# Bioenergetic and Epigenetic Reprogramming by Obesity in Sepsis

> **NIH NIH R01** · CLEVELAND CLINIC LERNER COM-CWRU · 2020 · $370,543

## Abstract

Summary
 Obesity increases morbidity and resource utilization of critically ill including sepsis; sepsis, the most expensive condition in
the US, is the leading cause of death in critically ill patients. The early hyper-inflammatory response of sepsis quickly
transitions to hypo-inflammatory and immunosuppressive phase. Most patients die during the immunosuppressive phase of
late sepsis, because they cannot clear infections. We have shown previously, that the lean (C57Bl/6 wild type: WT) mice and
their monocytes undergo an early/hyper-inflammatory (endotoxin responsive), late/hypo-inflammatory (endotoxin tolerant)
and resolution (return of endotoxin response) phases, however, in leptin deficient-obese ob/ob mice, we found that the hyper-
inflammatory phase transitioned quickly to a prolonged hypo-inflammatory phase and that survival was decreased compared
to lean mice. The transition from the hyper- to hypo-inflammatory phase is accompanied by profound changes in monocyte
metabolism in mice and obese-sepsis patients; monocytes depend on glycolysis energy during the hyper- but fatty acid
oxidation during the hypo-inflammatory phase. The switch from glycolytic/hyper- to fatty acid-dependent/hypo-inflammation
is controlled by the NAD+ sensor sirtuin (SIRT) family of proteins (SIRTs 1-7). Earlier we showed that in lean/WT mice,
increased SIRT1 controls the switch from hyper- to hypo-inflammation; SIRT1 inhibition during hypo-inflammation improves
survival. In ob/ob mice, increased SIRT2 expression controls the switch and prolongs the hypo-inflammation; SIRT2 inhibition
during hypo-inflammation reverses the endotoxin tolerance and improves survival. In contrast to our findings in lean mice, we
found that the SIRT1 inhibition during the hypo-inflammatory phase of ob/ob- sepsis decreased survival. Thus our published
and preliminary data support an obesity-specific role for SIRT2. In this proposal, we will elucidate the role of SIRT2 in
modulation of immuno-metabolic responses in clinically relevant, leptin resistant nutritionally obese (diet induced obese: DIO)
mice with sepsis. This proposal’s general working hypothesis is that SIRT2 a critical regulator of immuno-metabolic responses in diet-induced
obesity with sepsis. We propose two Specific Aims, designed to develop this new concept. Aim 1 will define the role of SIRT2
in regulating immuno-metabolic responses in obesity with sepsis, using genetic and pharmacological modification of SIRT2 in
lean and obese mice during early vs. late sepsis. Aim 2 will determine how SIRT2 protein levels and function themselves are
regulated in obesity with sepsis. Impact: Completing these aims will deepen our understanding of how obesity alters immuno-
metabolic properties of sepsis-inflammation. Sepsis, the most expensive condition in the US kills >200,000 people each year.
A better understanding of how obesity and sepsis interact could shorten the hypo-inflammatory phase, thereby having a
marked impact on morbidity,...

## Key facts

- **NIH application ID:** 9941115
- **Project number:** 5R01GM099807-10
- **Recipient organization:** CLEVELAND CLINIC LERNER COM-CWRU
- **Principal Investigator:** Vidula Vachharajani
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $370,543
- **Award type:** 5
- **Project period:** 2012-07-01 → 2022-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9941115

## Citation

> US National Institutes of Health, RePORTER application 9941115, Bioenergetic and Epigenetic Reprogramming by Obesity in Sepsis (5R01GM099807-10). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9941115. Licensed CC0.

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