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SOCS2 deletion protects against hepatic steatosis but worsens insulin resistance in high‐fat‐diet‐fed mice
Author(s) -
Zadjali Fahad,
SantanaFarre Ruyman,
Vesterlund Mattias,
Carow Berit,
MireckiGarrido Mercedes,
HernandezHernandez Irene,
FlodströmTullberg Malin,
Parini Paolo,
Rottenberg Martin,
Norstedt Gunnar,
FernandezPerez Leandro,
FloresMorales Amilcar
Publication year - 2012
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fj.12-205583
Subject(s) - socs2 , medicine , endocrinology , steatosis , insulin resistance , fatty liver , biology , chemistry , insulin , disease , cancer , suppressor
Hepatic steatosis is a prominent feature in patients with growth hormone (GH) deficiency. The ubiquitin ligase SOCS2 attenuates hepatic GH signaling by inhibiting the Janus kinase 2 (JAK2)‐signal transducer and activator of transcription 5b (STAT5b) axis. Here, we investigated the role of SOCS2 in the development of diet‐induced hepatic steatosis and insulin resistance. SOCS2‐knockout (SOCS2 −/− ) mice and wild‐type littermates were fed for 4 mo with control or high‐fat diet, followed by assessment of insulin sensitivity, hepatic lipid content, and expression of inflammatory cytokines. SOCS2 −/− mice exhibited increased hepatic TG secretion by 77.6% ( P < 0.001) as compared with wild‐type control mice and were protected from high‐fat‐diet (HFD)‐induced hepatic steatosis, showing 49.3% ( P <0.01) reduction in liver TG levels compared to HFD‐fed wild‐type littermates. In contrast, we found that HFD‐triggered attenuation of systemic insulin sensitivity was more marked in SOCS2 −/− mice. Livers from the HFD‐fed SOCS2 −/− mice showed increased NF‐κB activity as well as elevated expression of genes for the inflammatory cytokines IFN‐γ and IL‐6. An inhibitory role of SOCS2 on Toll‐like receptor 4 signaling was demonstrated in macrophages obtained from the SOCS2 −/− and wild‐type mice. This study identified SOCS2 as an important regulator of hepatic homeostasis under conditions of high‐fat dietary stress.—Zadjali, F., Santana‐Farre, R., Vesterlund, M., Carow, B., Mirecki‐Garrido, M., Hernandez‐Hernandez, I., Flodström‐Tullberg, M., Parini, P., Rottenberg, M., Norstedt, G., Fernandez‐Perez, L., Flores‐Morales, A. SOCS2 deletion protects against hepatic steatosis but worsens insulin resistance in high‐fat‐diet‐fed mice. FASEB J. 26, 3282–3291 (2012). www.fasebj.org