title: Prolonged treatment of genetically obese mice with conjugated linoleic acid improves glucose tolerance and lowers plasma insulin concentration: possible involvement of PPAR activation.
abstract: BACKGROUND
  Studies in rodents and some studies in humans have shown that conjugated linoleic acid (CLA), especially its trans-10, cis-12 isomer, reduces body fat content. However, some but not all studies in mice and humans (though none in rats) have found that CLA promotes insulin resistance. The molecular mechanisms responsible for these effects are unclear, and there are conflicting reports on the effects of CLA on peroxisomal proliferator-activated receptor-gamma (PPARgamma) activation and expression. We have conducted three experiments with CLA in obese mice over three weeks, and one over eleven weeks. We have also investigated the effects of CLA isomers in PPARgamma and PPARalpha reporter gene assays.
  
  
  RESULTS
  Inclusion of CLA or CLA enriched with its trans-10, cis-12 isomer in the diet of female genetically obese (lepob/lepob) mice for up to eleven weeks reduced body weight gain and white fat pad weight. After two weeks, in contrast to beneficial effects obtained with the PPARgamma agonist rosiglitazone, CLA or CLA enriched with its trans-10, cis-12 isomer raised fasting blood glucose and plasma insulin concentrations, and exacerbated glucose tolerance. After 10 weeks, however, CLA had beneficial effects on glucose and insulin concentrations. At this time, CLA had no effect on the plasma TNFalpha concentration, but it markedly reduced the plasma adiponectin concentration. CLA and CLA enriched with either isomer raised the plasma triglyceride concentration during the first three weeks, but not subsequently. CLA enriched with its trans-10, cis-12 isomer, but not with its cis-9, trans-11 isomer, stimulated PPARgamma-mediated reporter gene activity; both isomers stimulated PPARalpha-mediated reporter gene activity.
  
  
  CONCLUSIONS
  CLA initially decreased but subsequently increased insulin sensitivity in lepob/lepob mice. Activation of both PPARgamma and PPARalpha may contribute to the improvement in insulin sensitivity. In the short term, however, another mechanism, activated primarily by trans-10, cis-12-CLA, which probably leads to reduced adipocyte number and consequently reduced plasma adiponectin concentration, may decrease insulin sensitivity.
authors.affiliation: Clore Laboratory for Life Sciences, University of Buckingham, Buckingham, MK18 1EG, UK. ed.wargent@buckingham.ac.uk
authors.forename: Ed
authors.initials: E
authors.lastname: Wargent
authors.forename: Matthew V
authors.initials: MV
authors.lastname: Sennitt
authors.forename: Claire
authors.initials: C
authors.lastname: Stocker
authors.forename: Andrew E
authors.initials: AE
authors.lastname: Mayes
authors.forename: Louise
authors.initials: L
authors.lastname: Brown
authors.forename: Jacqueline
authors.initials: J
authors.lastname: O'Dowd
authors.forename: Steven
authors.initials: S
authors.lastname: Wang
authors.forename: Alexandra W C
authors.initials: AW
authors.lastname: Einerhand
authors.forename: Inge
authors.initials: I
authors.lastname: Mohede
authors.forename: Jonathan R S
authors.initials: JR
authors.lastname: Arch
authors.forename: Michael A
authors.initials: MA
authors.lastname: Cawthorne
mesh_terms: D052242:Adiponectin / Q000097:blood; D000818:Animals; D001699:Biometry; D001786:Blood Glucose / Q000378:metabolism*; D001835:Body Weight / Q000187:drug effects; D002460:Cell Line; D002522:Chlorocebus aethiops; D005260:Female; D006801:Humans; D007328:Insulin / Q000097:blood*; D044243:Linoleic Acids, Conjugated / Q000493:pharmacokinetics / Q000494:pharmacology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008820:Mice, Obese / Q000033:anatomy & histology; D047492:Peroxisome Proliferator-Activated Receptors / Q000235:genetics / Q000378:metabolism*; D013997:Time Factors; D014280:Triglycerides / Q000097:blood; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: D052242:Adiponectin; C499919:Adipoq protein, mouse; D001786:Blood Glucose; D007328:Insulin; D044243:Linoleic Acids, Conjugated; D047492:Peroxisome Proliferator-Activated Receptors; D014280:Triglycerides; D014409:Tumor Necrosis Factor-alpha