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 GDF15 concentrations increase in response to atherosclerosis, ischemia/reperfusion injury and heart failure. [13] In patients with coronary artery disease (CAD), GDF15 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]
GDF15 is being evaluated as a therapeutic target for treatment of cancer cachexia. In September 2024, Pfizer disclosed that the anti-GDF15 monoclonal antibody ponsegromab led to significant increases in body weight in patients with non-small cell lung cancer, pancreatic cancer, and colorectal cancer. [22] [23]
Cachexia is a complex syndrome associated with an underlying illness, causing ongoing muscle loss that is not entirely reversed with nutritional supplementation. A range of diseases can cause cachexia, most commonly cancer, congestive heart failure, chronic obstructive pulmonary disease, chronic kidney disease, and AIDS. Systemic inflammation from these conditions can cause detrimental changes to metabolism and body composition. In contrast to weight loss from inadequate caloric intake, cachexia causes mostly muscle loss instead of fat loss. Diagnosis of cachexia can be difficult due to the lack of well-established diagnostic criteria. Cachexia can improve with treatment of the underlying illness but other treatment approaches have limited benefit. Cachexia is associated with increased mortality and poor quality of life.
Cluster of differentiation 40, CD40 is a type I transmembrane protein found on antigen-presenting cells and is required for their activation. The binding of CD154 (CD40L) on TH cells to CD40 activates antigen presenting cells and induces a variety of downstream effects.
The p75 neurotrophin receptor (p75NTR) was first identified in 1973 as the low-affinity nerve growth factor receptor (LNGFR) before discovery that p75NTR bound other neurotrophins equally well as nerve growth factor. p75NTR is a neurotrophic factor receptor. Neurotrophic factor receptors bind Neurotrophins including Nerve growth factor, Neurotrophin-3, Brain-derived neurotrophic factor, and Neurotrophin-4. All neurotrophins bind to p75NTR. This also includes the immature pro-neurotrophin forms. Neurotrophic factor receptors, including p75NTR, are responsible for ensuring a proper density to target ratio of developing neurons, refining broader maps in development into precise connections. p75NTR is involved in pathways that promote neuronal survival and neuronal death.
Mothers against decapentaplegic homolog 3 also known as SMAD family member 3 or SMAD3 is a protein that in humans is encoded by the SMAD3 gene.
Receptor activator of nuclear factor kappa-Β ligand (RANKL), also known as tumor necrosis factor ligand superfamily member 11 (TNFSF11), TNF-related activation-induced cytokine (TRANCE), osteoprotegerin ligand (OPGL), and osteoclast differentiation factor (ODF), is a protein that in humans is encoded by the TNFSF11 gene.
The Fas receptor, also known as Fas, FasR, apoptosis antigen 1, cluster of differentiation 95 (CD95) or tumor necrosis factor receptor superfamily member 6 (TNFRSF6), is a protein that in humans is encoded by the FAS gene. Fas was first identified using a monoclonal antibody generated by immunizing mice with the FS-7 cell line. Thus, the name Fas is derived from FS-7-associated surface antigen.
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 2 (GDF2) also known as bone morphogenetic protein (BMP)-9 is a protein that in humans is encoded by the GDF2 gene. GDF2 belongs to the transforming growth factor beta superfamily.
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 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.
Fibroblast growth factor receptor 3 (FGFR-3) is a protein that in humans is encoded by the FGFR3 gene. FGFR3 has also been designated as CD333. The gene, which is located on chromosome 4, location p16.3, is expressed in tissues such as the cartilage, brain, intestine, and kidneys.
Anaplastic lymphoma kinase (ALK) also known as ALK tyrosine kinase receptor or CD246 is an enzyme that in humans is encoded by the ALK gene.
Integrin beta-6 is a protein that in humans is encoded by the ITGB6 gene. It is the β6 subunit of the integrin αvβ6. Integrins are αβ heterodimeric glycoproteins which span the cell’s membrane, integrating the outside and inside of the cell. Integrins bind to specific extracellular proteins in the extracellular matrix or on other cells and subsequently transduce signals intracellularly to affect cell behaviour. One α and one β subunit associate non-covalently to form 24 unique integrins found in mammals. While some β integrin subunits partner with multiple α subunits, β6 associates exclusively with the αv subunit. Thus, the function of ITGB6 is entirely associated with the integrin αvβ6.
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.
The interleukin-2 receptor alpha chain is a protein involved in the assembly of the high-affinity interleukin-2 receptor, consisting of alpha (IL2RA), beta (IL2RB) and the common gamma chain (IL2RG). As the name indicates, this receptor interacts with interleukin-2, a pleiotropic cytokine which plays an important role in immune homeostasis.
Juven is a medical food that is manufactured by Abbott Laboratories and used to provide nutritional support under the care of a physician in individuals with muscle wasting due to AIDS or cancer, to promote wound healing following surgery or injury, or when otherwise recommended by a medical professional. It is a powdered nutritional supplement that contains 3 grams of calcium β-hydroxy β-methylbutyrate, 14 grams of L-arginine, and 14 grams of L-glutamine per two daily servings.
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