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

Published on Mar 1, 2020in Diabetes7.199
· DOI :10.2337/DB19-0701
Shahram Hedjazifar10
Estimated H-index: 10
(University of Gothenburg),
Roxana Khatib Shahidi1
Estimated H-index: 1
(University of Gothenburg)
+ 5 AuthorsUlf Smith84
Estimated H-index: 84
(University of Gothenburg)
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 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-IR), and the presence of non-alcoholic fatty liver disease (NAFLD) and non-alcoholic 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 potential therapeutic target in obesity and its complications T2D and NAFLD/NASH.
  • References (29)
  • Citations (3)
📖 Papers frequently viewed together
9 Authors (Jan Mauer, ..., Jens C. Brüning)
65 Citations
1 Citations
20162.78PLOS ONE
14 Authors (Yea Eun Kang, ..., Hyun-Jin Kim)
84 Citations
78% of Scinapse members use related papers. After signing in, all features are FREE.
#1Jenny M. Hoffmann (University of Gothenburg)H-Index: 6
#2John R. Grünberg (University of Gothenburg)H-Index: 2
Last. Ulf Smith (University of Gothenburg)H-Index: 84
view all 12 authors...
Abstract Objective Bone morphogenetic protein 4 (BMP4) adeno-associated viral vectors of serotype 8 (AAV8) gene therapy targeting the liver prevents the development of obesity in initially lean mice by browning the large subcutaneous white adipose tissue (WAT) and enhancing energy expenditure. Here, we examine whether this approach could also reduce established obesity. Methods Dietary-induced obese C57BL6/N mice received AAV8 BMP4 gene therapy at 17–18 weeks of age. They were kept on a high-fat...
1 CitationsSource
#1Louise R. Dutton ('QUB': Queen's University Belfast)
#2Christina L. O'Neill ('QUB': Queen's University Belfast)H-Index: 15
Last. Derek P. Brazil ('QUB': Queen's University Belfast)H-Index: 31
view all 4 authors...
2 CitationsSource
#1Ann Hammarstedt (University of Gothenburg)H-Index: 26
#2Silvia Gogg (University of Gothenburg)H-Index: 10
Last. Ulf Smith (University of Gothenburg)H-Index: 84
view all 5 authors...
The subcutaneous adipose tissue (SAT) is the largest and best storage site for excess lipids. However, it has a limited ability to expand by recruiting and/or differentiating available precursor ce...
15 CitationsSource
#1Jenny M. Hoffmann (University of Gothenburg)H-Index: 6
#2John R. Grünberg (University of Cambridge)H-Index: 2
Last. Ulf Smith (University of Gothenburg)H-Index: 84
view all 10 authors...
Summary We examined the effect of Bone Morphogenetic Protein 4 (BMP4) on energy expenditure in adult mature mice by targeting the liver with adeno-associated viral (AAV) BMP4 vectors to increase circulating levels. We verified the direct effect of BMP4 in inducing a brown oxidative phenotype in differentiating preadipocytes in vitro. AAV-BMP4-treated mice display marked browning of subcutaneous adipocytes, with increased mitochondria and Uncoupling Protein 1 (UCP1). These mice are protected from...
14 CitationsSource
#1Mansi Verma (Meerut Institute of Engineering and Technology)H-Index: 1
#2Shyam Ji Gupta (IICB: Indian Institute of Chemical Biology)H-Index: 3
Last. Vipin Kumar Garg (Meerut Institute of Engineering and Technology)H-Index: 14
view all 4 authors...
Abstract Diabetes mellitus and obesity are one of the most common health issues spread throughout world and raised the medical attention to find the new effective agents to treat these disease state. Occurrence of the drug resistance to the insulin and leptin receptor is also challenging major issues. The molecules that can overcome this resistance problem could be effective for the treatment of both type II diabetes and obesity. Protein Tyrosine Phosphatase (PTP) has emerged as new promising ta...
19 CitationsSource
#1Luca A. Lotta (University of Cambridge)H-Index: 14
#2Pawan Gulati (University of Cambridge)H-Index: 10
Last. Rob Scott (University of Cambridge)H-Index: 89
view all 30 authors...
Luca Lotta, Robert Scott, Stephen O’Rahilly, Claudia Langenberg, David Savage, Nicholas Wareham, Ines Barroso and colleagues identify 53 genomic regions associated with insulin resistance phenotypes. Their findings suggest that limited storage capacity of peripheral adipose tissue is an important etiological component in insulin-resistant cardiometabolic disease and highlight genes and mechanisms underpinning this link.
150 CitationsSource
#1Ulf Smith (University of Gothenburg)H-Index: 84
#2Barbara B. Kahn (BIDMC: Beth Israel Deaconess Medical Center)H-Index: 111
Obesity, the major cause of the current global epidemic of type 2 diabetes (T2D), induces insulin resistance in peripheral insulin target tissues. Several mechanisms have been identified related to cross-talk between adipose tissue, skeletal muscle and liver. These mechanisms involve both increased free fatty acid release and altered secretion of adipokines from adipose tissue. A major determinant of metabolic health is the ability of subcutaneous adipose tissue (SAT) to store excess fat rather ...
73 CitationsSource
#1Salvatore Modica (EPFL: École Polytechnique Fédérale de Lausanne)H-Index: 14
#2Leon G. Straub (EPFL: École Polytechnique Fédérale de Lausanne)H-Index: 6
Last. Christian Wolfrum (EPFL: École Polytechnique Fédérale de Lausanne)H-Index: 32
view all 12 authors...
Summary While Bmp4 has a well-established role in the commitment of mesenchymal stem cells into the adipogenic lineage, its role in brown adipocyte formation and activity is not well defined. Here, we show that Bmp4 has a dual function in adipogenesis by inducing adipocyte commitment while inhibiting the acquisition of a brown phenotype during terminal differentiation. Selective brown adipose tissue overexpression of Bmp4 in mice induces a shift from a brown to a white-like adipocyte phenotype. ...
30 CitationsSource
#1Zobair M. YounossiH-Index: 84
#2Aaron B. KoenigH-Index: 7
Last. Mark WymerH-Index: 1
view all 6 authors...
Nonalcoholic fatty liver disease (NAFLD) is a major cause of liver disease worldwide. We estimated the global prevalence, incidence, progression, and outcomes of NAFLD and nonalcoholic steatohepatitis (NASH). PubMed/MEDLINE were searched from 1989 to 2015 for terms involving epidemiology and progression of NAFLD. Exclusions included selected groups (studies that exclusively enrolled morbidly obese or diabetics or pediatric) and no data on alcohol consumption or other liver diseases. Incidence of...
1,321 CitationsSource
#1Joel SchmitzH-Index: 3
#2Nadine EversH-Index: 4
Last. Jens C. BrüningH-Index: 65
view all 9 authors...
Objective Obesity represents a major risk factor for the development of type 2 diabetes mellitus, atherosclerosis and certain cancer entities. Treatment of obesity is hindered by the long-term maintenance of initially reduced body weight, and it remains unclear whether all pathologies associated with obesity are fully reversible even upon successfully maintained weight loss.
23 CitationsSource
Cited By3
#1Grace Todd ('QUB': Queen's University Belfast)
#2Zhichun Gao ('QUB': Queen's University Belfast)
Last. Peter ten Dijke (LUMC: Leiden University Medical Center)H-Index: 92
view all 5 authors...
Abstract Bone morphogenetic proteins (BMPs) are multifunctional secreted cytokines that act in a highly context-dependent manner. BMP action extends beyond the induction of cartilage and bone formation, to encompass pivotal roles in controlling tissue and organ homeostasis during development and adulthood. BMPs signal via plasma membrane type I and type II serine/threonine kinase receptors and intracellular SMAD transcriptional effectors. Exquisite temporospatial control of BMP/SMAD signalling a...
#1Odile Fabre (UCPH: University of Copenhagen)H-Index: 6
#2Lorenzo Giordani (University of Paris)H-Index: 11
Last. E. Andersen (UCPH: University of Copenhagen)H-Index: 3
view all 23 authors...
Exercise training improves skeletal muscle function, notably through tissue regeneration by muscle stem cells. Here, we hypothesized that exercise training reprograms the epigenome of muscle cell, which could account for better muscle function. Genome-wide DNA methylation of myotube cultures established from middle-aged obese men before and after endurance exercise training identified a differentially methylated region (DMR) located downstream of Gremlin 1 (GREM1), which was associated with incr...