ITCH Deficiency Protects From Diet-Induced Obesity
- Arianna Marino1,
- Rossella Menghini1,
- Marta Fabrizi1,
- Viviana Casagrande1,
- Maria Mavilio1,
- Robert Stoehr1,
- Eleonora Candi2,
- Alessandro Mauriello3,
- Jose M. Moreno-Navarrete4,
- María Gómez-Serrano5,
- Belén Peral5,
- Gerry Melino2,6,
- Renato Lauro1,
- Jose M. Fernandez Real4 and
- Massimo Federici1,7⇑
- 1Department of Systems Medicine, University of Rome Tor Vergata, Rome, Italy
- 2Department of Experimental Medicine and Surgery, University of Rome Tor Vergata, Rome, Italy
- 3Department of Biopathology and Imaging, University of Rome Tor Vergata, Rome, Italy
- 4Department of Diabetes, Endocrinology and Nutrition, University Hospital of Girona “Dr. Josep Trueta,” Institut d’Investigacio Biomedica de Girona IdibGi, and CIBER Fisiopatologia de la Obesidad y Nutricion, Girona, Spain
- 5Instituto de Investigaciones Biomédicas, Alberto Sols, Consejo Superior de Investigaciones Científicas and Universidad Autónoma de Madrid, and CIBER Fisiopatología de la Obesidad y Nutrición Istituto De Salud Carlos III, Madrid, Spain
- 6Toxicology Unit, Medical Research Council, Leicester, U.K.
- 7Center for Atherosclerosis, University Hospital “Policlinico Tor Vergata,” Rome, Italy
- Corresponding author: Massimo Federici, .
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.
This article contains Supplementary Data online at http://diabetes.diabetesjournals.org/lookup/suppl/doi:10.2337/db13-0802/-/DC1.
- Received May 20, 2013.
- Accepted October 18, 2013.
- © 2014 by the American Diabetes Association.
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