DESIGN AND METHODS We fed a high-fat diet (HFD) to wild-type mice and three different immuno-compromised mouse models (lymphocyte-deficient Rag1 knockout, macrophage-depleted, and hematopoietic cell-specific Jun NH2-terminal kinase–deficient mice) and measured the time course of changes in macrophage content, inflammatory markers, and lipid accumulation in adipose tissue, liver, and skeletal muscle along with systemic insulin sensitivity.
RESULTS In wild-type mice, body weight and adipose tissue mass, as well as insulin resistance, were clearly increased by 3 days of HFD. Concurrently, in the short-term HFD period inflammation was selectively elevated in adipose tissue. Interestingly, however, all three immuno-compromised mouse models were not protected from insulin resistance induced by the short-term HFD. On the other hand, lipid content was markedly increased in liver and skeletal muscle at day 3 of HFD.
CONCLUSIONS These data suggest that the initial stage of HFD-induced insulin resistance is independent of inflammation, whereas the more chronic state of insulin resistance in established obesity is largely mediated by macrophage-induced proinflammatory actions. The early-onset insulin resistance during HFD feeding is more likely related to acute tissue lipid overload.
This article contains Supplementary Data online at http://diabetes.diabetesjournals.org/lookup/suppl/doi:10.2337/db11-0194/-/DC1.
- Received February 15, 2011.
- Accepted June 13, 2011.
- © 2011 by the American Diabetes Association.
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