title: Altered endocannabinoid signalling after a high-fat diet in Apoe(-/-) mice: relevance to adipose tissue inflammation, hepatic steatosis and insulin resistance.
abstract: OBJECTIVE
  Apolipoprotein E (ApoE) deficiency is associated with reduced fat accumulation in white adipose tissue (WAT) and high liver triacylglycerol content. Elevated levels of endocannabinoids and cannabinoid receptor type 1 (CB(1)) receptors in the liver and in epididymal vs subcutaneous WAT are associated with fatty liver, visceral adipose tissue, inflammatory markers and insulin resistance.
  
  
  METHODS
  We investigated, in Apoe (-/-) and wild-type (WT) mice, the effect of a high-fat diet (HFD) on: (1) subcutaneous and epididymal WAT accumulation, liver triacylglycerols, phospholipid-esterified fatty acids, inflammatory markers in WAT and liver, and insulin resistance; and (2) endocannabinoid levels, and the gene expression levels of the Cb ( 1 ) receptor and endocannabinoid metabolic enzymes in liver and WAT.
  
  
  RESULTS
  After a 16 week HFD, Apoe (-/-) mice exhibited lower body weight, WAT accumulation and fasting leptin, glucose and insulin levels, and higher hepatic steatosis, than WT mice. Glucose clearance and insulin-mediated glucose disposal following the HFD were slower in WT than Apoe (-/-) mice, which exhibited higher levels of mRNA encoding inflammatory markers (tumour necrosis factor-α [TNF-α], monocyte chemoattractant protein-1 [MCP-1], cluster of differentiation 68 [CD68] and EGF-like module-containing mucin-like hormone receptor-like 1 [EMR1]) in the liver, but lower levels in epididymal WAT. HFD-induced elevation of endocannabinoid levels in the liver or epididymal WAT was higher or lower, respectively, in Apoe (-/-) mice, whereas HFD-induced decrease of subcutaneous WAT endocannabinoid and CB(1) receptor levels was significantly less marked. Alterations in endocannabinoid levels reflected changes in endocannabinoid catabolic enzymes in WAT, or the availability of phospholipid precursors in the liver.
  
  
  CONCLUSIONS
  Liver and adipose tissue endocannabinoid tone following an HFD is altered on Apoe deletion and strongly associated with inflammation, insulin resistance and hepatic steatosis, or lack thereof.
authors.affiliation: Department of Biochemistry and Molecular Cell Biology, University Medical Center Hamburg-Eppendorf, Martinistrasse 52, 20246 Hamburg, Germany.
authors.forename: A
authors.initials: A
authors.lastname: Bartelt
authors.forename: P
authors.initials: P
authors.lastname: Orlando
authors.forename: C
authors.initials: C
authors.lastname: Mele
authors.forename: A
authors.initials: A
authors.lastname: Ligresti
authors.forename: K
authors.initials: K
authors.lastname: Toedter
authors.forename: L
authors.initials: L
authors.lastname: Scheja
authors.forename: J
authors.initials: J
authors.lastname: Heeren
authors.forename: V
authors.initials: V
authors.lastname: Di Marzo
mesh_terms: D052436:Adipose Tissue, White / Q000276:immunology / Q000378:metabolism; D000818:Animals; D001057:Apolipoproteins E / Q000235:genetics / Q000502:physiology*; D063385:Cannabinoid Receptor Modulators / Q000378:metabolism*; D002478:Cells, Cultured; D004041:Dietary Fats / Q000009:adverse effects*; D063388:Endocannabinoids; D005234:Fatty Liver / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D005786:Gene Expression Regulation; D022781:Hepatocytes / Q000378:metabolism / Q000473:pathology; D018836:Inflammation Mediators / Q000378:metabolism; D007333:Insulin Resistance; D050356:Lipid Metabolism; D008099:Liver / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D015434:Panniculitis / Q000276:immunology / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D043884:Receptor, Cannabinoid, CB1 / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D050151:Subcutaneous Fat / Q000276:immunology / Q000378:metabolism
chemical_list: D001057:Apolipoproteins E; D063385:Cannabinoid Receptor Modulators; D004041:Dietary Fats; D063388:Endocannabinoids; D018836:Inflammation Mediators; D012333:RNA, Messenger; D043884:Receptor, Cannabinoid, CB1