Research Paper|Volume 12, Issue 3|pp 2101—2122

CSF1R inhibitor PLX5622 and environmental enrichment additively improve metabolic outcomes in middle-aged female mice

Seemaab Ali^1,^2,³, Anthony G. Mansour^2,⁵, Wei Huang^1,², Nicholas J. Queen^1,², Xiaokui Mo⁴, Jacqueline M. Anderson^1,², Quais N. Hassan II^1,^2,³, Ripal S. Patel^1,², Ryan K. Wilkins^1,², Michael A. Caligiuri⁵, Lei Cao^1,²

¹Department of Cancer Biology and Genetics, College of Medicine, The Ohio State University, Columbus, OH 43210, USA
²The Ohio State University Comprehensive Cancer Center, The James Cancer Hospital and Solove Research Institute, Columbus, OH 43210, USA
³Medical Scientist Training Program, College of Medicine, The Ohio State University, Columbus, OH 43210, USA
⁴Department of Biomedical Informatics, College of Medicine, The Ohio State University, Columbus, OH 43210, USA
⁵Department of Hematological Malignancies and Stem Cell Transplantation, City of Hope National Medical Center and the Beckman Research Institute, Los Angeles, CA 91010, USA

Received: October 11, 2019Accepted: January 2, 2020Published: February 2, 2020

https://doi.org/10.18632/aging.102724

Copyright: © 2020 Ali et al. This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Abstract

As the elderly population grows, chronic metabolic dysfunction including obesity and diabetes are becoming increasingly common comorbidities. Hypothalamic inflammation through CNS resident microglia serves as a common pathway between developing obesity and developing systemic aging pathologies. Despite understanding aging as a life-long process involving interactions between individuals and their environment, limited studies address the dynamics of environment interactions with aging or aging therapeutics. We previously demonstrated environmental enrichment (EE) is an effective model for studying improved metabolic health and overall healthspan in mice, which acts through a brain-fat axis. Here we investigated the CSF1R inhibitor PLX5622 (PLX), which depletes microglia, and its effects on metabolic decline in aging in interaction with EE. PLX in combination with EE substantially improved metabolic outcomes in middle-aged female mice over PLX or EE alone. Chronic PLX treatment depleted 75% of microglia from the hypothalamus and reduced markers of inflammation without affecting brain-derived neurotrophic factor levels induced by EE. Adipose tissue remodeling and adipose tissue macrophage modulation were observed in response to CSF1R inhibition, which may contribute to the combined benefits seen in EE with PLX. Our study suggests benefits exist from combined drug and lifestyle interventions in aged animals.