# Harnessing Fasting Metabolism to Improve Survival in Bacterial Sepsis

> **NIH NIH R35** · UT SOUTHWESTERN MEDICAL CENTER · 2021 · $410,000

## Abstract

PROJECT SUMMARY
Anorexia of acute illness has traditionally been considered a maladaptive response in the face of a presumed
hyper-catabolic state. Surprisingly, we found that anorexia is protective in bacterial sepsis. Glucose
supplementation during the period of anorexia induced by bacterial sepsis is detrimental and promotes mortality,
even in the absence of live pathogen as in the mouse model of lipopolysaccharide (LPS) sepsis. Core fasting
metabolic pathways activated in LPS sepsis, including liberation of free fatty acids, ketogenesis, and production
of fibroblast growth factor-21 (FGF21), an endocrine FGF hormone that mediates adaptive responses to
metabolic stresses such as starvation, are suppressed by glucose supplementation. Knockout mice that are
deficient in FGF21 or in peroxisome proliferator-activated receptor alpha, which cannot produce FGF21 or
ketones, are more susceptible to bacterial sepsis. We have also found that similar to normal fasting responses,
lipid droplets accumulate in the liver and kidney during bacterial sepsis. Emerging evidence suggests that lipid
droplets may in fact reflect protective mechanisms against cellular stress rather than lipotoxicity. Based on our
preliminary data, we hypothesize that components of fasting metabolism are integral protective mechanisms that
support survival and tissue protection during bacterial sepsis. Over the next five years, key goals for the Huen
laboratory are to determine whether and how components of fasting metabolism: 1) FGF21, 2) ketogenesis, and
3) lipid droplet formation, are protective in bacterial sepsis. Proposed studies include using pharmacologic
targeting and genetic mouse models of tissue-specific deletion of key components of these metabolic processes.
Interdisciplinary methods will be used to investigate the interactive physiology between the innate immune
system and metabolic organs, in order to elucidate the complex interactions between multiple organ systems
including the brain, liver, kidney and heart as part of the adaptive response to bacterial sepsis. The overarching
objectives of our proposed studies aim to differentiate between pathologic and protective metabolic pathways in
bacterial sepsis, interrogate the beneficial aspects of fasting metabolism that support survival, and elucidate the
mechanisms of action.

## Key facts

- **NIH application ID:** 10238121
- **Project number:** 5R35GM137984-02
- **Recipient organization:** UT SOUTHWESTERN MEDICAL CENTER
- **Principal Investigator:** sarah huen
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $410,000
- **Award type:** 5
- **Project period:** 2020-09-01 → 2025-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10238121

## Citation

> US National Institutes of Health, RePORTER application 10238121, Harnessing Fasting Metabolism to Improve Survival in Bacterial Sepsis (5R35GM137984-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10238121. Licensed CC0.

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