Beyond Obesity Research: B6-hGDF15 Humanized Mice for Tumor, Diabetes, Morning Sickness, and Cardiovascular Studies

Obesity is a major global health issue, and the discovery of new targets and the development of new therapies have always been focal points for researchers and pharmaceutical companies. In recent years, Growth Differentiation Factor 15 (GDF15) and its receptor GFRAL have attracted widespread attention as biomarkers for various diseases, including obesity, diabetes, cancer, and metabolic dysfunction-associated steatotic liver disease (MASLD), previously known as non-alcoholic fatty liver disease (NAFLD). Cyagen's Gdf15 knockout (KO) mice (Product Number: S-KO-07013) have been used in research on the mechanism by which GDF15 plays a role in weight management during ketogenic diets. Related papers have been published in top journals in the field of metabolism.

GDF15 not only plays an important role in weight loss but is also considered a potential drug target for a variety of diseases. Its humanized model is crucial for the development of targeted drugs. Cyagen's B6-hGDF15 mouse model (Product Number: C001520) can be used to develop new therapies targeting the GDF15 gene or protein for treatment of tumors, obesity, and other cardiovascular and metabolic diseases. Today, we will explore the potential applications of the GDF15 target and humanized models.

Figure 1: GDF15 plays an important role in tumors and cachexia, as well as in various metabolic diseases such as MASLD/NAFLD, MASH/NASH, obesity, and diabetes.^[1]

The Discovery and Important Role of GDF15

GDF15 is a secreted ligand of the transforming growth factor-beta (TGF-β) superfamily, first discovered in 1997. GDF15 is widely expressed in various cell types and is a pleiotropic cytokine involved in the stress response following cellular injury, primarily associated with organ growth, differentiation, development, and cell repair.^[1] Under physiological conditions, GDF15 is expressed at low levels in most tissues except the placenta. However, under pathological conditions such as tissue hypoxia, inflammation, acute injury, and oxidative stress, the expression levels of GDF15 increase. This is associated with cardiovascular diseases such as myocardial hypertrophy, heart failure, and atherosclerosis, as well as obesity, diabetes, tumors, and cancer cachexia.^[2]

Figure 2: Different pathways of GDF15 in tumors, obesity, and cachexia.^[5]

GDF15 Is a Potential Key Target for the Treatment of Metabolic Diseases

In October 2017, Nature and Nature Medicine simultaneously published four research papers independently completed by NGM Biopharmaceuticals, with investments from Eli Lilly, Novo Nordisk, Johnson & Johnson, and Merck.^[3-6] These studies revealed the mechanism by which GDF15, through its receptor GFRAL, reduces food intake to achieve weight loss, establishing the important role of GDF15 in weight management. Consequently, GDF15 has also been referred to as the 'anorexia hormone,' known also as anorexigen. A series of research findings on the significant role of GDF15 in metabolism were subsequently published in top journals, including findings such as:

- Metformin's therapeutic and weight loss effects in type II diabetes through the upregulation of GDF15 expression (Nature, 2019; Nature Metab, 2019).^[7-8]

- GDF15 as a potential intervention target for type I diabetes (Cell Metab, 2020).^[9]

- GDF15 inducing anorexia through nausea and vomiting (Cell Metab, 2020).^[10]

- GDF15 coordinating resistance to inflammatory injury by regulating triglyceride metabolism (Cell, 2019).^[11]

- GDF15 promoting weight loss by increasing muscle energy expenditure (Nature, 2023).^[12]

- GDF15 as a key determinant of weight loss induced by a ketogenic diet (Cell Metab, 2023).^[13]

- GDF15 reducing weight and fat content by utilizing the leptin pathway (Cell Metab, 2023).^[14]

These findings indicate that GDF15 has a significant impact on obesity and other metabolic diseases, and it can serve as a potential therapeutic target for these conditions.

Figure 3: Various potential mechanisms by which GDF15 inhibits energy intake and obesity.^[1]

GDF15 as a Potential Therapeutic Target for Other Diseases, Including Cancers

GDF15 not only plays a role in metabolic diseases such as obesity, but as an immune checkpoint, GDF15 can inhibit the activation and maturation of dendritic cells and impede the activation of cytotoxic T lymphocytes, thereby promoting immune evasion of tumor cells. Consequently, GDF15 is significantly associated with the development of cancer, and high expression of GDF15 has been found in biopsies of various tumors.^[1-2] Many cancer patients experience cachexia, a condition characterized by anorexia and progressive loss of adipose tissue and skeletal muscle. Elevated GDF15 levels are highly correlated with cancer-related cachexia and shortened survival in cancer patients.^[1-2] Therefore, inhibiting GDF15 is seen as an important way to overcome resistance to standard cancer treatments and immunotherapy.^[15] 

Additionally, GDF15 expression increases significantly with age and is associated with aging and various age-related diseases.^[16] High levels of GDF15 in maternal blood are related to pregnancy-related nausea and the most severe form of hyperemesis gravidarum (HG), providing a theoretical basis for targeting GDF15 in the treatment and prevention of severe morning sickness.^[17] Moreover, GDF15 can alleviate metabolic dysfunction-associated steatotic liver disease (MASLD) [non-alcoholic fatty liver disease (NAFLD)] and metabolic dysfunction-associated steatohepatitis (MASH) [non-alcoholic steatohepatitis (NASH)] and provide cardioprotective effects by reducing atherosclerosis, cardiac hypertrophy, and ischemia-reperfusion injury.

Figure 4: The multiple effects of GDF15 in malignant tumors.^[2]

The importance of GDF15 has garnered significant attention from researchers and pharmaceutical companies. Currently, numerous drug studies targeting GDF15 and its receptor are underway, primarily focusing on diseases such as obesity, tumors, and related cachexia. To advance the development of GDF15-related therapies, Cyagen has developed a humanized mouse model of the Gdf15 gene, the B6-hGDF15 mouse (Product Number: C001520). Below is the phenotypic information of this model.

B6-hGDF15 Mice Only Express Human GDF15 Gene and Protein

The expression of the human gene and protein was detected using human GDF15 gene-specific primers and human GDF15 protein antibodies through RT-qPCR and Western Blot techniques. The results show that B6-hGDF15 mice successfully express the human GDF15 gene transcript and protein, and there is no expression of the mouse endogenous Gdf15 gene.

Figure 5: Detection of human GDF15 gene and protein expression in mice

(Note: The human GDF15 protein band present in wild-type mice is due to the high homology between human and mouse proteins.)

Conclusion

The B6-hGDF15 mouse model (Product Number: C001520) effectively expresses the human GDF15 gene without expressing the mouse endogenous Gdf15 gene. The expression of human GDF15 protein is significant in its liver. Therefore, this model can be used to develop new therapies targeting the GDF15 gene or protein for tumors, obesity, and other cardiovascular and metabolic diseases, or for conducting related mechanistic studies. Additionally, Cyagen has developed various genetic disease models, inducible disease models, and humanized target models in the fields of tumor and cardiovascular metabolic disease research. These models are available for researchers to develop targeted drugs for different diseases. For more information on our models, please contact us today to explore how we can support your research needs.

References:
[1]Wang et al. (2021). Nat Rev Endocrinol, 17(10), 592-607.
[2]Siddiqui et al. (2022). Cytokine Growth Factor Rev, 64, 71-83.
[3]Emmerson et al. (2017). Nat Med, 23(10), 1215-1219.
[4]Yang et al. (2017). Nat Med, 23(10), 1158-1166.
[5]Mullican et al. (2017). Nat Med, 23(10), 1150-1157.
[6]Hsu et al. (2017). Nature, 550(7675), 255-259.
[7]Day et al. (2019). Nat Metab, 1(12), 1202-1208.
[8]Coll et al. (2020). Nature, 578(7795), 444-448.
[9]Nakayasu et al. (2020). Cell Metab, 31(2), 363-374.e6.
[10]Borner et al. (2020). Cell Metab, 31(2), 351-362.e5.
[11]Luan et al. (2019). Cell, 178(5), 1231-1244.e11.
[12]Wang et al. (2023). Nature, 619(7968), 143-150.
[13]Lu et al. (2023). Cell Metab, 35(12), 2165-2182.e7.
[14]Breit et al. (2023). Cell Metab, 35(8), 1341-1355.e3.
[15]Suriben et al. (2020). Nat Med, 26(8), 1264-1270.
[16]Conte et al. (2022). Ageing Res Rev, 75, 101569.
[17]Fejzo et al. (2024). Nature, 625(7996), 760-767.