title: Obesity-induced lymphocyte hyperresponsiveness to chemokines: a new mechanism of Fatty liver inflammation in obese mice.
abstract: OBJECTIVE
  Hepatic lipid retention (steatosis) predisposes hepatitis. We investigated the mechanisms of lymphocyte homing to fatty liver and the role of lipopolysaccharide (LPS) in the onset of inflammation in ob/ob mice.
  
  
  METHODS
  We decreased intestinal bacterial compounds by oral antibiotic treatment to test the role of endogenous LPS in liver inflammation. Adoptive transfer of lymphocytes was used to study the respective contributions of steatosis and lymphocytes to liver inflammation. We tested lymphocyte response to chemokines by in vitro chemotaxis assays in ob/ob, their lean controls, and "non-obese ob/ob" mice, generated by controlling caloric intake to distinguish between the effects of obesity and leptin deficiency.
  
  
  RESULTS
  Antibiotic treatment decreased liver infiltration with CD4(+) T, CD8(+) T, natural killer (NK)T, B, and NK cells. Adoptive transfer of lymphocytes from ob/ob or control mice showed that (1) steatosis increased lymphocyte recruitment to the liver; (2) CD4(+) T, CD8(+) T, and B cells from ob/ob mice had a greater propensity to migrate specifically to the liver. This migration was enhanced by LPS. These results were also observed in a model of high-fat diet-induced obesity. CD4(+) T and B cells were hyperresponsive to CXCL12 and CXCL13, respectively. Weight normalization in "non-obese ob/ob" mice decreased liver inflammation, lymphocyte response to chemokines, and homing to the liver.
  
  
  CONCLUSIONS
  Our study provides the first evidence that liver inflammation in mice with genetic or diet-induced obesity results from both steatosis and lymphocyte hyperresponsiveness to chemokines expressed in the liver. These abnormalities are reversible with weight normalization.
authors.affiliation: INSERM, U764, Clamart, France; Univ Paris-Sud, Faculté de Médecine Paris-Sud, Institut Fédératif de Recherche 13, Clamart, France.
authors.forename: Amélie E
authors.initials: AE
authors.lastname: Bigorgne
authors.forename: Laurence
authors.initials: L
authors.lastname: Bouchet-Delbos
authors.forename: Sylvie
authors.initials: S
authors.lastname: Naveau
authors.forename: Ibrahim
authors.initials: I
authors.lastname: Dagher
authors.forename: Sophie
authors.initials: S
authors.lastname: Prévot
authors.forename: Ingrid
authors.initials: I
authors.lastname: Durand-Gasselin
authors.forename: Jacques
authors.initials: J
authors.lastname: Couderc
authors.forename: Philippe
authors.initials: P
authors.lastname: Valet
authors.forename: Dominique
authors.initials: D
authors.lastname: Emilie
authors.forename: Gabriel
authors.initials: G
authors.lastname: Perlemuter
mesh_terms: D000818:Animals; D001402:B-Lymphocytes / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D018925:Chemokines / Q000096:biosynthesis*; D002633:Chemotaxis; D004195:Disease Models, Animal; D005234:Fatty Liver / Q000209:etiology* / Q000378:metabolism / Q000473:pathology; D005434:Flow Cytometry; D006505:Hepatitis / Q000209:etiology* / Q000276:immunology / Q000473:pathology; D007150:Immunohistochemistry; D008099:Liver / Q000378:metabolism / Q000473:pathology; D018655:Lymphocyte Count; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009765:Obesity / Q000150:complications* / Q000276:immunology / Q000378:metabolism; D010641:Phenotype
chemical_list: D018925:Chemokines