title: SOCS2 deletion protects against hepatic steatosis but worsens insulin resistance in high-fat-diet-fed mice.
abstract: 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.
authors.affiliation: Novo Nordisk Foundation Center for Protein Research, Faculty of Health Sciences, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Fahad
authors.initials: F
authors.lastname: Zadjali
authors.forename: Ruyman
authors.initials: R
authors.lastname: Santana-Farre
authors.forename: Mattias
authors.initials: M
authors.lastname: Vesterlund
authors.forename: Berit
authors.initials: B
authors.lastname: Carow
authors.forename: Mercedes
authors.initials: M
authors.lastname: Mirecki-Garrido
authors.forename: Irene
authors.initials: I
authors.lastname: Hernandez-Hernandez
authors.forename: Malin
authors.initials: M
authors.lastname: Flodström-Tullberg
authors.forename: Paolo
authors.initials: P
authors.lastname: Parini
authors.forename: Martin
authors.initials: M
authors.lastname: Rottenberg
authors.forename: Gunnar
authors.initials: G
authors.lastname: Norstedt
authors.forename: Leandro
authors.initials: L
authors.lastname: Fernandez-Perez
authors.forename: Amilcar
authors.initials: A
authors.lastname: Flores-Morales
mesh_terms: D000818:Animals; D059305:Diet, High-Fat; D005234:Fatty Liver / Q000517:prevention & control*; D007333:Insulin Resistance / Q000502:physiology*; D007371:Interferon-gamma / Q000378:metabolism; D015850:Interleukin-6 / Q000378:metabolism; D050356:Lipid Metabolism; D008099:Liver / Q000378:metabolism; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D016328:NF-kappa B / Q000378:metabolism; D050826:Suppressor of Cytokine Signaling Proteins / Q000172:deficiency* / Q000502:physiology*; D051197:Toll-Like Receptor 4 / Q000037:antagonists & inhibitors; D014280:Triglycerides / Q000378:metabolism
chemical_list: D015850:Interleukin-6; D016328:NF-kappa B; C491409:Socs2 protein, mouse; D050826:Suppressor of Cytokine Signaling Proteins; C493487:Tlr4 protein, mouse; D051197:Toll-Like Receptor 4; D014280:Triglycerides; D007371:Interferon-gamma