GFRAL, short for GDNF family receptor α-like, is a key receptor for Growth differentiation factor 15 (GDF15), a cytokine in the TGF-β superfamily. GFRAL signals through the Ret coreceptor. The GDF15-GFRAL pathway is crucial in regulating energy homeostasis, appetite, and metabolism, and thus has implications for diseases like obesity, diabetes, non-alcoholic fatty liver disease, and anorexia-cachexia syndrome [1,3]. Genetic models, such as KO mouse models, have been instrumental in understanding its function.

In GFRAL-knockout mice, the GDF15-mediated reductions in food intake and body weight were abolished, indicating that GFRAL is required for the anti-obesity effects of GDF15 [2]. GFRAL-deficient mice also showed exacerbated diet-induced obesity and insulin resistance, suggesting a homeostatic role for this receptor in metabolism [4]. Additionally, treatment with an antibody targeting GFRAL reversed excessive lipid oxidation and prevented cancer cachexia in tumor-bearing mice, uncovering a peripheral sympathetic axis by which GDF15 elicits a lipolytic response in adipose tissue [5].

In conclusion, GFRAL is essential for mediating the metabolic effects of GDF15, playing a key role in regulating food intake, body weight, and metabolism. Studies using GFRAL KO mouse models have provided valuable insights into its role in obesity and cancer cachexia, highlighting its potential as a therapeutic target for these disease areas.

References:

1. Breit, Samuel N, Brown, David A, Tsai, Vicky Wang-Wei. 2020. The GDF15-GFRAL Pathway in Health and Metabolic Disease: Friend or Foe? In Annual review of physiology, 83, 127-151. doi:10.1146/annurev-physiol-022020-045449. https://pubmed.ncbi.nlm.nih.gov/33228454/

2. Yang, Linda, Chang, Chih-Chuan, Sun, Zhe, Yang, Wei, Jørgensen, Sebastian Beck. 2017. GFRAL is the receptor for GDF15 and is required for the anti-obesity effects of the ligand. In Nature medicine, 23, 1158-1166. doi:10.1038/nm.4394. https://pubmed.ncbi.nlm.nih.gov/28846099/

3. Tsai, Vicky W W, Husaini, Yasmin, Sainsbury, Amanda, Brown, David A, Breit, Samuel N. . The MIC-1/GDF15-GFRAL Pathway in Energy Homeostasis: Implications for Obesity, Cachexia, and Other Associated Diseases. In Cell metabolism, 28, 353-368. doi:10.1016/j.cmet.2018.07.018. https://pubmed.ncbi.nlm.nih.gov/30184485/

4. Mullican, Shannon E, Lin-Schmidt, Xiefan, Chin, Chen-Ni, Hunter, Michael J, Rangwala, Shamina M. 2017. GFRAL is the receptor for GDF15 and the ligand promotes weight loss in mice and nonhuman primates. In Nature medicine, 23, 1150-1157. doi:10.1038/nm.4392. https://pubmed.ncbi.nlm.nih.gov/28846097/

5. Suriben, Rowena, Chen, Michael, Higbee, Jared, Lindhout, Darrin A, Allan, Bernard B. 2020. Antibody-mediated inhibition of GDF15-GFRAL activity reverses cancer cachexia in mice. In Nature medicine, 26, 1264-1270. doi:10.1038/s41591-020-0945-x. https://pubmed.ncbi.nlm.nih.gov/32661391/