title: Differential effect of saturated and unsaturated free fatty acids on the generation of monocyte adhesion and chemotactic factors by adipocytes: dissociation of adipocyte hypertrophy from inflammation.
abstract: OBJECTIVE
  Obesity is associated with monocyte-macrophage accumulation in adipose tissue. Previously, we showed that glucose-stimulated production by adipocytes of serum amyloid A (SAA), monocyte chemoattractant protein (MCP)-1, and hyaluronan (HA) facilitated monocyte accumulation. The current objective was to determine how the other major nutrient, free fatty acids (FFAs), affects these molecules and monocyte recruitment by adipocytes.
  
  
  METHODS
  Differentiated 3T3-L1, Simpson-Golabi-Behmel syndrome adipocytes, and mouse embryonic fibroblasts were exposed to various FFAs (250 micromol/l) in either 5 or 25 mmol/l (high) glucose for evaluation of SAA, MCP-1, and HA regulation in vitro.
  
  
  RESULTS
  Saturated fatty acids (SFAs) such as laurate, myristate, and palmitate increased cellular triglyceride accumulation, SAA, and MCP-1 expression; generated reactive oxygen species (ROS); and increased nuclear factor (NF) kappaB translocation in both 5 and 25 mmol/l glucose. Conversely, polyunsaturated fatty acids (PUFAs) such as arachidonate, eicosapentaenate, and docosahexaenate (DHA) decreased these events. Gene expression could be dissociated from triglyceride accumulation. Although excess glucose increased HA content, SFAs, oleate, and linoleate did not. Antioxidant treatment repressed glucose- and palmitate-stimulated ROS generation and NFkappaB translocation and decreased SAA and MCP-1 expression and monocyte chemotaxis. Silencing toll-like receptor-4 (TLR4) markedly reduced SAA and MCP-1 expression in response to palmitate but not glucose. DHA suppressed NFkappaB translocation stimulated by both excess glucose and palmitate via a peroxisome prolifterator-activated receptor (PPAR) gamma-dependent pathway.
  
  
  CONCLUSIONS
  Excess glucose and SFAs regulate chemotactic factor expression by a mechanism that involves ROS generation, NFkappaB, and PPARgamma, and which is repressed by PUFAs. Certain SFAs, but not excess glucose, trigger chemotactic factor expression via a TLR4-dependent pathway.
authors.affiliation: Department of Medicine, University of Washington, Seattle, Washington, USA.
authors.forename: Chang
authors.initials: C
authors.lastname: Yeop Han
authors.forename: Atil Y
authors.initials: AY
authors.lastname: Kargi
authors.forename: Mohamed
authors.initials: M
authors.lastname: Omer
authors.forename: Christina K
authors.initials: CK
authors.lastname: Chan
authors.forename: Martin
authors.initials: M
authors.lastname: Wabitsch
authors.forename: Kevin D
authors.initials: KD
authors.lastname: O'Brien
authors.forename: Thomas N
authors.initials: TN
authors.lastname: Wight
authors.forename: Alan
authors.initials: A
authors.lastname: Chait
mesh_terms: D016475:3T3 Cells / Q000166:cytology / Q000187:drug effects / Q000502:physiology; D017667:Adipocytes / Q000187:drug effects / Q000473:pathology / Q000502:physiology*; D000273:Adipose Tissue / Q000166:cytology / Q000187:drug effects / Q000502:physiology* / Q000503:physiopathology; D000818:Animals; D002448:Cell Adhesion / Q000502:physiology; D002454:Cell Differentiation; D002633:Chemotaxis / Q000502:physiology; D004622:Embryo, Mammalian / Q000166:cytology / Q000502:physiology; D005227:Fatty Acids / Q000494:pharmacology*; D005231:Fatty Acids, Unsaturated / Q000494:pharmacology*; D005434:Flow Cytometry; D020868:Gene Silencing; D006801:Humans; D006984:Hypertrophy; D007249:Inflammation / Q000503:physiopathology*; D051379:Mice; D008810:Mice, Inbred C57BL; D009000:Monocytes / Q000187:drug effects / Q000502:physiology*; D012333:RNA, Messenger / Q000235:genetics; D017382:Reactive Oxygen Species / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D000685:Serum Amyloid A Protein / Q000235:genetics; D051197:Toll-Like Receptor 4 / Q000235:genetics
chemical_list: D005227:Fatty Acids; D005231:Fatty Acids, Unsaturated; D012333:RNA, Messenger; D017382:Reactive Oxygen Species; C076498:Saa3 protein, mouse; D000685:Serum Amyloid A Protein; C493487:Tlr4 protein, mouse; D051197:Toll-Like Receptor 4