title: Depletion of suppressor of cytokine signaling-1a causes hepatic steatosis and insulin resistance in zebrafish.
abstract: Suppressor of cytokine signaling-1a (SOCS1a) is a member of the suppressor of cytokine signaling family, a group of related molecules that mediate the negative regulation of the JAK-STAT pathway. Here, we depleted SOCS1a using the transcription activator-like (TAL) effector nuclease (TALEN) technique to understand its physiological roles in zebrafish. Although elevated levels of JAK-STAT5 activation and erythropoiesis have been observed in socs1a-deficient zebrafish, these animals exhibited normal growth during the early stages. Socs1a-deficient zebrafish began to grow slowly with certain mortalities after 20 days postfertilization (dpf), whereas the heterozygous socs1a-deficient zebrafish exhibited enhanced somatic growth. Decreased adiposity, hepatic steatosis, and insulin resistance were observed in our socs1a-deficient adult zebrafish, which is similar to the lipodystrophy phenotypes observed in mammals. Comparative transcriptomic analyses revealed elevated levels of gluconeogenesis, lipolysis, and hypoxia-inducible response and decreased activities of lipogenesis and glycolysis in the hepatocytes of socs1a-deflicient adult zebrafish. Evident mitochondrial dysfunction has also been observed in hepatocytes from socs1a-deficient zebrafish. Taken together, our results suggest that the negative regulatory roles of SOCS1a on JAK-STAT5 signaling may be involved in the suppression of the erythropoiesis and growth hormone activities, which was also reflected in the enhanced somatic growth performance observed in the heterozygous socs1a-deficient fish. The differences in the effects caused by SOCS1a depletion on insulin sensitivity, lipid metabolism, and inflammatory responses between zebrafish and mammalian models observed here may reflect differences between the functional mechanisms of SOCS members in terrestrial mammals and aquatic teleosts.
authors.affiliation: Key Laboratory of Molecular Biophysics, Ministry of Education, College of Life Science and Technology, Center for Human Genome Research, Huazhong University of Science and Technology, Wuhan, Hubei, China; Key Laboratory of Aquatic Biodiversity and Conservation of the Chinese Academy of Sciences, Institute of Hydrobiology, Chinese Academy of Sciences, Wuhan, Hubei, China; and.
authors.forename: Ziru
authors.initials: Z
authors.lastname: Dai
authors.affiliation: State Key Laboratory of Freshwater Ecology and Biotechnology, Wuhan, Hubei, China.
authors.forename: Hualin
authors.initials: H
authors.lastname: Wang
authors.affiliation: Key Laboratory of Aquatic Biodiversity and Conservation of the Chinese Academy of Sciences, Institute of Hydrobiology, Chinese Academy of Sciences, Wuhan, Hubei, China; and.
authors.forename: Xia
authors.initials: X
authors.lastname: Jin
authors.affiliation: State Key Laboratory of Freshwater Ecology and Biotechnology, Wuhan, Hubei, China.
authors.forename: Houpeng
authors.initials: H
authors.lastname: Wang
authors.affiliation: Key Laboratory of Aquatic Biodiversity and Conservation of the Chinese Academy of Sciences, Institute of Hydrobiology, Chinese Academy of Sciences, Wuhan, Hubei, China; and.
authors.forename: Jiangyan
authors.initials: J
authors.lastname: He
authors.affiliation: Key Laboratory of Molecular Biophysics, Ministry of Education, College of Life Science and Technology, Center for Human Genome Research, Huazhong University of Science and Technology, Wuhan, Hubei, China;
authors.forename: Mugen
authors.initials: M
authors.lastname: Liu
authors.affiliation: Key Laboratory of Molecular Biophysics, Ministry of Education, College of Life Science and Technology, Center for Human Genome Research, Huazhong University of Science and Technology, Wuhan, Hubei, China; Key Laboratory of Aquatic Biodiversity and Conservation of the Chinese Academy of Sciences, Institute of Hydrobiology, Chinese Academy of Sciences, Wuhan, Hubei, China; and.
authors.forename: Zhan
authors.initials: Z
authors.lastname: Yin
authors.affiliation: State Key Laboratory of Freshwater Ecology and Biotechnology, Wuhan, Hubei, China.
authors.forename: Yonghua
authors.initials: Y
authors.lastname: Sun
authors.affiliation: Key Laboratory of Aquatic Biodiversity and Conservation of the Chinese Academy of Sciences, Institute of Hydrobiology, Chinese Academy of Sciences, Wuhan, Hubei, China; and louqiyong@ihb.ac.cn.
authors.forename: Qiyong
authors.initials: Q
authors.lastname: Lou
mesh_terms: D000818:Animals; D030801:Animals, Genetically Modified; D001483:Base Sequence; D004625:Embryo, Nonmammalian; D005234:Fatty Liver / Q000235:genetics* / Q000378:metabolism; D017353:Gene Deletion; D013006:Growth Hormone / Q000378:metabolism; D007333:Insulin Resistance / Q000235:genetics*; D053612:Janus Kinases / Q000378:metabolism; D008969:Molecular Sequence Data; D050791:STAT Transcription Factors / Q000378:metabolism; D015398:Signal Transduction / Q000235:genetics; D000071222:Suppressor of Cytokine Signaling 1 Protein; D050826:Suppressor of Cytokine Signaling Proteins / Q000235:genetics*; D015027:Zebrafish / Q000196:embryology / Q000235:genetics / Q000378:metabolism; D029961:Zebrafish Proteins / Q000235:genetics*
chemical_list: D050791:STAT Transcription Factors; D000071222:Suppressor of Cytokine Signaling 1 Protein; D050826:Suppressor of Cytokine Signaling Proteins; D029961:Zebrafish Proteins; C540939:socs1a protein, zebrafish; D013006:Growth Hormone; D053612:Janus Kinases
keywords: gene targeting; hepatic steatosis; insulin resistance; suppressor of cytokine signaling-1a; zebrafish