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 #
5R01GM099807-09
Application #
9731511
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
2019-07-01
Budget End
2020-06-30
Support Year
9
Fiscal Year
2019
Total Cost
Indirect Cost
Name
Cleveland Clinic Lerner
Department
Other Basic Sciences
Type
Schools of Medicine
DUNS #
135781701
City
Cleveland
State
OH
Country
United States
Zip Code
44195
Wajih, Nadeem; Basu, Swati; Ucer, Kamil B et al. (2018) Erythrocytic bioactivation of nitrite and its potentiation by far-red light. Redox Biol 20:442-450
Wang, Xianfeng; Buechler, Nancy L; Long, David L et al. (2018) Cysteine thiol oxidation on SIRT2 regulates inflammation in obese mice with sepsis. Inflammation :
Long, David; Wu, Hanzhi; Tsang, Allen W et al. (2017) The Oxidative State of Cysteine Thiol 144 Regulates the SIRT6 Glucose Homeostat. Sci Rep 7:11005
Wajih, Nadeem; Basu, Swati; Jailwala, Anuj et al. (2017) Potential therapeutic action of nitrite in sickle cell disease. Redox Biol 12:1026-1039
Buechler, Nancy; Wang, Xianfeng; Yoza, Barbara K et al. (2017) Sirtuin 2 Regulates Microvascular Inflammation during Sepsis. J Immunol Res 2017:2648946
Wang, Xianfeng; Buechler, Nancy L; Martin, Ayana et al. (2016) Sirtuin-2 Regulates Sepsis Inflammation in ob/ob Mice. PLoS One 11:e0160431
Wang, XianFeng; Buechler, Nancy L; Yoza, Barbara K et al. (2016) Adiponectin treatment attenuates inflammatory response during early sepsis in obese mice. J Inflamm Res 9:167-174
Vachharajani, Vidula T; Liu, Tiefu; Wang, Xianfeng et al. (2016) Sirtuins Link Inflammation and Metabolism. J Immunol Res 2016:8167273
Millet, Patrick; Vachharajani, Vidula; McPhail, Linda et al. (2016) GAPDH Binding to TNF-? mRNA Contributes to Posttranscriptional Repression in Monocytes: A Novel Mechanism of Communication between Inflammation and Metabolism. J Immunol 196:2541-51
Smith, Lane M; Wells, Jonathan D; Vachharajani, Vidula T et al. (2015) SIRT1 mediates a primed response to immune challenge after traumatic lung injury. J Trauma Acute Care Surg 78:1034-8

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