title: The receptor CD44 is associated with systemic insulin resistance and proinflammatory macrophages in human adipose tissue.
abstract: OBJECTIVE
  Proinflammatory immune cell infiltration in human adipose tissue is associated with the development of insulin resistance. We previously identified, via a gene expression-based genome-wide association study, the cell-surface immune cell receptor CD44 as a functionally important gene associated with type 2 diabetes. We then showed that, compared with controls, Cd44 knockout mice were protected from insulin resistance and adipose tissue inflammation during diet-induced obesity. We thus sought to test whether CD44 is associated with adipose tissue inflammation and insulin resistance in humans.
  
  
  METHODS
  Participants included 58 healthy, overweight/moderately obese white adults who met predetermined criteria for insulin resistance or insulin sensitivity based on the modified insulin-suppression test. Serum was collected from 43 participants to measure circulating concentrations of CD44. Subcutaneous adipose tissue was obtained from 17 participants to compare CD44, its ligand osteopontin (OPN, also known as SPP1) and pro-inflammatory gene expression. CD44 expression on adipose tissue macrophage (ATM) surfaces was determined by flow cytometry.
  
  
  RESULTS
  Serum CD44 concentrations were significantly increased in insulin-resistant (IR) participants. CD44 gene expression in subcutaneous adipose tissue was threefold higher in the IR subgroup. The expression of OPN, CD68 and IL6 was also significantly elevated in IR individuals. CD44 gene expression correlated significantly with CD68 and IL6 expression. CD44 density on ATMs was associated with proinflammatory M1 polarisation.
  
  
  CONCLUSIONS
  CD44 and OPN in human adipose tissue are associated with localised inflammation and systemic insulin resistance. This receptor-ligand pair is worthy of further research as a potentially modifiable contributor to human insulin resistance and type 2 diabetes.
authors.affiliation: Division of Endocrinology, Department of Medicine, Stanford University, 300 Pasteur Drive, Rm S025, Stanford, CA, 94305-5103, USA.
authors.forename: Li Fen
authors.initials: LF
authors.lastname: Liu
authors.forename: Keiichi
authors.initials: K
authors.lastname: Kodama
authors.forename: Ke
authors.initials: K
authors.lastname: Wei
authors.forename: Lorna L
authors.initials: LL
authors.lastname: Tolentino
authors.forename: Okmi
authors.initials: O
authors.lastname: Choi
authors.forename: Edgar G
authors.initials: EG
authors.lastname: Engleman
authors.forename: Atul J
authors.initials: AJ
authors.lastname: Butte
authors.forename: Tracey
authors.initials: T
authors.lastname: McLaughlin
mesh_terms: D000273:Adipose Tissue / Q000166:cytology / Q000378:metabolism*; D015331:Cohort Studies; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics / Q000378:metabolism; D004032:Diet; D005260:Female; D015870:Gene Expression / Q000235:genetics; D055106:Genome-Wide Association Study; D006801:Humans; D018960:Hyaluronan Receptors / Q000235:genetics / Q000378:metabolism*; D007004:Hypoglycemic Agents / Q000494:pharmacology; D007249:Inflammation / Q000378:metabolism*; D007328:Insulin / Q000494:pharmacology; D007333:Insulin Resistance / Q000235:genetics / Q000502:physiology*; D008264:Macrophages / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D053495:Osteopontin / Q000378:metabolism; D050177:Overweight / Q000235:genetics / Q000378:metabolism; D050151:Subcutaneous Fat / Q000378:metabolism
chemical_list: D018960:Hyaluronan Receptors; D007004:Hypoglycemic Agents; D007328:Insulin; D053495:Osteopontin