TY - JOUR
T1 - SOCS2 deletion protects against hepatic steatosis but worsens insulin resistance in high-fat-diet-fed mice
AU - Zadjali, Fahad
AU - Santana-Farre, Ruyman
AU - Vesterlund, Mattias
AU - Carow, Berit
AU - Mirecki-Garrido, Mercedes
AU - Hernandez-Hernandez, Irene
AU - Flodström-Tullberg, Malin
AU - Parini, Paolo
AU - Rottenberg, Martin
AU - Norstedt, Gunnar
AU - Fernandez-Perez, Leandro
AU - Flores-Morales, Amilcar
PY - 2012/8
Y1 - 2012/8
N2 - 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.
AB - 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.
KW - Growth hormone
KW - Inflammation
KW - Suppressor of cytokine signaling
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U2 - 10.1096/fj.12-205583
DO - 10.1096/fj.12-205583
M3 - Article
C2 - 22562833
AN - SCOPUS:84864665833
SN - 0892-6638
VL - 26
SP - 3282
EP - 3291
JO - FASEB Journal
JF - FASEB Journal
IS - 8
ER -