TY - JOUR
T1 - ITCH deficiency protects from diet-induced obesity
AU - Marino, Arianna
AU - Menghini, Rossella
AU - Fabrizi, Marta
AU - Casagrande, Viviana
AU - Mavilio, Maria
AU - Stoehr, Robert
AU - Candi, Eleonora
AU - Mauriello, Alessandro
AU - Moreno-Navarrete, Jose M.
AU - Gómez-Serrano, María
AU - Peral, Belén
AU - Melino, Gerry
AU - Lauro, Renato
AU - Fernandez Real, Jose M.
AU - Federici, Massimo
PY - 2014/2
Y1 - 2014/2
N2 - 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 obesityrelated inflammation and insulin resistance, we compared wild-type and Itch2/2 mice in a context of diet-induced obesity (high-fat diet [HFD]). When subjected to HFD, Itch2/2 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 Itch2/2 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.
AB - 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 obesityrelated inflammation and insulin resistance, we compared wild-type and Itch2/2 mice in a context of diet-induced obesity (high-fat diet [HFD]). When subjected to HFD, Itch2/2 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 Itch2/2 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.
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U2 - 10.2337/db13-0802
DO - 10.2337/db13-0802
M3 - Article
C2 - 24170694
AN - SCOPUS:84893046564
VL - 63
SP - 550
EP - 561
JO - Diabetes
JF - Diabetes
SN - 0012-1797
IS - 2
ER -