title: Visceral adipose inflammation in obesity is associated with critical alterations in tregulatory cell numbers.
abstract: BACKGROUND
  The development of insulin resistance (IR) in mouse models of obesity and type 2 diabetes mellitus (DM) is characterized by progressive accumulation of inflammatory macrophages and subpopulations of T cells in the visceral adipose. Regulatory T cells (Tregs) may play a critical role in modulating tissue inflammation via their interactions with both adaptive and innate immune mechanisms. We hypothesized that an imbalance in Tregs is a critical determinant of adipose inflammation and investigated the role of Tregs in IR/obesity through coordinated studies in mice and humans.
  
  
  RESULTS
  Foxp3-green fluorescent protein (GFP) "knock-in" mice were randomized to a high-fat diet intervention for a duration of 12 weeks to induce DIO/IR. Morbidly obese humans without overt type 2 DM (n = 13) and lean controls (n = 7) were recruited prospectively for assessment of visceral adipose inflammation. DIO resulted in increased CD3(+)CD4(+), and CD3(+)CD8(+) cells in visceral adipose with a striking decrease in visceral adipose Tregs. Treg numbers in visceral adipose inversely correlated with CD11b(+)CD11c(+) adipose tissue macrophages (ATMs). Splenic Treg numbers were increased with up-regulation of homing receptors CXCR3 and CCR7 and marker of activation CD44. In-vitro differentiation assays showed an inhibition of Treg differentiation in response to conditioned media from inflammatory macrophages. Human visceral adipose in morbid obesity was characterized by an increase in CD11c(+) ATMs and a decrease in foxp3 expression.
  
  
  CONCLUSIONS
  Our experiments indicate that obesity in mice and humans results in adipose Treg depletion. These changes appear to occur via reduced local differentiation rather than impaired homing. Our findings implicate a role for Tregs as determinants of adipose inflammation.
authors.affiliation: Davis Heart and Lung Research Institute, The Ohio State University, Columbus, Ohio, United States of America. deiuliis.1@osu.edu
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Deiuliis
authors.forename: Zubair
authors.initials: Z
authors.lastname: Shah
authors.forename: Nilay
authors.initials: N
authors.lastname: Shah
authors.forename: Bradley
authors.initials: B
authors.lastname: Needleman
authors.forename: Dean
authors.initials: D
authors.lastname: Mikami
authors.forename: Vimal
authors.initials: V
authors.lastname: Narula
authors.forename: Kyle
authors.initials: K
authors.lastname: Perry
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Hazey
authors.forename: Thomas
authors.initials: T
authors.lastname: Kampfrath
authors.forename: Madhukar
authors.initials: M
authors.lastname: Kollengode
authors.forename: Qinghua
authors.initials: Q
authors.lastname: Sun
authors.forename: Abhay R
authors.initials: AR
authors.lastname: Satoskar
authors.forename: Carey
authors.initials: C
authors.lastname: Lumeng
authors.forename: Susan
authors.initials: S
authors.lastname: Moffatt-Bruce
authors.forename: Sanjay
authors.initials: S
authors.lastname: Rajagopalan
mesh_terms: D000818:Animals; D015703:Antigens, CD / Q000032:analysis; D016022:Case-Control Studies; D006801:Humans; D007249:Inflammation / Q000276:immunology / Q000473:pathology*; D007333:Insulin Resistance; D050152:Intra-Abdominal Fat / Q000473:pathology*; D018655:Lymphocyte Count; D051379:Mice; D009765:Obesity / Q000276:immunology / Q000473:pathology*; D050378:T-Lymphocytes, Regulatory / Q000473:pathology*
chemical_list: D015703:Antigens, CD