title: Osteopontin is required for the early onset of high fat diet-induced insulin resistance in mice.
abstract: 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.
  
  
  RESULTS
  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.
authors.affiliation: Pfizer Inc., San Diego, California, United States of America.
authors.forename: Justin
authors.initials: J
authors.lastname: Chapman
authors.forename: Philip D
authors.initials: PD
authors.lastname: Miles
authors.forename: Jachelle M
authors.initials: JM
authors.lastname: Ofrecio
authors.forename: Jaap G
authors.initials: JG
authors.lastname: Neels
authors.forename: Joseph G
authors.initials: JG
authors.lastname: Yu
authors.forename: Jamie L
authors.initials: JL
authors.lastname: Resnik
authors.forename: Jason
authors.initials: J
authors.lastname: Wilkes
authors.forename: Saswata
authors.initials: S
authors.lastname: Talukdar
authors.forename: Divya
authors.initials: D
authors.lastname: Thapar
authors.forename: Kristen
authors.initials: K
authors.lastname: Johnson
authors.forename: Dorothy D
authors.initials: DD
authors.lastname: Sears
mesh_terms: D000273:Adipose Tissue / Q000187:drug effects / Q000378:metabolism; D000328:Adult; D000818:Animals; D001854:Bone Marrow Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D002454:Cell Differentiation / Q000187:drug effects; D016207:Cytokines / Q000378:metabolism; D004041:Dietary Fats / Q000008:administration & dosage*; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D007004:Hypoglycemic Agents / Q000494:pharmacology; D007328:Insulin / Q000494:pharmacology; D007333:Insulin Resistance; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008875:Middle Aged; D053495:Osteopontin / Q000235:genetics / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D051381:Rats; D011924:Rats, Zucker; D020133:Reverse Transcriptase Polymerase Chain Reaction; D017154:Stromal Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D045162:Thiazolidinediones / Q000494:pharmacology
chemical_list: D016207:Cytokines; D004041:Dietary Fats; D007004:Hypoglycemic Agents; D007328:Insulin; D045162:Thiazolidinediones; D053495:Osteopontin; C089946:2,4-thiazolidinedione; D051057:Proto-Oncogene Proteins c-akt