title: ITCH deficiency protects from diet-induced obesity.
abstract: Classically activated macrophages (M1) secrete proinflammatory cytokine and are predominant in obese adipose tissue. M2 macrophages, prevalent in lean adipose tissue, are induced by IL-13 and IL-4, mainly secreted by Th2 lymphocytes, and produce the anti-inflammatory cytokine IL-10. ITCH is a ubiquitously expressed E3 ubiquitin ligase involved in T-cell differentiation and in a wide range of inflammatory pathways. ITCH downregulation in lymphocytes causes aberrant Th2 differentiation. To investigate the role of Th2/M2 polarization in obesity-related inflammation and insulin resistance, we compared wild-type and Itch(-/-) mice in a context of diet-induced obesity (high-fat diet [HFD]). When subjected to HFD, Itch(-/-) mice did not show an increase in body weight or insulin resistance; calorimetric analysis suggested an accelerated metabolism. The molecular analysis of metabolically active tissue revealed increased levels of M2 markers and genes involved in fatty acid oxidation. Histological examination of livers from Itch(-/-) mice suggested that ITCH deficiency protects mice from obesity-related nonalcoholic fatty liver disease. We also found a negative correlation between ITCH and M2 marker expression in human adipose tissues. Taken together, our data indicate that ITCH E3 ubiquitin ligase deficiency protects from the metabolic disorder caused by obesity.
authors.affiliation: Department of Systems Medicine, University of Rome Tor Vergata, Rome, Italy.
authors.forename: Arianna
authors.initials: A
authors.lastname: Marino
authors.forename: Rossella
authors.initials: R
authors.lastname: Menghini
authors.forename: Marta
authors.initials: M
authors.lastname: Fabrizi
authors.forename: Viviana
authors.initials: V
authors.lastname: Casagrande
authors.forename: Maria
authors.initials: M
authors.lastname: Mavilio
authors.forename: Robert
authors.initials: R
authors.lastname: Stoehr
authors.forename: Eleonora
authors.initials: E
authors.lastname: Candi
authors.forename: Alessandro
authors.initials: A
authors.lastname: Mauriello
authors.forename: Jose M
authors.initials: JM
authors.lastname: Moreno-Navarrete
authors.forename: María
authors.initials: M
authors.lastname: Gómez-Serrano
authors.forename: Belén
authors.initials: B
authors.lastname: Peral
authors.forename: Gerry
authors.initials: G
authors.lastname: Melino
authors.forename: Renato
authors.initials: R
authors.lastname: Lauro
authors.forename: Jose M
authors.initials: JM
authors.lastname: Fernandez Real
authors.forename: Massimo
authors.initials: M
authors.lastname: Federici
mesh_terms: D002001:Adipose Tissue, Brown / Q000378:metabolism; D052436:Adipose Tissue, White / Q000502:physiology; D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D004041:Dietary Fats / Q000009:adverse effects*; D005786:Gene Expression Regulation / Q000502:physiology; D006801:Humans; D037181:Lectins, C-Type / Q000235:genetics / Q000378:metabolism; D008099:Liver / Q000378:metabolism; D017737:Macrophages, Peritoneal / Q000502:physiology; D000090323:Mannose Receptor; D037241:Mannose-Binding Lectins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D009765:Obesity / Q000209:etiology* / Q000378:metabolism; D011956:Receptors, Cell Surface / Q000235:genetics / Q000378:metabolism; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000378:metabolism*
chemical_list: D015415:Biomarkers; D004041:Dietary Fats; D037181:Lectins, C-Type; D000090323:Mannose Receptor; D037241:Mannose-Binding Lectins; D011956:Receptors, Cell Surface; C471637:Itch protein, mouse; D044767:Ubiquitin-Protein Ligases