Growth differentiation factor 15 (GDF15), being a kind of endocrine hormone and a member of transforming growth factor β (TGF β) superfamily, acts as an autocrine regulatory molecule in macrophages, which was identified and found from the clone of activated macrophage cell line. According to GDF15's tissue source or function, it is given different names: MIC-1, PLAB, PTGF-β, NAG-1, PDF, etc.
GDF15 is mainly involved in organ growth, differentiation and development, as well as the cell repair. Under physiological condition, the GDF15 expression is low in other tissues except placenta, but under pathologic condition such as inflammation or traumatic stress, its expression is up-regulated, with many stimulating factors such as TGF β, interleukin 1β (IL-1β) and tumor necrosis factor-α (TNF-α). GDF15 expression in the liver cell can be induced by the IL-1β or tunicamycin stimulated endoplasmic reticulum stress, and its expression in the liver cell in patients with non-alcoholic fatty liver disease (NAFLD) is directly related to the content of IL-1β and the severity of steatosis. Thus, GDF15 can be used as an inflammatory marker or stress response protein. A large number of studies have shown that the rise of GDF15 is related to cardiovascular diseases, such as myocardial hypertrophy, heart failure, atherosclerosis, and endothelial dysfunction, as well as obesity, diabetes, cancer and cachexia, and it has been proved that GDF15 is a new biomarker in the diagnosis, progression and prognosis of the above diseases. As the biomarker of obesity, diabetes, tumor, NAFLD, and ischemic diseases, GDF15 has become the new target of new drug R&D.
The application of GDF15 target in the disease
1. GDF15 and obesity and metabolic related diseases
GDF15 is able to control the food intake and energy metabolism, which promotes the study on target GDF15's potential function to the overnutrition (obesity) and malnutrition (anorexia / cachexia) under the pathological condition. GDNF family receptor alpha like (GFRAL), located in the area postrema neuron, is a receptor necessary for anorexia mediated by GDF15, which the ligand-receptor relationship has outlined a new pathway to control energy homeostasis. GDF15 has some same characteristics with other endocrine factors controlling food intake, but it still has its uniqueness, for example, the regulation of GDF15/GFRAL is beneficial to increase and maintain its extensive tissue expression level under many conditions; Unlike short-term postprandial anorexia signals, the postprandial GDF15 level will not increase.
With the dual function of regulating appetite suppression and increasing peripheral energy consumption, GDF15 plays an important role in preventing and treating obesity. The discovery of GDF15 opens up a new idea for anti-obesity treatment. Studies have shown that anorexia of patients with advanced cancer is related to the TGFβ pathway and mediated by the regulation of feeding center by MIC-1. Normal mouses given systemic MIC-1 and transgenic mouses overexpressing MIC-1 showed insufficient swallowing and weight loss. In addition, as a star molecule of anti-diabetes drugs, metformin's anti-obesity function has also been proved to be related to GDF15, which it can increase the GDF15 in serum, reduce the food intake and lose weight by limiting brain stem, and it has nothing to do with reducing blood glucose. GDF15 has been proved to be the biomarker in patients with abnormal blood glucose taking metformin, which concentration reflects the dose of metformin. And the increased serum GDF15 in patients with Type 2 diabetes taking metformin is also related to the weight loss. Therefore, it is possible to develop drugs to treat obesity and cancer-induced cachexia based on the brain GDF15-GFRAL-RET receptor signal transduction complex. In addition to the central function of inhibiting food intake, GDF15 also plays an anti-obesity role by peripheral functions such as promoting thermogenesis and reducing lipogenesis. During cold exposure and adrenaline stimulation, GDF15, released by brown and beige adipose tissues, can target macrophage, mediate the downregulation of local inflammation pathway, and play a the...
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