Microglia in the hypothalamus respond to tumor-derived factors and are protective against cachexia during pancreatic cancer

Kevin G. Burfeind, Xinxia Zhu, Mason A. Norgard, Peter R. Levasseur, Christian Huisman, Katherine A. Michaelis, Brennan Olson, Daniel L. Marks

Research output: Contribution to journalArticle

Abstract

Microglia in the mediobasal hypothalamus (MBH) respond to inflammatory stimuli and metabolic perturbations to mediate body composition. This concept is well studied in the context of high fat diet induced obesity (HFDO), yet has not been investigated in the context of cachexia, a devastating metabolic syndrome characterized by anorexia, fatigue, and muscle catabolism. We show that microglia accumulate specifically in the MBH early in pancreatic ductal adenocarcinoma (PDAC)-associated cachexia and assume an activated morphology. Furthermore, we observe astrogliosis in the MBH and hippocampus concurrent with cachexia initiation. We next show that circulating immune cells resembling macrophages infiltrate the MBH. PDAC-derived factors induced microglia to express a transcriptional profile in vitro that was distinct from that induced by lipopolysaccharide (LPS). Microglia depletion through CSF1-R antagonism resulted in accelerated cachexia onset and increased anorexia, fatigue, and muscle catabolism during PDAC. This corresponded with increased hypothalamic–pituitary–adrenal (HPA) axis activation. CSF1-R antagonism had little effect on inflammatory response in the circulation, liver, or tumor. These findings demonstrate that microglia are protective against PDAC cachexia and provide mechanistic insight into this function.

Original languageEnglish (US)
JournalGLIA
DOIs
StateAccepted/In press - Jan 1 2020

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Keywords

  • brain
  • cachexia
  • hypothalamus
  • microglia
  • neuroinflammation
  • pancreatic cancer

ASJC Scopus subject areas

  • Neurology
  • Cellular and Molecular Neuroscience

Cite this

Burfeind, K. G., Zhu, X., Norgard, M. A., Levasseur, P. R., Huisman, C., Michaelis, K. A., Olson, B., & Marks, D. L. (Accepted/In press). Microglia in the hypothalamus respond to tumor-derived factors and are protective against cachexia during pancreatic cancer. GLIA. https://doi.org/10.1002/glia.23796