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

Artikel i vetenskaplig tidskrift
Författare Shahram Hedjazifar
Roxana Khatib Shahidi
Ann Hammarstedt
Laurianne Bonnet
C. Church
Jeremie Boucher
M. Bluher
Ulf Smith
Publicerad i Diabetes
Volym 69
Nummer/häfte 3
Sidor 331-341
ISSN 0012-1797
Publiceringsår 2020
Publicerad vid Institutionen för biomedicin, avdelningen för medicinsk kemi och cellbiologi
Institutionen för medicin, avdelningen för molekylär och klinisk medicin
Sidor 331-341
Språk en
Länkar dx.doi.org/10.2337/db19-0701
Ämnesord bmp4 gene-therapy, adipose-tissue, nonalcoholic steatohepatitis, protein, inflammation, sensitivity, obesity, white, differentiation, adipogenesis, Endocrinology & Metabolism
Ämneskategorier Endokrinologi och diabetes

Sammanfattning

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.

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