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, mortality, and costs associated with sepsis.

Public Health Relevance

Sepsis, the 11th leading cause of death in the US, has no specific therapy thus far. Obesity increases the morbidity and resource utilization, increasing cost of care in sepsis patients further. This proposal focuses on studying the molecular mechanisms in obese individuals with sepsis. Completion of these studies will potentially lead to specific therapies in sepsis and obesity with sepsis.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
2R01GM099807-06A1
Application #
9381097
Study Section
Surgery, Anesthesiology and Trauma Study Section (SAT)
Program Officer
Dunsmore, Sarah
Project Start
2012-07-01
Project End
2021-06-30
Budget Start
2017-07-01
Budget End
2018-06-30
Support Year
6
Fiscal Year
2017
Total Cost
Indirect Cost
Name
Wake Forest University Health Sciences
Department
Anesthesiology
Type
Schools of Medicine
DUNS #
937727907
City
Winston-Salem
State
NC
Country
United States
Zip Code
27157
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