SOCS2 deletion protects against hepatic steatosis but worsens insulin resistance in high-fat-diet-fed mice

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 - Animals

KW - Diet, High-Fat

KW - Fatty Liver

KW - Insulin Resistance

KW - Interferon-gamma

KW - Interleukin-6

KW - Lipid Metabolism

KW - Liver

KW - Male

KW - Mice

KW - Mice, Knockout

KW - NF-kappa B

KW - Suppressor of Cytokine Signaling Proteins

KW - Toll-Like Receptor 4

KW - Triglycerides

U2 - 10.1096/fj.12-205583

DO - 10.1096/fj.12-205583

M3 - Journal article

C2 - 22562833

SN - 0892-6638

VL - 26

SP - 3282

EP - 3291

JO - F A S E B Journal

JF - F A S E B Journal

IS - 8

ER -