title: Mice Lacking Free Fatty Acid Receptor 1 (GPR40/FFAR1) are Protected Against Conjugated Linoleic Acid-Induced Fatty Liver but Develop Inflammation and Insulin Resistance in the Brain.
abstract: OBJECTIVE
  Conjugated linoleic acids (CLAs) affect body fat distribution, induce insulin resistance and stimulate insulin secretion. The latter effect is mediated through the free fatty acid receptor-1 (GPR40/FFAR1). This study examines whether GPR40/FFAR1 interacts with tissue specific metabolic changes induced by CLAs.
  
  
  RESULTS
  After chronic application of CLAs C57BL/6J wild type (WT) and GPR40/FFAR1 (Ffar1(-/-)) knockout mice developed insulin resistance. Although CLAs accumulated in liver up to 46-fold genotype-independently, hepatic triglycerides augmented only in WT mice. This triglyceride deposition was not associated with increased inflammation. In contrast, in brain of CLA fed Ffar1(-/-) mice mRNA levels of TNF-α were 2-fold higher than in brain of WT mice although CLAs accumulated genotype-independently in brain up to 4-fold. Concomitantly, Ffar1(-/-) mice did not respond to intracerebroventricular (i.c.v.) insulin injection with an increase in cortical activity while WT mice reacted as assessed by radiotelemetric electrocorticography (ECoG) measurements. In vitro incubation of primary murine astrocytes confirmed that CLAs stimulate neuronal inflammation independent of GPR40/FFAR1.
  
  
  CONCLUSIONS
  This study discloses that GPR40/FFAR1 indirectly modulates organ-specific effects of CLAs: the expression of functional GPR40/FFAR1 counteracts CLA-induced inflammation and insulin resistance in the brain, but favors the development of fatty liver.
authors.affiliation: Department of Internal Medicine, Division of Endocrinology, Diabetology, Vascular Disease, Nephrology and Clinical Chemistry, Member of the German Center for Diabetes Research (DZD), University of Tuebingen, Germany.
authors.forename: Tina
authors.initials: T
authors.lastname: Sartorius
authors.forename: Andrea
authors.initials: A
authors.lastname: Drescher
authors.forename: Madhura
authors.initials: M
authors.lastname: Panse
authors.forename: Petr
authors.initials: P
authors.lastname: Lastovicka
authors.forename: Andreas
authors.initials: A
authors.lastname: Peter
authors.forename: Cora
authors.initials: C
authors.lastname: Weigert
authors.forename: Evi
authors.initials: E
authors.lastname: Kostenis
authors.forename: Susanne
authors.initials: S
authors.lastname: Ullrich
authors.forename: Hans-Ulrich
authors.initials: HU
authors.lastname: Häring
mesh_terms: D000818:Animals; D001921:Brain / Q000378:metabolism*; D005234:Fatty Liver / Q000378:metabolism*; D005260:Female; D007249:Inflammation / Q000378:metabolism*; D007328:Insulin / Q000378:metabolism; D007333:Insulin Resistance / Q000502:physiology*; D044243:Linoleic Acids, Conjugated / Q000494:pharmacology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D043562:Receptors, G-Protein-Coupled / Q000378:metabolism*; D014280:Triglycerides / Q000378:metabolism
chemical_list: C473036:Ffar1 protein, mouse; D007328:Insulin; D044243:Linoleic Acids, Conjugated; D043562:Receptors, G-Protein-Coupled; D014280:Triglycerides