title: Implication of the Tpl2 kinase in inflammatory changes and insulin resistance induced by the interaction between adipocytes and macrophages.
abstract: Adipose tissue inflammation is associated with the development of insulin resistance. In obese adipose tissue, lipopolysaccharides (LPSs) and saturated fatty acids trigger inflammatory factors that mediate a paracrine loop between adipocytes and macrophages. However, the inflammatory signaling proteins underlying this cross talk remain to be identified. The mitogen-activated protein kinase kinase kinase tumor progression locus 2 (Tpl2) is activated by inflammatory stimuli, including LPS, and its expression is up-regulated in obese adipose tissue, but its role in the interaction between adipocytes and macrophages remains ill-defined. To assess the implication of Tpl2 in the cross talk between these 2 cell types, we used coculture system and conditioned medium (CM) from macrophages. Pharmacological inhibition of Tpl2 in the coculture markedly reduced lipolysis and cytokine production and prevented the decrease in adipocyte insulin signaling. Tpl2 knockdown in cocultured adipocytes reduced lipolysis but had a weak effect on cytokine production and did not prevent the alteration of insulin signaling. By contrast, Tpl2 silencing in cocultured macrophages resulted in a marked inhibition of cytokine production and prevented the alteration of adipocyte insulin signaling. Further, when Tpl2 was inhibited in LPS-activated macrophages, the produced CM did not alter adipocyte insulin signaling and did not induce an inflammatory response in adipocytes. By contrast, Tpl2 silencing in adipocytes did not prevent the deleterious effects of a CM from LPS-activated macrophages. Together, these data establish that Tpl2, mainly in macrophages, is involved in the cross talk between adipocytes and macrophages that promotes inflammatory changes and alteration of insulin signaling in adipocytes.
authors.affiliation: INSERM Unité 1065/Centre Méditerranéen de Médecine Moléculaire (C3M) and Université de Nice Sophia Antipolis (F.C., F.B., J.J., K.D, M.C., J.-F.T.), F-06204, Nice, France.
authors.forename: Franck
authors.initials: F
authors.lastname: Ceppo
authors.forename: Flavien
authors.initials: F
authors.lastname: Berthou
authors.forename: Jennifer
authors.initials: J
authors.lastname: Jager
authors.forename: Karine
authors.initials: K
authors.lastname: Dumas
authors.forename: Mireille
authors.initials: M
authors.lastname: Cormont
authors.forename: Jean-François
authors.initials: JF
authors.lastname: Tanti
mesh_terms: D041721:3T3-L1 Cells; D017667:Adipocytes / Q000166:cytology*; D000273:Adipose Tissue / Q000378:metabolism; D000818:Animals; D001854:Bone Marrow Cells / Q000166:cytology; D002460:Cell Line; D018920:Coculture Techniques; D017077:Culture Media, Conditioned / Q000737:chemistry; D016207:Cytokines / Q000378:metabolism; D020868:Gene Silencing; D007249:Inflammation; D007328:Insulin / Q000378:metabolism; D007333:Insulin Resistance; D008066:Lipolysis; D008070:Lipopolysaccharides / Q000737:chemistry; D020930:MAP Kinase Kinase Kinases / Q000378:metabolism*; D008264:Macrophages / Q000166:cytology* / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009765:Obesity / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D015398:Signal Transduction
chemical_list: D017077:Culture Media, Conditioned; D016207:Cytokines; D007328:Insulin; D008070:Lipopolysaccharides; D011518:Proto-Oncogene Proteins; D020930:MAP Kinase Kinase Kinases; C489843:Map3k8 protein, mouse