The Novel Adipokine Gremlin 1 Antagonizes Insulin Action and Is Increased in Type 2 Diabetes and NAFLD/NASH

被引:55
作者
Hedjazifar, Shahram [1 ]
Khatib Shahidi, Roxana [1 ]
Hammarstedt, Ann [1 ]
Bonnet, Laurianne [1 ,2 ]
Church, Christopher [3 ]
Boucher, Jeremie [1 ,2 ,4 ]
Blueher, Matthias [5 ]
Smith, Ulf [1 ]
机构
[1] Univ Gothenburg, Sahlgrenska Acad, Dept Mol & Clin Med, Lundberg Lab Diabet Res, Gothenburg, Sweden
[2] Univ Gothenburg, Wallenberg Ctr Mol & Translat Med, Gothenburg, Sweden
[3] AstraZeneca, Biosci Metab Res & Early Dev, BioPharmaceut R&D, Cardiovasc Renal & Metab CVRM, Cambridge, England
[4] AstraZeneca, Biosci Metab Res & Early Dev, BioPharmaceut R&D, Cardiovasc Renal & Metab CVRM, Gothenburg, Sweden
[5] Univ Leipzig, Dept Med, Leipzig, Germany
基金
英国医学研究理事会;
关键词
BMP4; GENE-THERAPY; ADIPOSE-TISSUE; NONALCOHOLIC STEATOHEPATITIS; PROTEIN; INFLAMMATION; SENSITIVITY; OBESITY; WHITE; DIFFERENTIATION; ADIPOGENESIS;
D O I
10.2337/db19-0701
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
The BMP2/4 antagonist and novel adipokine Gremlin 1 is highly expressed in human adipose cells and increased in hypertrophic obesity. As a secreted antagonist, it inhibits the effect of BMP2/4 on adipose precursor cell commitment/differentiation. We examined mRNA levels of Gremlin 1 in key target tissues for insulin and also measured tissue and serum levels in several carefully phenotyped human cohorts. Gremlin 1 expression was high in adipose tissue, higher in visceral than in subcutaneous tissue, increased in obesity, and further increased in type 2 diabetes (T2D). A similar high expression was seen in liver biopsies, but expression was considerably lower in skeletal muscles. Serum levels were increased in obesity but most prominently in T2D. Transcriptional activation in both adipose tissue and liver as well as serum levels were strongly associated with markers of insulin resistance in vivo (euglycemic clamps and HOMA of insulin resistance), and the presence of nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH). We also found Gremlin 1 to antagonize insulin signaling and action in human primary adipocytes, skeletal muscle, and liver cells. Thus, Gremlin 1 is a novel secreted insulin antagonist and biomarker as well as a potential therapeutic target in obesity and its complications T2D and NAFLD/NASH.
引用
收藏
页码:331 / 341
页数:11
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