Growth differentiation factor 15 (GDF15), also known as macrophage inhibitory cytokine-1 (MIC-1) and non-steroidal anti-inflammatory drug (NSAID)-activated gene-1 (NAG-1), is a member of the TGFβ superfamily. It plays diverse roles in controlling hematopoietic growth, energy homeostasis, adipose tissue metabolism, body growth, bone remodeling, and response to stress signals [3]. GDF15 signals through binding to glial cell-derived neurotrophic factor family receptor alpha-like (GFRAL) and recruitment of the receptor tyrosine kinase RET in the hindbrain, which is involved in reducing food intake and body mass, and may also have anti-inflammatory effects [1].

In GDF15-or its receptor GFRAL-deficient mice, the effects of a ketogenic diet (KD) on reducing energy intake and body weight disappeared, demonstrating an essential role of GDF15-GFRAL signaling in KD-mediated weight loss. Hepatic knockdown of Gdf15 by AAV8 also abrogated the obesity management effect of KD in mice, suggesting a hepatic origin of GDF15 production [2]. In Gdf15 knockout mice, intrahepatic microenvironment during fibrosis showed more inflammation, while GDF15 overexpression alleviated liver fibrosis. GDF15 exerts its effects by reprogramming the metabolic pathways of macrophages [4]. In HCC, gene ablation of GDF15 can convert an immunosuppressive tumor microenvironment to an inflammatory state, revealing its role in HCC-related immunosuppression [5]. Kidney-specific knockdown of GDF15 expression negated the ability of metformin to lower food intake and body weight gain, indicating the importance of kidney-derived GDF15 in metformin-mediated energy regulation [6].

In conclusion, GDF15 is a pleiotropic factor involved in multiple biological processes. Through gene knockout mouse models, its roles in obesity management, liver fibrosis, HCC-related immunosuppression, and metformin-mediated energy regulation have been revealed. These studies help to understand the biological functions of GDF15 and its potential as a therapeutic target in related diseases.

References:

1. Wang, Dongdong, Day, Emily A, Townsend, Logan K, Jørgensen, Sebastian Beck, Steinberg, Gregory R. 2021. GDF15: emerging biology and therapeutic applications for obesity and cardiometabolic disease. In Nature reviews. Endocrinology, 17, 592-607. doi:10.1038/s41574-021-00529-7. https://pubmed.ncbi.nlm.nih.gov/34381196/

2. Lu, Jun Feng, Zhu, Meng Qing, Xia, Bo, Li, Xiao Miao, Wu, Jiang Wei. . GDF15 is a major determinant of ketogenic diet-induced weight loss. In Cell metabolism, 35, 2165-2182.e7. doi:10.1016/j.cmet.2023.11.003. https://pubmed.ncbi.nlm.nih.gov/38056430/

3. Siddiqui, Jawed Akhtar, Pothuraju, Ramesh, Khan, Parvez, Nasser, Mohd Wasim, Batra, Surinder Kumar. 2021. Pathophysiological role of growth differentiation factor 15 (GDF15) in obesity, cancer, and cachexia. In Cytokine & growth factor reviews, 64, 71-83. doi:10.1016/j.cytogfr.2021.11.002. https://pubmed.ncbi.nlm.nih.gov/34836750/

4. Li, Xiaolei, Huai, Qian, Zhu, Cheng, Dai, Hanren, Wang, Hua. 2023. GDF15 Ameliorates Liver Fibrosis by Metabolic Reprogramming of Macrophages to Acquire Anti-Inflammatory Properties. In Cellular and molecular gastroenterology and hepatology, 16, 711-734. doi:10.1016/j.jcmgh.2023.07.009. https://pubmed.ncbi.nlm.nih.gov/37499753/

5. Wang, Zhaowei, He, Lei, Li, Weina, Zhang, Cun, Li, Meng. . GDF15 induces immunosuppression via CD48 on regulatory T cells in hepatocellular carcinoma. In Journal for immunotherapy of cancer, 9, . doi:10.1136/jitc-2021-002787. https://pubmed.ncbi.nlm.nih.gov/34489334/

6. Zhang, Song-Yang, Bruce, Kyla, Danaei, Zahra, Reich, Heather N, Lam, Tony K T. 2023. Metformin triggers a kidney GDF15-dependent area postrema axis to regulate food intake and body weight. In Cell metabolism, 35, 875-886.e5. doi:10.1016/j.cmet.2023.03.014. https://pubmed.ncbi.nlm.nih.gov/37060902/