@article{7bda456a418d48c4b39e86289fd91b23,
title = "Microglia in the hypothalamus respond to tumor-derived factors and are protective against cachexia during pancreatic cancer",
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.",
keywords = "brain, cachexia, hypothalamus, microglia, neuroinflammation, pancreatic cancer",
author = "Burfeind, {Kevin G.} and Xinxia Zhu and Norgard, {Mason A.} and Levasseur, {Peter R.} and Christian Huisman and Michaelis, {Katherine A.} and Brennan Olson and Marks, {Daniel L.}",
note = "Funding Information: We would like to thank Drs. Parm Singh and Andrey Reymar from Plexxikon for proving PLX5622. We would also like to thank Dr. Elizabeth Jaffee from Johns Hopkins for providing KPC tumor cells. We thank Matthew Michaelis for his assistance with the graphical abstract. Dr. Daniel L. Marks is a paid consultant for Pfizer, Inc. and this potential conflict of interest is managed by the OHSU integrity office. Funding for this work was provided by R01CA184324‐01, R01CA217989‐01, and Brenden‐Colson Center for Pancreatic Care to D.L.M., as well as 5F30CA213745‐03 to K.G.B. Funding Information: We would like to thank Drs. Parm Singh and Andrey Reymar from Plexxikon for proving PLX5622. We would also like to thank Dr. Elizabeth Jaffee from Johns Hopkins for providing KPC tumor cells. We thank Matthew Michaelis for his assistance with the graphical abstract. Dr. Daniel L. Marks is a paid consultant for Pfizer, Inc. and this potential conflict of interest is managed by the OHSU integrity office. Funding for this work was provided by R01CA184324-01, R01CA217989-01, and Brenden-Colson Center for Pancreatic Care to D.L.M., as well as 5F30CA213745-03 to K.G.B. Publisher Copyright: {\textcopyright} 2020 The Authors. Glia published by Wiley Periodicals, Inc.",
year = "2020",
month = jul,
day = "1",
doi = "10.1002/glia.23796",
language = "English (US)",
volume = "68",
pages = "1479--1494",
journal = "GLIA",
issn = "0894-1491",
publisher = "John Wiley and Sons Inc.",
number = "7",
}