Growth/differentiation factor 15 is a protein that in humans is encoded by the GDF15 gene. GDF15 was first identified as Macrophage inhibitory cytokine-1 or MIC-1. [5]
It is a protein belonging to the transforming growth factor beta superfamily. Under normal conditions, GDF15 is expressed in low concentrations in most organs and upregulated because of injury of organs such as liver, kidney, heart and lung. [6] [7] [8]
The function of GDF15 is not fully clear but it seems to have a role in regulating inflammatory pathways and to be involved in regulating apoptosis, angiogenesis, cell repair and cell growth, which are biological processes observed in cardiovascular and neoplastic disorders. [6] [9] [10] [11]
GDF15 has shown to be a strong prognostic protein in patients with different diseases such as heart diseases and cancer. [12] In cardiovascular tissues it is shown that GDF-15 concentrations increase in response to atherosclerosis, ischemia/reperfusion-injury and heart failure. [13] In patients with coronary artery disease (CAD), GDF-15 is shown to be associated with adverse outcome such as mortality, myocardial infarction, stroke and with bleeding. [14]
However, elevated GDF15 levels in diseases such as cancer and heart disease may be the result of inflammation caused by these diseases. Note that GDF15 is necessary for surviving both bacterial and viral infections, as well as sepsis. The protective effects of GDF15 were largely independent of pathogen control or the magnitude of inflammatory response, suggesting a role in disease tolerance. [15]
Metformin was shown to cause increased levels of GDF15. This increase mediates the effect of body weight loss by metformin. [16] Further study has shown weight loss is promoted by maintaining energy expenditure in addition to appetite suppression. [17]
Elevations in GDF15 reduce food intake and body mass in animal models through binding to glial cell-derived neurotrophic factor family receptor alpha-like (GFRAL) and the recruitment of the receptor tyrosine kinase RET in the hindbrain. [18]
In both mice and humans have shown that metformin and exercise increase circulating levels of GDF15. GDF15 might also exert anti-inflammatory effects through mechanisms that are not fully understood. These unique and distinct mechanisms for suppressing food intake and inflammation makes GDF15 an appealing candidate to treat many metabolic diseases, including obesity, type 2 diabetes mellitus, non-alcoholic fatty liver disease, cardiovascular disease and cancer cachexia. [18]
Treatment of rodents fed a high-fat diet with recombinant growth differentiating factor 15 (GDF15) reduces obesity and improves glycemic control through glial-cell-derived neurotrophic factor family receptor α-like (GFRAL)-dependent suppression of food intake. [19]
Fibroblast-specific loss of GDF15 expression in a model of 3D reconstructed human skin induced epidermal thinning, a hallmark of skin aging. GDF15 plays a so far undisclosed role in mitochondrial homeostasis to delay both the onset of cellular senescence and the appearance of age-related changes in a 3D human skin model. [20]
It has been also associated as a causal factor in hyperemesis gravidarum, a severe form of morning sickness. [21]
Transforming growth factor beta (TGF-β) is a multifunctional cytokine belonging to the transforming growth factor superfamily that includes three different mammalian isoforms and many other signaling proteins. TGFB proteins are produced by all white blood cell lineages.
Growth/differentiation factor 9 is a protein that in humans is encoded by the GDF9 gene.
Transforming growth factor beta 1 or TGF-β1 is a polypeptide member of the transforming growth factor beta superfamily of cytokines. It is a secreted protein that performs many cellular functions, including the control of cell growth, cell proliferation, cell differentiation, and apoptosis. In humans, TGF-β1 is encoded by the TGFB1 gene.
Activin A receptor, type I (ACVR1) is a protein which in humans is encoded by the ACVR1 gene; also known as ALK-2. ACVR1 has been linked to the 2q23-24 region of the genome. This protein is important in the bone morphogenic protein (BMP) pathway which is responsible for the development and repair of the skeletal system. While knock-out models with this gene are in progress, the ACVR1 gene has been connected to fibrodysplasia ossificans progressiva, an extremely rare progressive genetic disease characterized by heterotopic ossification of muscles, tendons and ligaments. It is a bone morphogenetic protein receptor, type 1.
Transforming growth factor-beta 2 (TGF-β2) is a secreted protein known as a cytokine that performs many cellular functions and has a vital role during embryonic development. It is an extracellular glycosylated protein. It is known to suppress the effects of interleukin dependent T-cell tumors. There are two named isoforms of this protein, created by alternative splicing of the same gene.
Growth differentiation factors (GDFs) are a subfamily of proteins belonging to the transforming growth factor beta superfamily that have functions predominantly in development.
Growth differentiation factor 1 (GDF1) is a protein that in humans is encoded by the GDF1 gene.
Growth differentiation factor-3 (GDF3), also known as Vg-related gene 2 (Vgr-2) is protein that in humans is encoded by the GDF3 gene. GDF3 belongs to the transforming growth factor beta (TGF-β) superfamily. It has high similarity to other TGF-β superfamily members including Vg1 and GDF1.
Growth/differentiation factor 5 is a protein that in humans is encoded by the GDF5 gene.
Growth differentiation factor 6 (GDF6) is a protein that in humans is encoded by the GDF6 gene.
Growth differentiation factor 7 (GDF7) is a protein that in humans is encoded by the GDF7 gene.
Growth differentiation factor 10 (GDF10) also known as bone morphogenetic protein 3B (BMP-3B) is a protein that in humans is encoded by the GDF10 gene.
Growth differentiation factor 11 (GDF11), also known as bone morphogenetic protein 11 (BMP-11), is a protein that in humans is encoded by the growth differentiation factor 11 gene. GDF11 is a member of the Transforming growth factor beta family.
AP-2 complex subunit alpha-1 is a protein that in humans is encoded by the AP2A1 gene.
Transforming growth factor beta-3 is a protein that in humans is encoded by the TGFB3 gene.
Insulin gene enhancer protein ISL-1 is a protein that in humans is encoded by the ISL1 gene.
Tumor necrosis factor receptor superfamily member 12A also known as the TWEAK receptor (TWEAKR) is a protein that in humans is encoded by the TNFRSF12A gene.
DNA-damage-inducible transcript 4 (DDIT4) protein also known as protein regulated in development and DNA damage response 1 (REDD1) is a protein that in humans is encoded by the DDIT4 gene.
Forkhead box protein H1 is a protein that in humans is encoded by the FOXH1 gene.
Fibroblast growth factor 17 is a protein that in humans is encoded by the FGF17 gene.
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