Jiahui Lyu1,2 · Wang Cheng2  · Chun‑Yue Li6  · Jiayan Wang7  · Xiaorong Zhang8  · Huifang Lou3  · Yalin Hu9  · Zhihua Gao3,4,5 · Shumin Duan3,4,5  · Kelei Cao2

1 MOE Frontiers Center for Brain Science, Institute for Translational Brain Research, Fudan University, Shanghai 200032, China 

2 Department of Anatomy and Physiology, Shanghai Key Laboratory of Emotions and Affective Disorders, Songjiang Research Institute, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China 

3 Department of Neurology of Second Affiliated Hospital and School of Brain Science and Brain Medicine, Zhejiang University School of Medicine, Hangzhou 310058, China 

4 Liangzhu Laboratory, MOE Frontier Science Center for Brain Science and Brain‑Machine Integration, State Key Laboratory of Brain‑Machine Intelligence, Zhejiang University, Hangzhou 310058, China 

5 NHC and CAMS Key Laboratory of Medical Neurobiology, Zhejiang University, Hangzhou 310058, China 

6 National Clinical Research Center for Aging and Medicine, Huashan Hospital, Fudan University, Shanghai 200433, China 

7 School of Basic Medicine, Nanjing Medical University, Nanjing 211166, China 

8 The First Affiliated Hospital, Bengbu Medical University, Bengbu 233004, China 

9 The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310058, China

Abstract

Colony-stimulating factor 1 receptor (CSF1R) inhibitors, such as PLX5622 and PLX3397 (pexidartinib), are widely used for in vivo microglial depletion and for investigating microglial functions and therapeutic potential. Although CSF1R inhibitor-based studies have uncovered important roles for microglia in processes, such as anesthesia, addiction, and obesity, whether the resulting phenotypes reflect microglial depletion alone remains increasingly debated. Our previous work has shown that PLX5622 activates hepatic constitutive androstane receptor (CAR)-dependent xenobiotic metabolism, altering the metabolism of anesthetics and addictive drugs, and amplifying apparent microglial phenotypes. Whether other CSF1R inhibitors, particularly the FDA-approved PLX3397, exert systemic metabolic effects that may influence the interpretation of brain phenotypes remains unknown. Here, we demonstrate that PLX3397 exerts hepatic metabolic effects that are mechanistically distinct from those induced by PLX5622. Although PLX3397 only weakly affects xenobiotic metabolism, it markedly enhances endogenous hepatic lipid metabolism, inducing a fasting-like state characterized by increased lipid utilization and ketogenesis despite the absence of nutrient deprivation. By uncovering previously unrecognized peripheral effects of PLX3397, our findings identify brain-periphery interactions as a potential source of confounding in studies of microglial function. These results suggest that systemic metabolic effects should be carefully considered when interpreting neural or behavioral phenotypes in pharmacological microglia depletion paradigms.

Keywords

PLX3397·PLX5622; Microglial depletion; Lipid metabolism; Xenobiotic metabolism

[SpringerLink]