Glucocorticoids Mediate Short-Term High-Fat Diet Induction of Neuroinflammatory Priming, the NLRP3 Inflammasome, and the Danger Signal HMGB1.
The impact of the foods we eat on metabolism and cardiac physiology has been studied for decades, yet less is known about the effects of foods on the CNS, or the behavioral manifestations that may result from these effects. Previous studies have shown that long-term consumption of high-fat foods leading to diet-induced obesity sensitizes the inflammatory response of the brain to subsequent challenging stimuli, causing deficits in the formation of long-term memories. The new findings reported here demonstrate that short-term consumption of a high-fat diet (HFD) produces the same outcomes, thus allowing the examination of mechanisms involved in this process long before obesity and associated comorbidities occur. Rats fed an HFD for 3 d exhibited increases in corticosterone, the inflammasome-associated protein NLRP3 (nod-like receptor protein 3), and the endogenous danger signal HMGB1 (high-mobility group box 1) in the hippocampus. A low-dose (10 μg/kg) lipopolysaccharide (LPS) immune challenge potentiated the neuroinflammatory response in the hippocampus of rats fed the HFD, and caused a deficit in the formation of long-term memory, effects not observed in rats fed regular chow. The blockade of corticosterone action with the glucocorticoid receptor antagonist mifepristone prevented the NLRP3 and HMGB1 increases in unchallenged animals, normalized the proinflammatory response to LPS, and prevented the memory impairment. These data suggest that short-term HFD consumption increases vulnerability to memory disruptions caused by an immune challenge by upregulating important neuroinflammatory priming and danger signals in the hippocampus, and that these effects are mediated by increases in hippocampal corticosterone.
Department of Psychology and Neuroscience, and the Center for Neuroscience, University of Colorado Boulder , Boulder, Colorado 80309-0345.
Julia L
JL
Sobesky
Department of Psychology and Neuroscience, and the Center for Neuroscience, University of Colorado Boulder , Boulder, Colorado 80309-0345.
Heather M
HM
D'Angelo
Department of Psychology and Neuroscience, and the Center for Neuroscience, University of Colorado Boulder , Boulder, Colorado 80309-0345.
Michael D
0000-0003-2690-7738
MD
Weber
Department of Psychology and Neuroscience, and the Center for Neuroscience, University of Colorado Boulder , Boulder, Colorado 80309-0345.
Nathan D
ND
Anderson
Department of Psychology and Neuroscience, and the Center for Neuroscience, University of Colorado Boulder , Boulder, Colorado 80309-0345.
Matthew G
0000-0001-8613-6897
MG
Frank
Department of Psychology and Neuroscience, and the Center for Neuroscience, University of Colorado Boulder , Boulder, Colorado 80309-0345.
Linda R
LR
Watkins
Department of Psychology and Neuroscience, and the Center for Neuroscience, University of Colorado Boulder , Boulder, Colorado 80309-0345.
Steven F
SF
Maier
Department of Psychology and Neuroscience, and the Center for Neuroscience, University of Colorado Boulder , Boulder, Colorado 80309-0345.
Ruth M
0000-0001-7224-4109
RM
Barrientos
D000818:Animals; D003345:Corticosterone / Q000378:metabolism; D059305:Diet, High-Fat / Q000009:adverse effects*; D004926:Escherichia coli; D005938:Glucocorticoids / Q000378:metabolism*; D024243:HMGB1 Protein / Q000378:metabolism*; D006624:Hippocampus / Q000187:drug effects / Q000276:immunology*; D006727:Hormone Antagonists / Q000494:pharmacology; D058847:Inflammasomes / Q000187:drug effects / Q000378:metabolism*; D053583:Interleukin-1beta / Q000378:metabolism; D008070:Lipopolysaccharides; D008297:Male; D008569:Memory Disorders / Q000209:etiology / Q000276:immunology / Q000517:prevention & control; D057567:Memory, Long-Term / Q000187:drug effects / Q000502:physiology; D015735:Mifepristone / Q000494:pharmacology; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein / Q000378:metabolism*; D015213:Neuroimmunomodulation / Q000187:drug effects / Q000502:physiology; D011897:Random Allocation; D017208:Rats, Wistar; D011965:Receptors, Glucocorticoid / Q000037:antagonists & inhibitors / Q000378:metabolism; D013997:Time Factors
D005938:Glucocorticoids; D024243:HMGB1 Protein; C104200:Hbp1 protein, rat; D006727:Hormone Antagonists; C000594089:IL1B protein, rat; D058847:Inflammasomes; D053583:Interleukin-1beta; D008070:Lipopolysaccharides; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; C573346:Nlrp3 protein, rat; D011965:Receptors, Glucocorticoid; D015735:Mifepristone; D003345:Corticosterone
: danger-associated molecular patterns; hippocampus; neuroimmunology; neuroinflammation; neuroinflammatory priming; short-term high-fat diet