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Cell. 2019 Apr 4;177(2):399-413.e12. doi: 10.1016/j.cell.2019.01.050. Epub 2019 Mar 7.

Energetic Trade-Offs and Hypometabolic States Promote Disease Tolerance.

Author information

1
Cardiovascular Research Institute, University of California, San Francisco, San Francisco, CA 94143, USA.
2
Cardiovascular Research Institute, University of California, San Francisco, San Francisco, CA 94143, USA; Centre for Inflammatory Diseases, Department of Medicine, School of Clinical Sciences at Monash Health, Monash University, Melbourne, VIC, Australia.
3
Department of Biochemistry, University of Utah, Salt Lake City, UT 84112, USA; Metabolomics Core Research Facility, University of Utah, Salt Lake City, UT 84112, USA.
4
Cardiovascular Research Institute, University of California, San Francisco, San Francisco, CA 94143, USA; Departments of Physiology and Medicine, University of California, San Francisco, San Francisco, CA 94143, USA. Electronic address: ajay.chawla@ucsf.edu.

Abstract

Host defenses against pathogens are energetically expensive, leading ecological immunologists to postulate that they might participate in energetic trade-offs with other maintenance programs. However, the metabolic costs of immunity and the nature of physiologic trade-offs it engages are largely unknown. We report here that activation of immunity causes an energetic trade-off with the homeothermy (the stable maintenance of core temperature), resulting in hypometabolism and hypothermia. This immunity-induced physiologic trade-off was independent of sickness behaviors but required hematopoietic sensing of lipopolysaccharide (LPS) via the toll-like receptor 4 (TLR4). Metabolomics and genome-wide expression profiling revealed that distinct metabolic programs supported entry and recovery from the energy-conserving hypometabolic state. During bacterial infections, hypometabolic states, which could be elicited by competition for energy between maintenance programs or energy restriction, promoted disease tolerance. Together, our findings suggest that energy-conserving hypometabolic states, such as dormancy, might have evolved as a mechanism of tissue tolerance.

KEYWORDS:

caloric restriction; dormancy; hibernation; innate immunity; ketones; metabolism; resistance; thermoneutrality; torpor; triglycerides

PMID:
30853215
PMCID:
PMC6456449
[Available on 2020-04-04]
DOI:
10.1016/j.cell.2019.01.050

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