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 exerts its functions through binding to glial cell-derived neurotrophic factor family receptor alpha-like (GFRAL) and recruiting the receptor tyrosine kinase RET in the hindbrain, regulating food intake and body mass, and may also have anti-inflammatory effects through unclear mechanisms [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 [2]. Hepatic Gdf15 knockdown by AAV8 abrogated the obesity management effect of KD in mice, corroborating a hepatic origin of Gdf15 production [2]. In Gdf15 knockout mice, intrahepatic microenvironment during fibrosis showed more inflammation, while AAV8-mediated Gdf15 overexpression in hepatocytes diminished this inflammation and alleviated liver fibrosis [4].

In conclusion, Gdf15 is a key factor in multiple biological processes. Gene knockout mouse models have revealed its importance in obesity management, such as in the context of a ketogenic diet, and in liver fibrosis. These models help us understand how Gdf15-related signaling pathways are involved in these disease-associated biological processes, providing insights for potential therapeutic strategies targeting these conditions.