Cecal Ligation and Puncture-Induced Sepsis Promotes Brown Adipose Tissue Inflammation Without Any Impact on Expression of Thermogenic-Related Genes

Moreno-Navarrete, José María; Comas, Ferran; Jager, Vincent D de; Fernández‐Real, José Manuel; Bouma, Hjalmar R.

doi:10.3389/fphys.2021.692618

Cited by 3 publications

(3 citation statements)

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“…As BAT UCP1 expression was not altered in mild sepsis and had a decrease after severe sepsis, we infer that fever was mediated by tail vasoconstriction rather than an increase in non-shivering thermogenesis. Although we did not measure oxygen consumption as an index of non-shivering thermogenesis, a previous report corroborates our results, showing that CLP does not increase the expression of genes related to thermogenesis in the BAT, including Ucp1gene [22]. We speculate that cytokines such as IL-6, which has a thermogenic effect in chronic situations [23,24], reduces BAT thermogenesis in acute conditions like sepsis due to its potent proin ammatory effects [25,26].…”

Section: Discussionsupporting

confidence: 86%

“…Despite the extensive research in experimental sepsis, there are several unsolved questions about the thermoregulatory dynamics during this disease. Body temperature was accessed in previous studies using the CLP method and both fever [17][18][19] and hypothermia [20][21][22] were observed, but none of these publications focused on the intrinsic body mechanisms associated with the changes in Tb and their relation with Ta.…”

Section: Discussionmentioning

confidence: 99%

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Thermoregulatory adjustments in sepsis: insights from the cecal ligation and puncture experimental model

Costa,

Trajano,

Passaglia

et al. 2024

Preprint

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Sepsis remains as a major health concern, given its high prevalence and mortality worldwide. Changes in body temperature (Tb), i.e., hypothermia or fever, are important diagnostic clues and part of the pathophysiology of this condition. Experimental studies often use bacterial lipopolysaccharide (LPS) to investigate the changes in Tb during sepsis, however, this model poorly mimics the complexity of this disease. In this work we aimed to characterize the thermoregulatory mechanisms during sepsis by using a clinically relevant murine model, the cecal ligation and puncture (CLP), and describe how sepsis severity and ambient temperature (Ta) modulate Tb regulation. We show that at thermoneutral Ta (28℃) the degree of the febrile response is proportional to the disease severity and the inflammatory response. In this condition, tail vasoconstriction, rather than non-shivering thermogenesis, seems to be the main generator of CLP-induced fever. On the other hand, when housed in a subthermoneutral Ta (22℃), animals are able to maintain Tb during mild sepsis, but develop a moderate hypothermia in a severe condition. This reduction in Tb was associated to lower UCP1 expression in the brown adipose tissue and less consistent tail vasoconstriction than the observed in mild sepsis. Although we observe differences in the thermoregulatory responses at the two Ta conditions, sepsis induced a persistent inflammatory response and increased the production of hypothalamic PGE2, a critical mediator of body temperature adjustments during an inflammatory condition. Mortality rate in response to severe sepsis was dramatically impacted by Ta (80% mortality at 28℃ and 0% mortality at 22℃). Our results demonstrate that the ambient temperature and the magnitude of the inflammatory insult deeply modulate the thermoregulatory responses and survival during sepsis.

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Section: Discussionsupporting

confidence: 86%

Section: Discussionmentioning

confidence: 99%

Thermoregulatory adjustments in sepsis: insights from the cecal ligation and puncture experimental model

Costa,

Trajano,

Passaglia

et al. 2024

Preprint

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“…Apesar de experimentos in vitro terem demonstrado que o meio condicionado com macrófagos atenuou a atividade de adipócitos marrons induzida por frio e que a ativação de receptores que realizam a mediação da via de LPS inibiu a UCP-1 e a respiração mitocondrial em adipócitos marrons, nesse estudo, nenhum efeito da sepse induzida por CLP foi observado na expressão de genes relacionados à atividade termogênica e mitocondrial. Assim, embora a sepse induzida por CLP promova a inflamação de tecido adiposo branco e tecido adiposo marrom, essa condição inflamatória aguda afeta somente a expressão do gene da adipogênese no tecido adiposo branco, sem efeitos significativos sobre os genes termogênicos no tecido adiposo marrom, sugerindo uma dissociação da inflamação aguda da disfunção do tecido adiposo no tecido adiposo marrom, porém não no tecido adiposo branco (Moreno-Navarrete JM et al, 2021).…”

Section: Discussionunclassified

Efeito da tolerância ao Lipopolissacarídeo (LPS) no desacoplamento mitocondrial da sepse

Silvestre¹

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Sepsis has organic dysfunctions due to a dysregulated inflammatory response that alters cellular functions. This cell damage occurs with significant changes to metabolic pathways and to cellular function. Uncoupling proteins (UCPs) are located in the inner mitochondrial membrane, playing roles that include heat production and regulation of the production of reactive oxygen species by mitochondria. Mitochondrial respiration results in proton extrusion (H+) outside the mitochondria and inside the intermembrane space, establishing the mitochondrial membrane potential. UCPs pump protons from the intermembrane space to the mitochondrial matrix and, thus, dissipate the proton gradient, reduce ATP production, and decrease superoxide production. Hence, UCPs play important roles in redox regulation and in mitochondrial and metabolic processes. This study has the purpose of evaluating the effects of LPS tolerance in mitochondrial uncoupling in an experimental model of sepsis, in addition to evaluating mitochondrial damage through the amount of mitochondria present in liver tissue and investigating oxygen consumption in mitochondria isolated from the liver tissue. Male, 7week-old, Balb/c mice were used, which underwent sepsis stimulation through cecal ligation and puncture (CLP) technique and induction of Escherichia coli lipopolysaccharide (LPS) tolerance. The animals were euthanized 24 hours after CLP procedure and the material was collected. The results found in this study show increased levels of UCP-1 in both groups undergoing CLP procedure, and tolerance did not change animal response. On the other hand, a reduction was seen in UCP-2 and UCP-3 levels both in the liver and in the heart of animals undergoing CLP procedure when compared to Control and Tolerant groups, also with no influence of tolerance on these UCPs. The quantification of mitochondrial DNA showed that there were no statistical differences when comparing the groups under analysis. Data showed a reduction in oxygen consumption in CLP group in State 2 when compared to Control and Tolerant groups, as well as a reduction in oxygen consumption in CLPT group in State 2 when compared to the Tolerant group, showing a deficit in oxidative metabolism in septic animals. Future studies with other periods may elucidate the metabolism cycle of UCPs in tolerance and in sepsis.

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Thermoregulation and survival during sepsis: insights from the cecal ligation and puncture experimental model

Costa,

Trajano,

Passaglia

et al. 2024

ICMx

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Background Sepsis remains a major global health concern due to its high prevalence and mortality. Changes in body temperature (Tb), such as hypothermia or fever, are diagnostic indicators and play a crucial role in the pathophysiology of sepsis. This study aims to characterize the thermoregulatory mechanisms during sepsis using the cecal ligation and puncture (CLP) model and explore how sepsis severity and ambient temperature (Ta) influence Tb regulation and mortality. Rats were subjected to mild or severe sepsis by CLP while housed at thermoneutral (28 °C) or subthermoneutral (22 °C) Ta, and their Tb was monitored for 12 h. Blood and hypothalamus were collected for cytokines and prostaglandin E2 (PGE2) analysis. Results At 28 °C, febrile response magnitude correlated with sepsis severity and inflammatory response, with tail vasoconstriction as the primary heat retention mechanism. At 22 °C, Tb was maintained during mild sepsis but dropped during severe sepsis, linked to reduced UCP1 expression in brown adipose tissue and less effective vasoconstriction. Despite differences in thermoregulatory responses, both Ta conditions induced a persistent inflammatory response and increased hypothalamic PGE2 production. Notably, mortality in severe sepsis was significantly higher at 28 °C (80%) compared to 22 °C (0%). Conclusions Our findings reveal that ambient temperature and the inflammatory burden critically influence thermoregulation and survival during early sepsis. These results emphasize the importance of considering environmental factors in preclinical sepsis studies. Although rodents in experimental settings are often adapted to cold environments, these conditions may not fully translate to human sepsis, where cold adaptation is rare. Thus, researchers should carefully consider these variables when designing experiments and interpreting translational implications. Graphical Abstract

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Cecal Ligation and Puncture-Induced Sepsis Promotes Brown Adipose Tissue Inflammation Without Any Impact on Expression of Thermogenic-Related Genes

Cited by 3 publications

References 41 publications

Thermoregulatory adjustments in sepsis: insights from the cecal ligation and puncture experimental model

Thermoregulatory adjustments in sepsis: insights from the cecal ligation and puncture experimental model

Efeito da tolerância ao Lipopolissacarídeo (LPS) no desacoplamento mitocondrial da sepse

Thermoregulation and survival during sepsis: insights from the cecal ligation and puncture experimental model

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