TY - JOUR
T1 - Osteopontin is required for the early onset of high fat diet-induced insulin resistance in mice
AU - Chapman, Justin
AU - Miles, Philip D.
AU - Ofrecio, Jachelle M.
AU - Neels, Jaap G.
AU - Yu, Joseph G.
AU - Resnik, Jamie L.
AU - Wilkes, Jason
AU - Talukdar, Saswata
AU - Thapar, Divya
AU - Johnson, Kristen
AU - Sears, Dorothy D.
N1 - Funding Information:
Support for this research was provided, in part, by the University of California Discovery Program Project #bio03-10383 with matching grant funds provided by Pfizer Inc (DDS, JMO). JC is an employee and shareholder of Pfizer and participated as a collaborator in sample and data analysis for the project and preparing the manuscript. This does not alter the authors' adherence to all the PLoS ONE policies on sharing data and materials. The terms of this arrangement have been reviewed and approved by the University of California San Diego in accordance with its conflict of interest policies. Other than JC's participation as described above, no other person or entity of Pfizer Inc. had a role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
PY - 2010
Y1 - 2010
N2 - Background: Insulin resistance is manifested in muscle, adipose tissue, and liver and is associated with adipose tissue inflammation. The cellular components and mechanisms that regulate the onset of diet-induced insulin resistance are not clearly defined. Methodology and Principal Findings:We initially observed osteopontin (OPN) mRNA over-expression in adipose tissue of obese, insulin resistant humans and rats which was normalized by thiazolidinedione (TZD) treatment in both species. OPN regulates inflammation and is implicated in pathogenic maladies resulting from chronic obesity. Thus, we tested the hypothesis that OPN is involved in the early development of insulin resistance using a 2-4 week high fat diet (HFD) model. OPN KO mice fed HFD for 2 weeks were completely protected from the severe skeletal muscle, liver and adipose tissue insulin resistance that developed in wild type (WT) controls, as determined by hyperinsulinemic euglycemic clamp and acute insulin-stimulation studies. Although two-week HFD did not alter body weight or plasma free fatty acids and cytokines in either strain, HFD-induced hyperleptinemia, increased adipose tissue inflammation (macrophages and cytokines), and adipocyte hypertrophy were significant in WT mice and blunted or absent in OPN KO mice. Adipose tissue OPN protein isoform expression was significantly altered in 2- and 4-week HFD-fed WT mice but total OPN protein was unchanged. OPN KO bone marrow stromal cells were more osteogenic and less adipogenic than WT cells in vitro. Interestingly, the two differentiation pathways were inversely affected by HFD in WT cells in vitro. Conclusions:The OPN KO phenotypes we report reflect protection from insulin resistance that is associated with changes in adipocyte biology and adipose tissue inflammatory status. OPN is a key component in the development of HFD-induced insulin resistance.
AB - Background: Insulin resistance is manifested in muscle, adipose tissue, and liver and is associated with adipose tissue inflammation. The cellular components and mechanisms that regulate the onset of diet-induced insulin resistance are not clearly defined. Methodology and Principal Findings:We initially observed osteopontin (OPN) mRNA over-expression in adipose tissue of obese, insulin resistant humans and rats which was normalized by thiazolidinedione (TZD) treatment in both species. OPN regulates inflammation and is implicated in pathogenic maladies resulting from chronic obesity. Thus, we tested the hypothesis that OPN is involved in the early development of insulin resistance using a 2-4 week high fat diet (HFD) model. OPN KO mice fed HFD for 2 weeks were completely protected from the severe skeletal muscle, liver and adipose tissue insulin resistance that developed in wild type (WT) controls, as determined by hyperinsulinemic euglycemic clamp and acute insulin-stimulation studies. Although two-week HFD did not alter body weight or plasma free fatty acids and cytokines in either strain, HFD-induced hyperleptinemia, increased adipose tissue inflammation (macrophages and cytokines), and adipocyte hypertrophy were significant in WT mice and blunted or absent in OPN KO mice. Adipose tissue OPN protein isoform expression was significantly altered in 2- and 4-week HFD-fed WT mice but total OPN protein was unchanged. OPN KO bone marrow stromal cells were more osteogenic and less adipogenic than WT cells in vitro. Interestingly, the two differentiation pathways were inversely affected by HFD in WT cells in vitro. Conclusions:The OPN KO phenotypes we report reflect protection from insulin resistance that is associated with changes in adipocyte biology and adipose tissue inflammatory status. OPN is a key component in the development of HFD-induced insulin resistance.
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U2 - 10.1371/journal.pone.0013959
DO - 10.1371/journal.pone.0013959
M3 - Article
C2 - 21103061
AN - SCOPUS:78649759561
SN - 1932-6203
VL - 5
JO - PloS one
JF - PloS one
IS - 11
M1 - e13959
ER -