Obesity is a growing problem in the developed world and underlies chronic comorbidities that reduce overall life expectancy (e.g., hypertension and diabetes) [
Research into the mechanisms and effects of obesity has relied on both diet- and genetically induced animal obesity models (e.g., leptin or leptin-receptor-deficient mice) [
This systematic review was prepared using the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidance for literature review and extraction of data, and a completed PRISMA checklist is provided in the Supplementary Material. Complete methods are provided in the Supplementary Material.
Using published guidelines [
Data were extracted by two authors (WZ and PQE) for each survival experiment in a report as described in the supplemental methods. The primary outcome examined was the effect of obesity on the odds ratio of survival based on the number of animals reported living at the end of observation periods. Group sizes, animal weights, fat masses, and blood glucose levels were determined as described in the supplemental methods. Secondary outcomes, presented in the supplemental methods, included the effect of obesity on organ injury based on physiologic or histologic measures; bacterial or viral clearance assessed by reported bacteria or viral counts in blood or tissue; and inflammatory cytokine and leptin levels in serum or tissue. Study quality and risk of bias were assessed in studies based on the Systemic Review Center for Laboratory animal Experimentation (SYRCLE) grading system and as previously described [
The odds ratio of survival with obesity versus a nonobese control was estimated using a random-effects model [
From 4,569 references identified in the literature search, 21 studies met inclusion criteria (Figure
Flow diagram that summarizes the results of the literature search.
Study characteristics.
Study (author, year) | Exp # | Species | Age (wk) | Sex | Obesity model | Challenge | Observation period | ||||
---|---|---|---|---|---|---|---|---|---|---|---|
Type | GT/DC | Type | Strain | Route | Dose | ||||||
|
|||||||||||
Hsu, 2007 | 1 | Mouse | 8–12 | F | Gen | ob/ob |
|
n/a | IT | 105 CFU | 10 d |
2 | Mouse | 8–12 | M | Gen | ob/ob/lep |
|
n/a | IT | 105 CFU | 10 d | |
Strandberg, 2009 | 3 | Mouse | 5–7 | M | Gen | ob/ob |
|
n/a | IV | 5 × 107 CFU | 17 d |
4 | Mouse | 5–7 | M | DIO | HFD |
|
n/a | IV | 5 × 107 CFU | 17 d | |
Mancuso, 2014 | 5 | Mouse | 16–18 | F | Gen | CPEF/F |
|
n/a | IT | 5 × 104 CFU | 10 d |
Svahn, 2015 | 6 | Mouse | 6 | M | DIO | HFDP |
|
n/a | IV | 3.8–4.5 × 107 CFU | 17 d |
7 | Mouse | 6 | M | DIO | HFDS |
|
n/a | IV | 3.8–4.5 × 107 CFU | 17 d | |
8 | Mouse | 6 | M | DIO | HFDS-HP |
|
n/a | IV | 3.8–4.5 × 107 CFU | 17 d | |
9 | Mouse | 6 | M | DIO | HFDS-LP |
|
n/a | IV | 3.8–4.5 × 107 CFU | 17 d | |
Svahn, 2016 | 10 | Mouse | 6 | M | DIO | HFDS |
|
n/a | IV | 3–5.4 × 107 CFU | 17 d |
11 | Mouse | 6 | M | DIO | HFDw6 |
|
n/a | IV | 3–5.4 × 107 CFU | 17 d | |
Wan, 2016 | 12 | Mouse | 3-4 | M | DIO | HFD |
|
n/a | IN | 109 CFU | 96 h |
13 | Mouse | 3-4 | M | DIO | HFD |
|
n/a | IN | 1010 CFU | 96 h | |
|
|||||||||||
Tschop, 2010 | 14 | Mouse | 6–10 | M | Gen | ob/ob | Polymicrobial | n/a | IP | n/a | 240 h |
15 | Mouse | 6–10 | M | DIO | HFD | Polymicrobial | n/a | IP | n/a | 240 h | |
16 | Mouse | 6–10 | M | Gen | ob/ob | Polymicrobial | n/a | IP | n/a | 240 h | |
Kaplan, 2012 | 17 | Mouse | 6 | M | DIO | HFD | Polymicrobial | n/a | IP | n/a | 30 h |
Siegl, 2014 | 18 | Mouse | 19 | M | DIO | HFD | Polymicrobial | n/a | IP | n/a | 240 h |
Kaplan, 2016 | 19 | Mouse | 6 | M | DIO | HFD | Polymicrobial | n/a | IP | n/a | 48 h |
|
|||||||||||
Fagioni, 1998 | 20 | Mouse | 5 | F | Gen | ob/ob |
|
n/a | IP | 30 |
7 d |
21 | Mouse | 5 | F | Gen | ob/ob |
|
n/a | IP | 100 |
7 d | |
22 | Mouse | 5 | F | Gen | ob/ob |
|
n/a | IP | 300 |
7 d | |
23 | Mouse | 5 | F | Gen | db/db |
|
n/a | IP | 30 |
7 d | |
24 | Mouse | 5 | F | Gen | db/db |
|
n/a | IP | 100 |
7 d | |
25 | Mouse | 5 | F | Gen | db/db |
|
n/a | IP | 300 |
7 d | |
Segersvard, 2003 | 26 | Rat | NR | M | DIO | HFD35 |
|
n/a | IP | 2 mg | 72 h |
27 | Rat | NR | M | DIO | HFD60 |
|
n/a | IP | 2 mg | 72 h | |
Suto, 2007 | 28 | Mouse | NR | F | Gen | B6AY12w |
|
n/a | IP | 50 |
7 d |
29 | Mouse | NR | F | Gen | B6Ay12w |
|
n/a | IP | 100 |
7 d | |
30 | Mouse | NR | F | Gen | B6-ob/ob |
|
n/a | IP | 100 |
7 d | |
31 | Mouse | NR | F | Gen | B6Ay12w |
|
n/a | IP | 200 |
7 d | |
32 | Mouse | NR | F | Gen | B6Ay10m |
|
n/a | IP | 50 |
7 d | |
33 | Mouse | NR | F | Gen | B6Ay10m |
|
n/a | IP | 100 |
7 d | |
Sakai, 2013 | 34 | Rat | 4 | M | DIO | HFD |
|
n/a | IP | 10 mg/kg | 24 h |
Fujiwara, 2014 | 35 | Rat | 4 | M | DIO | HFD |
|
n/a | IP | 10 mg/kg | 12 h |
36 | Rat | 4 | M | DIO | HFD |
|
n/a | IP | 10 mg/kg | 12 h | |
|
|||||||||||
Smith, 2007 | 37 | Mouse | NR | NR | DIO | HFD | H1N1 influenza A | A/PR8 | IN | 2 HG units | 10 d |
Easterbrook, 2011 | 38 | Mouse | 20 | M | DIO | HFD | H1N1 influenza A | CA/09 | IN | 2.5 × 105 pfu | 15 d |
39 | Mouse | 20 | M | DIO | HFD | H1N1 influenza A | NY312 | IN | 2.5 × 105 pfu | 15 d | |
40 | Mouse | 20 | M | DIO | HFD | H1N1 influenza A | Sw31 | IN | 50ul-SW31 | 15 d | |
Milner, 2013 | 41 | Mouse | NR | M | DIO | HFD-UP | H1N1 influenza A | A/PR8 | PO | 5.3 × 105 TCID50 | 13 d |
42 | Mouse | NR | M | DIO | HFD-P | H1N1 influenza A | A/PR8 | PO | 5.3 × 105TCID50 | 13 d | |
Radigan, 2014 | 43 | Mouse | 8–12 | NR | Gen | db/db | H1N1 influenza A | A/WSN/33 | IT | 500 pu | 14 d |
44 | Mouse | 8–12 | NR | Gen | db/db | H1N1 influenza A | A/WSN/33 | IT | 1500 pu | 14 d | |
O’Brien, 2015 |
45 | Mouse | 11 | M | DIO | HFD | H1N1 influenza A | CA/09 |
IN | 1 × 105 TCID50 | 10 d |
46 | Mouse | 8 | M | Gen | ob/ob | H1N1 influenza A | CA/09 | IN | 1 × 105 TCID50 | 10 d | |
47 | Mouse | 11 | M | DIO | HFD | H3N2 influenza A | HK68 | IN | 6.3 × 105 TCID50 | 10 d | |
48 | Mouse | 8 | M | Gen | ob/ob | H3N2 influenza A | HK68 | IN | 6.3 × 105 TCID50 | 10 d | |
Milner, 2015 | 49 | Mouse | 14–16 | M | DIO | HFD | H1N1 influenza A | CA/09 | IN | 5.8 × 105 | 14 d |
50 | Mouse | 14–16 | M | DIO | HFD | H1N1 influenza A | CA/09 | IN | 1.3 × 103 | 14 d | |
51 | Mouse | 13–16 | M | Gen | LepRH-/- | H1N1 influenza A | CA/09 | IN | 5.8 × 105 | 14 d | |
52 | Mouse | 13–16 | F | Gen | LepRH-/- | H1N1 influenza A | CA/09 | IN | 5.8 × 105 | 14 d |
B6-ob/ob: leptin-deficient mice; B6Ay10m and 12m: 10- and 12-week-old agouti peptide positive hyperphagic mice; CPE: lack functional carboxypeptidase enzyme; db/db: leptin receptor-deficient mice; DC: diet composition; DIO: diet-induced obesity; Exp: experiment; F: female; Gen: genetic-induced obesity; GT: genotype; HFD35: 35% of the energy from fat; HFD60: 60% of the energy from fat; HFD: high-fat diet; HFD-P: primed with virus; HFD-UP: unprimed; HFDP: polyunsaturated; HFDS-HP: high protein-to-carbohydrate ratio; HFDS-LP: low protein-to-carbohydrate ratio; HFDS: saturated; HFDw6: omega-6 fatty acid rich; IN: intranasal; IP: intraperitoneal; IT: intubation; IV: intravenous; LepRH-/-: lack leptin receptor signaling in hypothalamic neurons; M: male; n/a: not applicable; ob/ob: leptin-deficient mice; PO: oral administration; wk: week.
Survival, weight, fat mass, and glucose level table.
Study (author, year) | Exp # | Species | Obesity model | Weight (g) | Fat mass (g) | Glucose (mg/dl) | Control | Obese | |||||||
---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
Type | GT/DC | Control | Obese | Control | Obese | Control | Obese | Tot | Surv | Rep | Tot | Surv | |||
|
|||||||||||||||
Hsu, 2007 | 1 | Mo | Gen | ob/ob | NR | NR | NR | NR | NR | NR | 10 | 9 | 1 | 17 | 3 |
2 | Mo | Gen | ob/ob/lep | NR | NR | NR | NR | NR | NR | 10 | 9 | 1 | 18 | 8 | |
Strandberg, 2009 | 3 | Mo | Gen | ob/ob | 28.8 ± 0.5 | 39.3 ± 1.1 | NR | NR | NR | NR | 15 | 12 | 0 | 18 | 5 |
4 | Mo | DIO | HFD | 28.8 ± 0.5 | 39.3 ± 1.1 | 5.5 ± 0.2 | 17.0 ± 0 | NR | NR | 21 | 18 | 0 | 18 | 8 | |
Mancuso, 2014 | 5 | Mo | Gen | CPEF/F | 20 ± 0.5 | 47.5 ± 1 | NR | NR |
120 ± 5 | 180 ± 5 | 6 | 2 | 0 | 6 | 3 |
Svahn, 2015 | 6 | Mo | DIO | HFDP | 30 ± 1 | 35 ± 1 | 7.0 ± 0.5 | 14 ± 0.5 | NR | NR | 20 | 13 | 1 | 20 | 17 |
7 | Mo | DIO | HFDS | 30 ± 1 | 45 ± 1 | 7.0 ± 0.5 | 20.0 ± 0.5 | NR | NR | 20 | 13 | 1 | 20 | 4 | |
8 | Mo | DIO | HFDS-HP | 30 ± 1 | 45 ± 1 | 14.05 ± 0.5 | 20.0 ± 0.5 | NR | NR | 20 | 16 | 0 | 20 | 8 | |
9 | Mo | DIO | HFDS-LP | 30 ± 1 | 45 ± 1 | 14.05 ± 0.5 | 20.0 ± 0.5 | NR | NR | 20 | 17 | 0 | 20 | 8 | |
Svahn, 2016 | 10 | Mo | DIO | HFDS | 39 ± 1 | 45 ± 1 | 15 ± 0.5 | 20.0 ± 0.5 | NR | NR | 20 | 14 | 1 | 20 | 3 |
11 | Mo | DIO | HFDw6 | 39 ± 1 | 42.5 ± 1 | 15 ± 0.5 | 20.0 ± 0.5 | NR | NR | 20 | 14 | 1 | 20 | 8 | |
Wan, 2016 | 12 | Mo | DIO | HFD | 37.5 ± 1 | 47.5 ± 1 | NR | NR | 225 ± 40 | 350 ± 25 | 18 | 18 | 0 | 18 | 18 |
13 | Mo | DIO | HFD | 37.5 ± 1 | 47.5 ± 1 | NR | NR | 225 ± 40 | 350 ± 25 | 18 | 15 | 0 | 18 | 10 | |
|
|||||||||||||||
Tschop, 2010 | 14 | Mo | Gen | ob/ob | NR | NR | NR | NR | NR | NR | 20 | 4 | 1 | 20 | 0 |
15 | Mo | DIO | HFD | NR | NR | NR | NR | NR | NR | 20 | 4 | 1 | 7 | 4 | |
16 | Mo | Gen | ob/ob | NR | NR | NR | NR | NR | NR | 11 | 3 | 0 | 11 | 0 | |
Kaplan, 2012 | 17 | Mo | DIO | HFD | 23.4 ± 0.4 | 25.2 ± 0.4 | MRI |
MRI-inc |
NR | NR | 12 | 6 | 0 | 12 | 1 |
Siegl, 2014 | 18 | Mo | DIO | HFD | 27.7 ± 0.2 | 34.4 ± 0.5 | NR | NR | NR | NR | 10 | 1 | 0 | 14 | 10 |
Kaplan, 2016 | 19 | Mo | DIO | HFD | 27 ± 0.5 | 33 ± 1 | 2 ± 0.5 | 9.6 ± 2 | 165 ± 5 | 190 ± 5 | 12 | 4 | 0 | 12 | 2 |
|
|||||||||||||||
Fagioni, 1998 | 20 | Mo | Gen | ob/ob | 20 | 40 | NR | NR | 100 ± 5 | 190 ± 5 | 5 | 5 | 0 | 5 | 3 |
21 | Mo | Gen | ob/ob | 20 | 40 | NR | NR | 100 ± 5 | 190 ± 5 | 5 | 5 | 0 | 5 | 2 | |
22 | Mo | Gen | ob/ob | 20 | 40 | NR | NR | 100 ± 5 | 190 ± 5 | 5 | 4 | 0 | 5 | 0 | |
23 | Mo | Gen | db/db | 20 | 40 | NR | NR | 110 ± 5 | 310 ± 50 | 5 | 4 | 0 | 5 | 4 | |
24 | Mo | Gen | db/db | 20 | 40 | NR | NR | 110 ± 5 | 310 ± 50 | 5 | 1 | 0 | 5 | 1 | |
25 | Mo | Gen | db/db | 20 | 40 | NR | NR | 110 ± 5 | 310 ± 50 | 5 | 0 | 0 | 5 | 0 | |
Segersvard, 2003 | 26 | Ra | DIO | HFD35 | 415 ± 9 | 436 ± 8 | 3.4 ± 0.2 |
5.2 ± 0.2 |
NR | NR | 12 | 10 | 1 | 16 | 9 |
27 | Ra | DIO | HFD60 | 415 ± 9 | 466 ± 5 | 3.4 ± 0.2 |
6.2 ± 0.2 |
NR | NR | 12 | 10 | 1 | 16 | 10 | |
Suto, 2007 | 28 | Mo | Gen | B6AY12- | 19.6 | 25.1 | NR | NR | NR | NR | 20 | 20 | 0 | 20 | 18 |
29 | Mo | Gen | B6Ay12- | 19.6 | 25.1 | NR | NR | NR | NR | 20 | 17 | 1 | 20 | 7 | |
30 | Mo | Gen | B6-ob/ob | 19.6 | 52.8 | NR | NR | NR | NR | 20 | 17 | 1 | 24 | 0 | |
31 | Mo | Gen | B6Ay12- | 19.6 | 25.1 | NR | NR | NR | NR | 15 | 6 | 0 | 15 | 0 | |
32 | Mo | Gen | B6Ay10m | 19.6 | 51 | NR | NR | NR | NR | 6 | 2 | 0 | 5 | 0 | |
33 | Mo | Gen | B6Ay10m | 19.6 | 51 | NR | NR | NR | NR | 11 | 2 | 0 | 10 | 0 | |
Sakai, 2013 | 34 | Ra | DIO | HFD | 289 ± 3.5 | 310.6 ± 1.9 | 3.2 ± 0.3 |
6.8 ± 0.3 |
102.0 ± 2.2 | 116 ± 3.7 | 7 | 6 | 0 | 8 | 1 |
Fujiwara, 2014 | 35 | Ra | DIO | HFD | 275 ± 1 | 294 ± 2.8 | NR | NR | NR | NR | 10 | 9 | 0 | 10 | 9 |
36 | Ra | DIO | HFD | 450 ± 1 | 504.4 ± 7.3 | NR | NR | NR | NR | 7 | 5 | 0 | 7 | 1 | |
|
|||||||||||||||
Smith, 2007 | 37 | Mo | DIO | HFD | NR | NR | NR | NR | 86 ± 3 | 108 ± 9 | 18 | 17 | 0 | 18 | 10 |
Easterbrook, 2011 | 38 | Mo | DIO | HFD | NR | NR | NR | NR | NR | NR | 5 | 5 | 0 | 5 | 1 |
39 | Mo | DIO | HFD | NR | NR | NR | NR | NR | NR | 5 | 5 | 0 | 5 | 5 | |
40 | Mo | DIO | HFD | NR | NR | NR | NR | NR | NR | 5 | 0 | 0 | 5 | 0 | |
Milner, 2013 | 41 | Mo | DIO | HFD-UP | 30 ± 1 | 42.5 ± 1 | NR | NR | NR | NR | 4 | 0 | 0 | 4 | 0 |
42 | Mo | DIO | HFD-P | 30 ± 1 | 42.5 ± 1 | NR | NR | NR | NR | 46 | 46 | 0 | 46 | 44 | |
Radigan, 2014 | 43 | Mo | Gen | db/db | 20–25 | 30–35 | NR | NR | NR | NR | 10 | 3 | 0 | 10 | 0 |
44 | Mo | Gen | db/db | 20–25 | 30–35 | NR | NR | NR | NR | 10 | 0 | 0 | 10 | 0 | |
O’Brien, 2015 | 45 | Mo | DIO | HFD | 21 | 35 | NR | NR | NR | NR | 28 | 22 | 1 | 28 | 3 |
46 | Mo | Gen | ob/ob | 21 | 53 | NR | NR | NR | NR | 28 | 22 | 1 | 28 | 6 | |
47 | Mo | DIO | HFD | 21 | 35 | NR | NR | NR | NR | 28 | 21 | 1 | 28 | 0 | |
48 | Mo | Gen | ob/ob | 21 | 53 | NR | NR | NR | NR | 28 | 21 | 1 | 28 | 0 | |
Milner, 2015 | 49 | Mo | DIO | HFD | 30 ± 1 | 42.5 ± 1 | NR | NR | 70 ± 5 | 105 ± 5 | 21 | 21 | 0 | 21 | 4 |
50 | Mo | DIO | HFD | 30 ± 1 | 42.5 ± 1 | NR | NR | 70 ± 5 | 105 ± 5 | 12 | 2 | 0 | 12 | 0 | |
51 | Mo | Gen | LepRH-/- | 30 ± 1 | 42.5 ± 1 | NR | NR | NR | NR | 20 | 18 | 0 | 10 | 5 | |
52 | Mo | Gen | LepRH-/- | 30 ± 1 | 42.5 ± 1 | NR | NR | NR | NR | 20 | 19 | 0 | 13 | 4 |
Exp: experiment; db/db: leptin receptor-deficient mice; DC: diet composition; DIO: diet-induced obesity; Gen: genetic; GT: genotype; HFD: high-fat diet; Mo: mouse; NR: not recorded; ob/ob: leptin-deficient mice; Ra: Rat; Rep: repeating control animals; Surv: number of animals surviving; Tot: total number of animals studied; wk: week.
In all 43 experiments providing data, the weight of animals employed was greater in obese compared to control groups (Table
In each study including more than one experiment in the same obesity model type (diet or genetic), the effects of obesity on the odds ratio of survival (95% CI) (OR) in individual experiments were never qualitatively different and heterogeneity for the combined ORs for these experiments was never significant (
Obesity was associated with reduced survival in 19 studies, and in 11 of these, the reductions were significant (Figure
The number of total and surviving animals in obese and control groups for each of the 21 analyzed studies and the effects of obesity on the odds ratios (OR (95% CI)) of survival for each study. Also shown is the OR (95% CI) for the 21 studies and the associated
The number of total and surviving animals in obese and control groups for studies employing either a diet-induced obesity model or genetic-induced obesity model and the effects of obesity on the odds ratios (OR (95% CI)) of survival for each study and the overall OR (95% CI) for each type of obesity model and the associated
The number of total and surviving animals in obese and control groups for studies examining obesity in either mouse (18 studies) or rat (3 studies) and the effects of obesity on the odds ratios (OR (95% CI)) of survival for each study and the overall OR (95% CI) for each of the two species and the associated
The number of total and surviving animals in obese and control groups for studies employing either a single strain bacterial infection model (
The slope (±SE) for the relationship between the ratio of obese to control animal weights versus the ln(OR) with obesity in individual experiments was consistent, with an increasing detrimental effect of obesity on survival with increasing weight ratio, but this was not significant (−0.81 (0.52),
The effect of obesity on measures of organ injury and on microbe, host inflammatory cytokine, and leptin levels was then examined in experiments providing data based on the type of infectious or septic challenge that was employed. For organ injury, with a single bacterial strain challenge, lung wet-to-dry weight ratios (
Effect of obesity compared to controls on parameters of organ injury.
Author (year) | Exp # | Model | Site of infection | Significant changes in organ injury comparing obese and nonobese groups | Overall effect of obesity on measure of organ injury |
---|---|---|---|---|---|
|
|||||
Wan ’16 | 12 | DIO | IN | Lung wet/dry ratio increased at 24 h with obesity | ↑ |
13 | DIO | IN | Lung wet/dry ratio increased at 24 and 96 h with obesity | ↑ | |
|
|||||
Tschop ’10 | 14 | Gen | IP | BUN as a marker of renal injury increased at 24 h with obesity |
↑ |
Kaplan ’12 | 17 | DIO | IP | Histologic lung injury score increased at 6 h with obesity | ↑ |
Kaplan ’16 | 19 | DIO | IP | ALT as a marker of liver injury increased at 6 h with obesity | ↑ |
|
|||||
Sakai ’13 | 34 | DIO | IP | AST and liver histology score increased with obesity at 6 h | ↑ |
Fujiwara ‘14 | 35 | DIO | IP | No significant differences in lung septal thickness or |
NSD |
36 | DIO | IP | No significant differences in lung septal thickness or |
NSD | |
|
|||||
Smith ‘07 | 37 | DIO | IN | No significant difference in histologic lung injury score | NSD |
Milner ‘13 | 42 | DIO | PO | Histologic lung injury increased at 5 d and BAL protein increased at 5 d and 6 d with obesity | ↑ |
Radigan ‘14 | 43 | Gen | IT | BAL protein not significantly different at 4 d | NSD |
44 | Gen | IT | BAL protein significantly increased at 4 d with obesity | ↑ | |
O’Brien | 45 | DIO | IN | Decreased lung epithelial regeneration and increased BAL albumin at 3 d and 6 d with obesity | ↑ |
O’Brien | 46 | Gen | IN | Decreased lung epithelial regeneration and increased BAL albumin at 3 d and 6 d with obesity | ↑ |
Milner ‘15 | 49 | DIO | IN | BAL protein and albumin increased at 4 d and BAL protein increased at 8 d with obesity | ↑ |
51 | Gen | IN | BAL protein increased at 8 d with obesity | ↑ |
Exp: experiment; ALT: alanine aminotransferase; AST: aspartate aminotransferase; BAL: bronchoalveolar lavage; BUN: blood urea nitrogen; DIO: diet-induced obesity model; Gen: genetic model of obesity; NSD: no significant difference.
In experiments reporting microbial data, with single-strain bacteria, obesity significantly increased blood and/or tissue bacteria counts at ≥48 h in five experiments and had no significant effect in five others (Table
Table
Randomization, blinding, sample size calculations, and/or numbers of animals withdrawn from the study were not possible or described in studies. Therefore, the risk of bias was unclear or high in all studies examined and study quality was judged to be low (Table
This systematic review retrieved 21 studies that assessed the effect of a diet or genetic animal obesity model on survival following a single bacterial strain, CLP, LPS, or viral influenza challenge. In 19 studies, obesity was associated with reduced odds ratios of survival, 11 statistically significantly. The negative effect of obesity did not differ significantly comparing diet
Microbial clearance data, while limited, provide one possible basis for the decreased survival and increased organ injury seen with obesity in these models. Of the 23 experiments reporting data, obesity significantly increased blood or tissue bacteria or virus counts in 8 experiments and no experiment reported a decrease. Obesity-related insulin resistance and hyperglycemia or other changes may have impaired microbial clearance and worsened survival and organ injury [
Different from these findings in animal obesity models, two recent systematic reviews of observational clinical studies and a retrospective analysis of a large patient database found that obese body mass indices (BMI) appeared to increase survival in septic patients [
However, improved survival with obesity in clinical sepsis studies may be confounded by several factors. For comparably severe infection, obese patients may be admitted to the ICU more frequently where treatment is more comprehensive than in the non-ICU setting [
Different from clinical sepsis studies, but more consistent with the present findings in animal models, two systematic reviews and meta-analyses of influenza virus infection, with 6 studies in one and 22 in the other, suggested that obese BMIs are associated with worsened combined outcomes including mortality and the need for ICU admission and organ system support [
Two important questions these preclinical studies do not address are the following. First, how does obesity impact the outcome of septic patients who survive their initial course of acute infection and inflammation but progress to later sepsis with more chronic inflammation? Inflammation in these patients is characterized by both pro- and anti-inflammatory host responses. These patients frequently require prolonged invasive intensive care unit support, and maladaptive anti-inflammatory responses are believed to predispose them to secondary infection. However, clinical studies have not yet attempted to differentiate the impact of obesity on outcomes in acute versus chronically ill septic patients. Furthermore, animal models needed to test this question, although necessary, would be complex, requiring both an initial and follow-up septic challenges and prolonged observation. The second question has to do with whether comorbidities impact the outcome of sepsis and presumably then, whether obesity’s impact on outcome in septic patients is influenced by these comorbidities. Comorbidities such as heart, lung, and kidney disease are all known to worsen the outcome from sepsis. Interestingly, though, a recent retrospective analysis of a large patient database which noted a protective effect of obesity in septic patients did not find that such comorbidities influenced these effects [
The findings from this analysis in combination with data from clinical studies point to several questions that should be addressed in future preclinical studies. Would the use of antimicrobial agents blunt or reverse the harmful survival effects of obesity in preclinical models? Related to that question, does dosing antimicrobial therapy based on weight increase its effectiveness on either microbial clearance or survival? Would blood glucose control alter the effect of obesity on microbial clearance and outcome in preclinical obesity models? Similarly, would cardiopulmonary support with or without antimicrobial therapy and glucose control reverse the harmful effects of obesity in preclinical models?
The present study has limitations. Organ injury and microbe and cytokine data were not provided in many reports which prevent firm conclusions regarding the basis for obesity’s adverse effects in these preclinical studies. Weights were not reported for 9 studies and only 11 studies reported animal fat masses, although the obesity models employed are recognized to produce increases in each. Most studies did not include baseline data prior to the start of obese diets or infectious challenge. The literature search was conducted through January 2017, but it retrieved a relatively large number of reports included in the analysis and the overall survival findings were very similar across studies. Finally, the risk of bias was unclear or high across studies and study quality was judged to be low.
Determining whether obesity improves or worsens survival in critically ill patients with infection or sepsis is important. While the animal studies examined here support an adverse effect, some clinical data suggest the opposite. However as noted, in almost all cases, animal models lacked the types of support (e.g., antimicrobial therapy or glucose control) patients receive. If obesity is indeed protective during sepsis, understanding these beneficial effects might lead to new therapeutic approaches. But if obesity is detrimental for the acutely infected patient, then developing therapeutic approaches to counteract those harmful effects are necessary. These preclinical and clinical experiences together emphasize the need for prospective clinical studies that can accurately assess obesity’s impact on survival during severe infection.
The results of the preclinical studies examined here are not consistent with the reported protective effects obesity has in retrospective, observational studies of patients with bacterial infection and sepsis but are consistent with obesity’s reported harmful effects during influenza. These preclinical and clinical studies together emphasize the need for prospective studies in patients accurately assessing obesity’s impact on survival during severe infection whether from a bacterial or viral influenza source.
Alanine aminotransferase
Aspartate aminotransferase
Body mass indices
Blood urea nitrogen
Cecal ligation and puncture
Confidence interval
Intensive care units
Interleukin
Lipopolysaccharide
Macrophage inflammatory protein 2-alpha
Odds ratio of survival
Preferred Reporting Items for Systematic Reviews and Meta-Analyses
Systemic Review Center for Laboratory animal Experimentation
Tumor necrosis factor
Wet-to-dry weight ratios.
The authors declare that they have no conflicts of interest.
WX extracted, analyzed, and interpreted data and helped write and edit the manuscript. DP helped design the study and conduct the literature search and edited the manuscript. JS performed statistical analysis and edited the manuscript. JW designed and conducted the literature search and edited the manuscript. XC performed data analysis and edited the manuscript. PQE helped design the study, extracted and analyzed data, and helped write and edit the paper.
This work was supported by the Intramural Program of the NIH, Clinical Center, Critical Care Medicine Department. The authors thank Ms. Kelly Byrne for editorial assistance with this manuscript.
Supplementary Materials: search strategies and supplemental references showing the reports included in the analysis. Figure S1: this figure shows for each report including more than one experiment in the same diet-induced obesity model type the effects of obesity on the odds ratio of survival (95% CI) (OR) in individual experiments as well as the overall OR and its