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Hepatic steatosis is a prominent feature in growth
hormone (GH)-deficient patients and hepatic GH receptor knockout mice. SOCS2, a
GH-induced protein, attenuates hepatic GH signalling by inhibiting the JAK2-STAT5b
axis. Here we investigated the role of SOCS2 in the development of diet-induced
hepatic steatosis and insulin resistance. We demonstrated that SOCS2 knockout
(SOCS2−/−) mice are protected from high-fat diet (HFD)-induced
hepatic steatosis. This phenotype is explained by the enhanced expression of
genes involved in triglyceride (TG) synthesis coupled with increased hepatic TG
secretion. In contrast, we found that HFD-triggered attenuation of systemic and
hepatic insulin sensitivity was more marked in SOCS2−/− mice. Livers
from the HFD-fed SOCS2−/− mice showed increased NFkB activity as well as
elevated expression of genes for the inflammatory cytokines INF-g and IL-6. The latter effects were also observed in white
adipose tissues. An inhibitory role of SOCS2 on Toll-like receptor 4 signalling
was demonstrated in bone marrow-derived macrophages obtained from the SOCS2−/−
and wild-type mice. In addition to an exacerbated inflammatory response, the
HFD-fed SOCS2−/− mice showed increased obesity and TG deposition in
muscle tissues, which further contributed to metabolic deterioration in these mice.
Conclusions: To our best knowledge, we
are the first to provide evidence that SOCS2 plays an important role in regulating the response to
high-fat dietary stress through actions that control hepatic steatosis and
inflammation.
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