title: Deconstructing metabolic inflammation using cellular systems.
abstract: Over the past years, we have embarked in a systematic analysis of the effect of obesity or fatty acids on circulating monocytes, microvascular endothelial cells, macrophages, and skeletal muscle cells. With the use of cell culture strategies, we have deconstructed complex physiological systems and then reconstructed "partial equations" to better understand cell-to-cell communication. Through these approaches, we identified that in high saturated fat environments, cell-autonomous proinflammatory pathways are activated in monocytes and endothelial cells, promoting monocyte adhesion and transmigration. We think of this as a paradigm of the conditions promoting immune cell infiltration into tissues during obesity. In concert, it is possible that muscle and adipose tissue secrete immune cell chemoattractants, and indeed, our tissue culture reconstructions reveal that myotubes treated with the saturated fatty acid palmitate, but not the unsaturated fatty acid palmitoleate, release nucleotides that attract monocytes and other compounds that promote proinflammatory classically activated "(M1)-like" polarization in macrophages. In addition, palmitate directly triggers an M1-like macrophage phenotype, and secretions from these activated macrophages confer insulin resistance to target muscle cells. Together, these studies suggest that in pathophysiological conditions of excess fat, the muscle, endothelial and immune cells engage in a synergistic crosstalk that exacerbates tissue inflammation, leukocyte infiltration, polarization, and consequent insulin resistance.
authors.affiliation: Cell Biology Program, The Hospital for Sick Children, Toronto, Ontario, Canada.|Department of Physiology, University of Toronto, Ontario, Canada; and.
authors.forename: Kenny L
authors.initials: KL
authors.lastname: Chan
authors.affiliation: Cell Biology Program, The Hospital for Sick Children, Toronto, Ontario, Canada.|Department of Biochemistry, University of Toronto, Ontario Canada.
authors.forename: Parastoo
authors.initials: P
authors.lastname: Boroumand
authors.affiliation: Cell Biology Program, The Hospital for Sick Children, Toronto, Ontario, Canada.
authors.forename: Marciane
authors.initials: M
authors.lastname: Milanski
authors.affiliation: Cell Biology Program, The Hospital for Sick Children, Toronto, Ontario, Canada.
authors.forename: Nicolas J
authors.initials: NJ
authors.lastname: Pillon
authors.affiliation: Cell Biology Program, The Hospital for Sick Children, Toronto, Ontario, Canada.
authors.forename: Philip J
authors.initials: PJ
authors.lastname: Bilan
authors.affiliation: Cell Biology Program, The Hospital for Sick Children, Toronto, Ontario, Canada; amira@sickkids.ca.|Department of Physiology, University of Toronto, Ontario, Canada; and.|Department of Biochemistry, University of Toronto, Ontario Canada.
authors.forename: Amira
authors.initials: A
authors.lastname: Klip
mesh_terms: D000818:Animals; D002450:Cell Communication / Q000502:physiology*; D002478:Cells, Cultured; D042783:Endothelial Cells / Q000166:cytology / Q000378:metabolism; D007249:Inflammation / Q000378:metabolism*; D007333:Insulin Resistance / Q000502:physiology*; D008264:Macrophages / Q000166:cytology / Q000378:metabolism; D018482:Muscle, Skeletal / Q000166:cytology / Q000378:metabolism*; D009765:Obesity / Q000378:metabolism*
keywords: cell-to-cell communication; endothelial; immune cell communication; insulin resistance; metabolic inflammation; muscle