CRITICAL CARE - ADULTS / REVIEW ARTICLE
The obesity paradox in murine sepsis models: a systematic review and meta-analysis
1
Department of Internal Medicine and Internal Medicine in Nursing, Medical University of Lublin, Poland
2
Department of Clinical Genetics, Medical University of Lublin, Poland
3
Department of Pediatrics and Allergology, University Children’s Hospital in Lublin, Poland
Submission date: 2025-02-28
Final revision date: 2025-06-03
Acceptance date: 2025-06-26
Publication date: 2025-07-25
Anaesthesiol Intensive Ther 2025;57(1):182-194
KEYWORDS
TOPICS
ABSTRACT
The obesity paradox, suggesting improved survival in obese individuals compared to those with normal weight, remains debated, particularly in sepsis. While it has been explored in clinical and experimental settings, conclusive evidence is lacking. This study systematically reviews and meta-analyses the relationship between obesity and survival in murine sepsis models. This systematic review and meta-analysis following PRISMA guidelines included studies from PubMed/Medline (up to January 31, 2025) comparing sepsis survival in obese and non-obese mice. All eligible murine studies were systematically reviewed, whereas only those employing diet induced obesity (DIO) and cecal ligation and puncture (CLP) were pooled in the meta-analysis and meta-regression. Twenty-one studies (38 survival experiments) met the criteria: CLP (n = 14), intraperitoneal lipopolysaccharide (n = 7), and other bacterial inoculation models (n = 17). Across all models, obesity increased survival in 10, decreased it in 9, and had no effect in 19 experiments. Quantitative synthesis of 10 CLP-DIO experiments (159 obese vs. 149 lean mice) showed no overall mortality difference (P = 0.391). Meta-regression explained 86% of heterogeneity: later highfat diet (HFD) initiation and longer feeding reduced mortality, whereas older age at sepsis induction increased mortality (all P < 0.001). Across the studies, obesity exerted mixed effects; pooled analysis of CLP DIO experiments showed no survival benefit. Variability among studies was associated with time related factors: age at HFD initiation, feeding duration, and age at sepsis induction, highlighting the need to investigate these relationships and to develop a time point standardized CLP DIO sepsis model.
REFERENCES (44)
1.
Fleischmann E, Teal N, Dudley J, May W, Bower JD, Salahudeen AK. Influence of excess weight on mortality and hospital stay in 1346 hemodialysis patients. Kidney Int 1999; 55: 1560-1567. DOI: 10.1046/j.1523-1755.1999.00389.x.
2.
Wurzinger B, Dünser MW, Wohlmuth C, Deutinger MC, Ulmer H, Torgersen C, et al. The association between body-mass index and patient outcome in septic shock: a retrospective cohort study. Wien Klin Wochenschr 2010; 122: 31-36. DOI: 10.1007/s00508-009-1241-4.
3.
Trivedi V, Bavishi C, Jean R. Impact of obesity on sepsis mortality: a systematic review. J Crit Care 2015; 30: 518-524. DOI: 10.1016/j.jcrc.2014.12.007.
4.
Pepper DJ, Sun J, Welsh J, Cui X, Suffredini AF, Eichacker PQ. Increased body mass index and adjusted mortality in ICU patients with sepsis or septic shock: a systematic review and meta-analysis. Crit Care 2016; 20: 181. DOI: 10.1186/s13054-016-1360-z.
5.
Wang S, Liu X, Chen Q, Liu C, Huang C, Fang X. The role of increased body mass index in outcomes of sepsis: a systematic review and meta-analysis. BMC Anesthesiol 2017; 17: 118. DOI: 10.1186/s12871-017-0405-4.
6.
Robinson J, Swift-Scanlan T, Salyer J. Obesity and 1-year mortality in adults after sepsis: a systematic review. Biol Res Nurs 2020; 22: 103-113. DOI: 10.1177/1099800419876070.
7.
Bai L, Huang J, Wang D, Zhu D, Zhao Q, Li T, Zhou X, Xu Y. Association of body mass index with mortality of sepsis or septic shock: an updated meta-analysis. J Intensive Care 2023; 11: 27. DOI: 10.1186/s40560-023-00677-0.
8.
Gao L, Liu JJ, Fan QC, Ling LT, Ding HB. Association of obesity and mortality in sepsis patients: a meta-analysis from observational evidence. Heliyon 2023; 9: e19556. DOI: 10.1016/j.heliyon.2023.e19556.
9.
Eng M, Suthaaharan K, Newton L, Sheikh F, Fox-Robichaud A. Sepsis and obesity: a scoping review of diet-induced obesity murine models. Intensive Care Medicine Experimental 2024; 12: 15. DOI: 10.1186/s40635-024-00603-0.
10.
Seok J, Warren HS, Cuenca AG, Mindrinos MN, Baker HV, Xu W, et al. Genomic responses in mouse models poorly mimic human inflammatory diseases. Proc Natl Acad Sci U S A 2013; 110: 3507-3512. DOI: 10.1073/pnas.1222878110.
11.
Demetrius L. Of mice and men. When it comes to studying ageing and the means to slow it down, mice are not just small humans. EMBO Rep 2005; 6 Spec No (Suppl 1): S39-S44. DOI: 10.1038/sj.embor.7400422.
12.
Stortz JA, Cox MC, Hawkins RB, Ghita GL, Brumback BA, Mohr AM, et al. Phenotypic heterogeneity by site of infection in surgical sepsis: a prospective longitudinal study. Crit Care 2020; 24: 203. DOI: 10.1186/s13054-020-02917-3.
13.
Wang W, Liu CF. Sepsis heterogeneity. World J Pediatr 2023; 19: 919-927. DOI: 10.1007/s12519-023-00689-8.
14.
Singer M, Deutschman CS, Seymour C, Shankar-Hari M, Annane D, et al. The third international consensus definitions for sepsis and septic shock (sepsis-3). JAMA 2016; 315: 801-810. DOI: 10.1001/jama.2016.0287.
15.
Kingsley SMK, Bhat BV. Differential paradigms in animal models of sepsis. Curr Infect Dis Rep 2016; 18: 26. DOI: 10.1007/s11908-016-0535-8.
16.
Korneev KV. Mouse models of sepsis and septic shock. Mol Biol (Mosk) 2019; 53: 799-814. DOI: 10.1134/S0026898419050100.
17.
Cai L, Rodgers E, Schoenmann N, Raju RP. Advances in rodent experimental models of sepsis. Int J Mol Sci 2023; 24. 9578. DOI: 10.3390/ijms24119578.
18.
WHO. Obesity [Internet]. Available from: https://www.who.int/health-top... (Assesed: 21.02.2024).
19.
Lutz TA, Woods SC. Overview of animal models of obesity. Curr Protoc Pharmacol 2012; Chapter 5: Unit5.61. DOI: 10.1002/0471141755.ph0561s58.
20.
Martins T, Castro-Ribeiro C, Lemos S, Ferreira T, Nascimento-Gonçalves E, Rosa E, et al. Murine models of obesity. Obesities 2022; 2: 127-147. DOI: https://doi.org/10.3390/obesit....
21.
Page MJ, McKenzie JE, Bossuyt PM, Boutron I, Hoffmann TC, Mulrow CD, et al. The PRISMA 2020 statement: an updated guideline for reporting systematic reviews. BMJ 2021; 372: n71. DOI: 10.1136/bmj.n71.
22.
Schünemann HJ, Brennan S, Akl EA, Hultcrantz M, Alonso-Coello P, Xia J, et al. The development methods of official GRADE articles and requirements for claiming the use of GRADE – a statement by the GRADE guidance group. J Clin Epidemiol 2023; 159: 79-84. DOI: 10.1016/j.jclinepi.2023.05.010.
23.
Berto-Pereira L, Nakama RP, Dos Santos LF, Malvezi AD, Thihara IRT, de Rossi LS, et al. Impact of metabolic syndrome on cardiovascular, inflammatory and hematological parameters in female mice subjected to severe sepsis. Biochem Biophys Res Commun 2024; 739: 150966. DOI: 10.1016/j.bbrc.2024.150966.
24.
Nakama RP, Dos Santos LF, Berto-Pereira L, de Rossi LS, Malvezi AD, Lovo-Martins MI, et al. Metabolic syndrome induces benefits in mice experiencing severe sepsis, comparable to the effects of low-dose aspirin pretreatment in septic mice lacking metabolic syndrome. Int Immunopharmacol 2024; 139: 112694. DOI: 10.1016/j.intimp.2024.112694.
25.
Nishimura M, Nakanishi T, Ichishi M, Matsushima Y, Watanabe M, Yamanaka K. Increased mortality risk at septic condition in inflammatory skin disorders and the effect of high-fat diet consumption. Int J Mol Sci 2023; 25: 478. DOI: 10.3390/ijms25010478.
26.
Bodilly L, Williamson L, Lahni P, Alder MN, Haslam DB, Kaplan JM. Obesity alters cytokine signaling and gut microbiome in septic mice. Innate Immunity 2023; 29: 161-170. DOI: 10.1177/17534259231205959.
27.
Gomes SV, Dias BV, Júnior PAM, Pereira RR, de Souza DMS, Bre-guez GS, et al. High-fat diet increases mortality and intensifies immunometabolic changes in septic mice. J Nutr Biochem 2023; 116: 109315. DOI: 10.1016/j.jnutbio.2023.109315.
28.
Petroni RC, de Oliveira SJS, Fungaro TP, Ariga SKK, Barbeiro HV, Soriano FG, de Lima TM. Short-term obesity worsens heart inflammation and disrupts mitochondrial biogenesis and function in an experimental model of endotoxemia. Inflammation 2022; 45: 1985-1999. DOI: 10.1007/s10753-022-01669-2.
29.
Vankrunkelsven W, Derde S, Gunst J, Vander Perre S, Declerck E, Pauwels L, et al. Obesity attenuates inflammation, protein catabolism, dyslipidaemia, and muscle weakness during sepsis, independent of leptin. J Cachexia Sarcopenia Muscle 2022; 13: 418-433. DOI: 10.1002/jcsm.12904.
30.
Lewis ED, Williams HC, Bruno MEC, Stromberg AJ, Saito H, Johnson LA, Starr ME. Exploring the obesity paradox in a murine model of sepsis: improved survival despite increased organ injury in obese mice. Shock 2022; 57: 151-159. DOI: 10.1097/SHK.0000000000001856.
31.
Martins ICA, Contieri LS, Amaral CL, Costa SO, Souza ACP, Ignacio-Souza LM, et al. Omega-3 supplementation prevents short-term high-fat diet effects on the α7 nicotinic cholinergic receptor expression and inflammatory response. Mediat Inflamm 2021; 2021: 5526940. DOI: 10.1155/2021/5526940.
32.
Nakama RP, Malvezi AD, Lovo-Martins MI, Dos Santos LF, Canizares Cardoso AP, Scacco G, et al. Metabolic syndrome improves cardiovascular dysfunction and survival during cecal ligation and puncture-induced mild sepsis in mice. Life Sci 2021; 286: 120033. DOI: 10.1016/j.lfs.2021.120033.
33.
Wang F, Cen Z, Liu Z, Gan J, Zhang X, Cui Q, et al. High-fat diet-induced fatty liver is associated with immunosuppressive response during sepsis in mice. Oxid Med Cell Longev 2021; 2021: 5833857. DOI: 10.1155/2021/5833857.
34.
Souza ACP, Souza CM, Amaral CL, Lemes SF, Santucci LF, Milanski M, et al. Short-term high-fat diet consumption reduces hypothalamic expression of the nicotinic acetylcholine receptor α7 subunit (α7nachr) and affects the anti-inflammatory response in a mouse model of sepsis. Front Immunol 2019; 10: 565. DOI: 10.3389/fimmu.2019.00565.
35.
Napier BA, Andres-Terre M, Massis LM, Hryckowian AJ, Higginbottom SK, Cumnock K, et al. Western diet regulates immune status and the response to LPS-driven sepsis independent of diet-associated microbiome. Proc Natl Acad Sci U S A 2019; 116: 3688-3694. DOI: 10.1073/pnas.1814273116.
36.
Frydrych LM, Bian G, Fattahi F, Morris SB, O’Rourke RW, Lumeng CN, et al. GM-CSF Administration improves defects in innate immunity and sepsis survival in obese diabetic mice. J Immunol 2019; 202: 931-942. DOI: 10.4049/jimmunol.1800713.
37.
Kaplan JM, Nowell M, Lahni P, Shen H, Shanmukhappa SK, Zingarelli B. Obesity enhances sepsis-induced liver inflammation and injury in mice. Obesity (Silver Spring, Md) 2016; 24: 1480-1488. DOI: 10.1002/oby.21504.
38.
Siegl D, Midura EF, Annecke T, Conzen P, Caldwell CC, Tschoep J. The effect of ghrelin upon the early immune response in lean and obese mice during sepsis. PLoS One 2015; 10: e0122211. DOI: 10.1371/journal.pone.0122211.
39.
Svahn SL, Grahnemo L, Pálsdóttir V, Nookaew I, Wendt K, Gabrielsson B, et al. Dietary polyunsaturated fatty acids increase survival and decrease bacterial load during septic Staphylococcus aureus infection and improve neutrophil function in mice. Infect Immun 2015; 83: 514-521. DOI: 10.1128/IAI.02349-14.
40.
Siegl D, Annecke T, Johnson BL 3rd, Schlag C, Martignoni A, Huber N, et al. Obesity-induced hyperleptinemia improves survival and immune response in a murine model of sepsis. Anesthesiology 2014; 121: 98-114. DOI: 10.1097/ALN.0000000000000192.
41.
Kaplan JM, Nowell M, Lahni P, O’Connor MP, Hake PW, Zingarelli B. Short-term high fat feeding increases organ injury and mortality after polymicrobial sepsis. Obesity (Silver Spring) 2012; 20: 1995-2002. DOI: 10.1038/oby.2012.40.
42.
Strandberg L, Verdrengh M, Enge M, Andersson N, Amu S, Onnheim K, et al. Mice chronically fed high-fat diet have increased mortality and disturbed immune response in sepsis. PLoS One 2009; 4: e7605. DOI: 10.1371/journal.pone.0007605.
43.
Clouva-Molyvdas P, Peck MD, Alexander JW. Short-term dietary lipid manipulation does not affect survival in two models of murine sepsis. JPEN J Parenter Enteral Nutr 1992; 16: 343-347. DOI: 10.1177/0148607192016004343.
44.
Xu W, Pepper D, Sun J, Welsh J, Cui X, Eichacker PQ. The effects of obesity on outcome in preclinical animal models of infection and sepsis: a systematic review and meta-analysis. J Obes 2020; 2020: 1508764. DOI: 10.1155/2020/1508764.
| eISSN: | 1731-2531 |
| ISSN: | 1642-5758 |
We process personal data collected when visiting the website. The function of obtaining information about users and their behavior is carried out by voluntarily entered information in forms and saving cookies in end devices. Data, including cookies, are used to provide services, improve the user experience and to analyze the traffic in accordance with the Privacy policy. Data are also collected and processed by Google Analytics tool (more).
You can change cookies settings in your browser. Restricted use of cookies in the browser configuration may affect some functionalities of the website.
You can change cookies settings in your browser. Restricted use of cookies in the browser configuration may affect some functionalities of the website.
