Repeated clodronate-liposome treatment results in neutrophilia and is not effective in limiting obesity-linked metabolic impairments

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Abstract
Objective: Depletion of macrophages is thought to be a therapeutic option for obesity-induced inflammation and metabolic dysfunction. However, whether the therapeutic effect is a direct result of reduced macrophage-derived inflammation or secondary to decreases in fat mass is controversial as macrophage depletion has been shown to disrupt energy homeostasis. This study was designed to determine if macrophage depletion via clodronate-liposome (CLD) treatment could serve as an effective intervention to reduce obesity-driven inflammatory and metabolic impairments independent of changes in energy intake. Methods: Following 16 weeks of high-fat diet (HFD) or AIN-76A control diet (LFD) (n=30/diet treatment), male C57BL/6J mice were assigned to either a CLD or PBS-liposome-treatment (n=15/group) for 4 weeks. PBS-liposome-treated groups were pair-fed to their CLD-treated dietary counterparts. Metabolic function was assessed pre- and post- liposome treatment. Adipose tissue as well as liver were investigated for macrophage infiltration and the presence of inflammatory mediators. Additionally, a complete blood count was performed. Results: CLD treatment reduced energy intake. When controlling for energy intake, CLD treatment was unable to rescue metabolic dysfunction or Non-Alcoholic-Fatty-Liver Disease development, and impaired adipose tissue insulin action. Moreover, CLD treatment induced neutrophilia, anemia, increased adipose tissue mRNA expression of the pro-inflammatory cytokines, IL-6 and IL-1β, and augmented circulating IL-6 and MCP-1 concentrations (p<0.05). Conclusion: This study suggests that the use of CLD treatment to deplete macrophages attenuates obesity by limiting energy intake. Moreover, after controlling for the benefits of weight loss, the accompanying detrimental side effects limit CLD treatment as an effective therapeutic strategy.
Funding Information
  • HHS | NIH | National Cancer Institute (NCI) (1R21CA191966, 1F99CA234920-01)
  • American Institute of Cancer Research (359566)

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