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. 2009 Feb 12;150(6):2660–2667. doi: 10.1210/en.2008-1622

Accelerated Recovery from Acute Hypoxia in Obese Mice Is Due to Obesity-Associated Up-Regulation of Interleukin-1 Receptor Antagonist

Christina L Sherry 1, Stephanie S Kim 1, Gregory G Freund 1
PMCID: PMC2689805  PMID: 19213834

Abstract

The proinflammatory consequences of obesity are thought to be due, in part, to macrophage infiltration into adipose tissue. There are, however, potential antiinflammatory consequences of obesity that include obesity-associated up-regulation of IL-1 receptor antagonist (IL-1RA). Here we show that obesity-associated up-regulation of IL-1RA speeds recovery from hypoxia. We found that high-fat diet-fed (HFD) mice recovered from acute hypoxia 5 times faster than normal-diet-fed (ND) mice. HFD mice had a 10-fold increase in serum IL-1RA when compared with ND mice. White adipose tissue (WAT) was a significant source of IL-RA, generating 330 ± 77 pg/mg protein in HFD mice as compared with 15 ± 5 pg/mg protein in ND mice. Peritoneal macrophages isolated from HFD mice showed little difference in IL-1RA production when compared with ND mice, but WAT macrophages from HFD mice generated 11-fold more IL-1RA than those from ND mice. When ND mice were given an ip transfer of the stromal vascular fraction portion of WAT from HFD mice, serum IL-1RA increased 836% and recovery from acute hypoxia was faster than in mice that did not receive a stromal vascular fraction transfer. To determine whether IL-1RA was important to this accelerated recovery, ND mice were administered exogenous IL-1RA prior to hypoxia, and their recovery matched that of HFD mice. Inversely, when IL-1RA was immunoabsorbed in HFD mice with IL-1RA antiserum, recovery from acute hypoxia was attenuated. Taken together these data demonstrate that HFD-induced obesity speeds recovery from hypoxia due to obesity-associated up-regulation of IL-1RA.

Recovery from acute hypoxia is accelerated in obese mice due to obesity-associated up-regulation of the anti-inflammatory molecule IL-1 receptor antagonist.

Obesity is a state of increased lipid accumulation in white adipose tissue (WAT) that is linked to not only weight gain but also chronic, low-grade inflammation (1). Long seen as just a passive storage tissue, fat is now considered an active endocrine organ that regulates satiety, metabolism, reproduction, and immune function (2). In addition to its elaboration of lipid molecules, fat is a pleiotropic source of proteins, hormones, chemokines, and cytokines (3,4). WAT, similar to many solid organs, is comprised of an eponymous cell, i.e. the adipocyte, supported by a fibrovascular stroma (4) containing capillaries (5) and tissue based macrophages (6). These resident adipose tissue macrophages (AtMφs) of the stromal vascular fraction (SVF) appear integral to obesity and its associated complications (7). Conversely, weight loss leads to a reduction in AtMφ numbers and obesity-associated inflammation (7).

With tissue-based macrophages, the local microenvironment contributes substantially to phenotypic heterogeneity, and this heterogeneity extends beyond intertissue differences to intratissue disparities (8). In general, macrophage activation is functionally defined as classical or alternative (9). However, between these defined activation states there exists a cornucopia of variations (8,10). The phenotype of AtMφs is not clearly defined, but there appears to be an activation state difference between AtMφs resident to WAT and those recruited to WAT during/after the onset of obesity (11). In addition, it has been suggested that the phenotype of recruited AtMφs in obesity skews to alternative (12) due to: 1) decreased expression/elaboration of IL-8, cyclooxygenase-2 (13), IL-6, inducible nitric oxide synthase, and C-C chemokine receptor 2 (11); 2) increased endocytic activity; and 3) augmented expression/elaboration of IL-10 and IL-1 receptor antagonist (IL-1RA) (14).

Although conventional wisdom associates obesity with a proinflammatory state (15), up-regulation of antiinflammatory mediators, such as IL-10 and IL-1RA, appear linked to adiposity as well. In obese humans, serum IL-1RA is increased (16) as it is in high-fat diet-fed (HFD) rodent models, Obesity also increases WAT-based IL-1RA (17,18). Whereas IL-1RA antagonizes the effect of IL-1 (19), its role in obesity, like that of IL-1, is not clear (20). In humans and mice, the IL-1 receptor appears to have an antiobesity effect with IL-1 receptor-1 knockout mice developing mature-onset obesity (21). Interestingly, IL-1 knockout mice have a wild-type phenotype and do not exhibit signs of obesity (weight gain, increased epididymal white adipose tissue, and leptin) unless it is coupled to a knockout of IL-6 (22). In contrast, IL-1RA knockout mice are resistant to the development of obesity and have a lean phenotype (23,24). Taken together, these data indicate that in mice, IL-1RA through the IL-1 receptor 1 promotes fatness.

In humans, obesity is associated with improved survival for certain diseases and conditions including heart failure (25,26), coronary artery disease (27,28), chronic kidney disease (29), and rheumatoid arthritis (30,31). In terms of mechanism, the enhanced survival in rheumatoid arthritis is the easiest to understand because anti-IL-1 therapy in the form of a derivitized IL-1RA (anakinra) is used clinically in the treatment of rheumatoid arthritis (32). Given that obesity is associated with increased serum levels of endogenous IL-1RA, it would seem reasonable to expect that obese patients would be protected from or have blunted complications to rheumatoid arthritis. We have recently shown that acute hypoxia up-regulates IL-1 in the brain and that this brain-based increase in IL-1β is responsible for behavioral deficits found during recovery from acute hypoxia (33). We also found that blocking IL-1 signaling through MyD88 knockout or inhibiting IL-1β production in the brain via intracerebroventricular administration of a caspase-1 inhibitor hastens mouse recovery from acute hypoxia (33). Here we tested whether obesity-associated IL-1RA up-regulation is beneficial to acute hypoxia recovery in a mouse model of obesity.

Materials and Methods

Materials

All reagents and chemicals were purchased from Sigma-Aldrich (St. Louis, MO) except as follows and where indicated: fetal calf serum (0.05 ng/ml, 0.48 U/ml endotoxin; Atlanta Biologicals, Atlanta, GA); Bio-Rad protein assay (500-0006) and Bio-Plex (X60000ZM08; Bio-Rad Laboratories, Hercules, CA); IL-1RA ELISA (MRA00) and leptin ELISA (MOB00; R&D Systems, Minneapolis, MN); collagenase type I (no. 4196; Worthington Biochemical Corp., Freehold, NJ); 60% fat diet (D12492; Research Diets, Inc., New Brunswick, NJ); sheep antirat IL-1RA serum (National Institute for Biological Standards and Control, Hertfordshire, UK); normal preimmune sheep serum (GTX73209, GeneTex, Inc. (San Antonio, TX); and anakinra (Amgen, Thousand Oaks, CA).

Animals

Animal use was conducted in accordance with the Guide for the Care and Use of Laboratory Animals as we have described (33). C56BL/6J male mice were bred in-house. Mice were housed in standard shoe box cages and allowed NIH 5K52 LabDiet pelleted food (Purina Mills, St. Louis, MO) and water ad libitum. Housing temperature (72 F) and humidity (45–55%) were controlled as was a 12-h reversed dark, 12-h light cycle (2000-0800 h). Obesity was induced by feeding a high-fat diet (60% fat) immediately after weaning for 12 wk. Normal-diet mice were fed a diet containing 10% fat for the same period of time.

Hypoxia

Hypoxia was induced as we have described (33,34). In brief, mice were placed in a 12- × 6- × 4-in. plastic container connected to a S. J. Smith & Co. (Davenport, IA)-certified gas cylinder containing 8% oxygen and 92% nitrogen for 2 h. Normoxic controls were tested in a similar 12- × 6- ×-4 in. plastic container with atmospheric air was blown into it at the same rate as mice receiving the 8% oxygen/92% nitrogen mix. Hypoxia was terminated by returning mice to their home cages in atmospheric air conditions.

Recovery from hypoxia

Hypoxia-induced social withdrawal was used to measure recovery from hypoxia, as we have described (33,34). In brief, a 3- to 4-wk-old novel, conspecific juvenile (challenge) mouse was enclosed in a 3- × 3-in. wire mesh cage that was placed in the home cage of the adult (test) mouse for 5 min immediately before hypoxia (−2 h) and for 5 min at 0, 2, 6, and 10 h after return of the test mouse to normal oxygen. Duration of test mouse-initiated exploratory behavior of the challenge mouse was determined from the video records. To control for mouse-to-mouse variability in baseline social exploration and allow comparison of relative changes in social exploration levels, the prehypoxia exposure (−2 h) measurement was used as an internal control for each mouse. Results are expressed as percentages of the baseline measurement.

Peritoneal lavage

As we previously described (35), mice were killed by CO2 asphyxiation and the peritoneum lavaged using 1 ml of ice-cold PBS (pH 7.4). Lavage fluid was clarified via centrifugation at 16,000 × g for 10 min. ELISAs were performed on clarified lavage fluid in 96-well plates at room temperature.

Peritoneal macrophage (PerMφ) isolation

As we previously described (35), mice were killed by CO2 asphyxiation. Peritoneal cells were collected by peritoneal lavage using 10 ml of ice-cold growth medium [RPMI 1640 supplemented with 10% fetal calf serum, 2 g/liter sodium bicarbonate, 110 mg/liter sodium pyruvate, 62.1 mg/liter penicillin, 100 mg/liter streptomycin, and 10 mm HEPES (pH 7.4)]. Lavage cells were pelleted and resuspended in 10 ml of hypertonic red blood cell lysis buffer [142 mm NaCl, 1 mm KHCO3, and 118 mm NaEDTA (pH 7.4)] at room temperature for 5 min and then mixed 1:1 with growth medium and repelleted and resuspended at 37 C. Cells were plated on plastic at 0.5 × 06 cells/ml, and after 1 h plates were washed twice to remove nonadherent cells, resulting in greater than 80% pure macrophages as confirmed by CD11b staining and morphology. Cells were incubated in fresh growth media cultured at 37 C in a 5% CO2 environment. For in vitro hypoxia experiments, macrophages were cultured in a modular incubator chamber (Billups-Rothenberg, Inc., Del Mar, CA) in an 8% oxygen/92% nitrogen environment at 37 C.

SVF isolation

Perigonadal WAT was collected and minced in 20 ml of Hanks’ balanced salt solution containing collagenase type I (1 mg/ml) and incubated with shaking for 1.5 h at 37 C. Suspensions were centrifuged at 500 × g for 5 min to separate buoyant layer from pellet. The pellet was resuspended in 10 ml of hypertonic RBC lysis buffer for 5 min at room temperature and then repelleted and resuspended in 500 μl of sterile saline for ip injection (pooled SVF from three HFD mice) or mixed 1:1 with growth media and plated on plastic for macrophage isolation. For macrophage isolation, cells were allowed to adhere for 1 h and then washed twice to remove nonadherent cells. Adherent cells were cultured in growth media at 37 C.

Blood glucose, total cholesterol, and triglycerides

Blood was collected from either the tail vein (blood glucose) or inferior vena cava (cholesterol and triglycerides). Briefly, mice were fasted for 8 h and blood glucose levels measured using a One Touch Ultra glucometer (Johnson & Johnson, New Brunswick, NJ) per the manufacturer’s instructions. Cholesterol and triglycerides were measured after a 14-h fast on a UniCel DxC 800 Synchron clinical system (Beckman Coulter, Fullerton, CA).

Cytokine measurements

For blood cytokine levels, inferior vena cava serum was analyzed by BioPlex for IL-1β, IL-4, IL-6, IL-10, IL-12 (p40), IL-12 (p70), IL-13, interferon-γ, and TNF-α and by ELISA for IL-1RA and leptin, all per the manufacturer’s instructions. For tissue cytokine levels, 75 mg of the indicated tissue were collected into 500 μl of ice-cold homogenization buffer [1% Triton X-100, 100 mm NaCl, 50 mm NaF, 1 mm dithiothreitol, 25 mm benzamidine, 1 mm phenylmethylsulfonyl fluoride, 1:1000 Protease Inhibitor Cocktail Set III, no. 539134 (Calbiochem, La Jolla, CA), 2 mm sodium orthovanadate, 250 nm okadaic acid, and 50 mm Tris (pH 7.4)]. Tissues were ground with a tissue tearor (BioSpec Products, Bartlesville, OK) and the homogenates centrifuged at 10,000 × g (4 C) for 10 min. Cytokine levels were measured in the clarified lysates and normalized to total tissue protein as measured by Bio-Rad protein assay.

RNA isolation and reverse transcription

Total RNA was extracted into TRIzol (Invitrogen, Carlsbad, CA). Reverse transcription was preformed with high-capacity cDNA reverse transcription kits (Applied Biosystems, Foster City, CA) per the manufacturer’s instructions. To minimize interassay variation, all RNA samples were reverse transcribed simultaneously.

Real-time PCR

Real-time PCR was performed as we have described (33,35). In brief, TaqMan gene expression primer for IL-1α (Mm00439620_m1), IL-1β (Mm0043228_m1), IL-1RA (Mm00446185_m1), and IL-1R2 (Mm00439622_m1) were used in real-time RT-PCR performed on a 7900 HT Fast real-time PCR system (Applied Biosystems) using TaqMan universal PCR master mix. To normalize gene expression, a parallel amplification of endogenous glyceraldehyde-3-phosphate dehydrogenase (Mm999999615_g1) was performed with TaqMan gene expression primer. Reactions with no reverse transcriptase and no template were included as negative controls. Relative quantitative evaluation of target gene levels was performed by comparing ΔCts, where Ct is the threshold concentration.

Statistical analysis

Data are presented as mean ± sem. The experimental design for hypoxia recovery experiments was a completely randomized design, with a 2 × 2 factorial arrangement of treatments (two levels of pretreatment and two levels of treatment). All data were analyzed using SAS Inst PROC MIXED procedures (SAS, Cary, NC). The statistical model for hypoxia recovery included the effects of diet/anakinra/SVF transfer/IL-1RA antiserum and hypoxia and time, with time as a repeated measure, and the interactions of diet/anakinra/SVF transfer/IL-1RA antiserum × hypoxia × time. Post hoc comparisons of individual group means were performed with the Tukey’s test. Where indicated, experimental data were analyzed by ANOVA using SAS. Statistical significance was denoted at P < 0.05.

Results

Obesity speeds recovery from acute hypoxia

Mice fed a HFD for 12 wk after weaning had a 37, 57, and 46% increase in body weight, fasting blood glucose, and total cholesterol, respectively (supplemental Table 1, published as supplemental data on The Endocrine Society’s Journals Online web site at http://endo.endojournals.org) when compared with mice fed a normal diet (ND). Figure 1 demonstrates that HFD mice recovered faster from acute hypoxia than ND mice. HFD mice had significantly improved recovery from hypoxia at 2 h (75 ± 9 vs. 36 ± 5%) and 6 h (101 ± 9 vs. 64 ± 9%) after hypoxia compared with ND mice. Three-way ANOVA (phenotype × hypoxia × time) revealed a significant diet × hypoxia interaction [F (1,16) = 2.98, P < 0.05] and a hypoxia × time interaction [F (3,48) = 33.73, P < 0.0001] but no diet × hypoxia × time interaction.

Figure 1.

Figure 1

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HFD-induced obesity speeds recovery from acute hypoxia. Baseline behavior was measured in ND and HFD mice immediately before hypoxia exposure (−2 h). Mice were then placed in either a normoxic or hypoxic environment for 2 h. Behavioral recovery from hypoxia was measured 0, 2, 6, and 10 h after return of animals to normoxia. Results are expressed as percentages of the baseline measurement, means ± sem: n = 6. *, P < 0.05, hypoxia vs. normoxia; #, P < 0.05, ND vs. HFD.

IL-1 and its counterregulatory proteins are altered by obesity

In the brain (Fig. 2, A and B), HFD mice had increased mRNA expression of IL-1α and -β basally when compared with ND mice [3.57 ± 0.53 vs. 1.09 ± 0.34 ΔmRNA, F (1,5) = 17.32, P < 0.005 and 3.59 ± 0.56 vs. 1.30 ± 0.42 ΔmRNA, F (1,11) = 11.26, P < 0.005, respectively]. Hypoxia increased IL-1α and -β mRNA expression in the brain but not differentially in HFD and ND mice. WAT mRNA expression of IL-1α and IL-1β was not impacted by obesity or hypoxia. Figure 2C demonstrates that WAT from HFD mice had increased basal expression of IL-1RA mRNA [55.38 ± 12.72 vs. 1.21 ± 0.32 ΔmRNA HFD vs. ND, F (1,10) = 21.73, P < 0.0005] and that IL-1RA mRNA was up-regulated by hypoxia significantly more in HFD than ND mice [412.30 ± 159.53 vs. 0.48 ± 0.16 HFD vs. ND at 0 h, F (1,14) = 7.33, P < 0.01; and 89.05 ± 15.74 vs. 0.37 ± 0.13 HFD vs. ND at 2 h, F (1,8) = 67.73, P < 0.0005]. In the brain, IL-1RA mRNA increased 42-fold 2 h after hypoxia in HFD mice but only 2-fold in ND mice. IL-1R2 mRNA expression (Fig. 2D) showed a similar pattern as IL-1RA in WAT [4.73 ± 1.38 vs. 1.17 ± 0.27 HFD vs. ND, basally, F (1,10) = 6.46, P < 0.05, and 16.48 ± 2.94 vs. 5.21 ± 1.34 HFD vs. ND, at 0 h, F (1,14) = 13.91, P < 0.005]. In the brain, IL-1R2 mRNA increased after hypoxia but showed no diet differential. Finally, supplemental Table 2 shows that IL-1RA was increased 11-fold in the serum of HFD mice basally when compared with ND animals. This was coupled to a 1.4-fold increase in leptin.

Figure 2.

Figure 2

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IL-1 and its counterregulatory proteins are altered by HFD-induced obesity. IL-1α (A), IL-1β (B), IL-1RA (C), and IL-1R2 (D) mRNA were measured in brain and perigonadal WAT by real-time RT-PCR. Results are expressed as relative change in target mRNA to glyceraldehyde-3-phosphate dehydrogenase (ΔmRNA) and as means ± sem: n = 6–8. *, P < 0.05, **, P < 0.001 ND vs. HFD; #, P < 0.05 −2 h vs. 0 h, 2 h ND; +, P < 0.05 −2 h vs. 0 h, 2 h HFD.

WAT in HFD mice is a key source of IL-1RA

Figure 3A demonstrates that IL-1RA protein expression (per milligram of tissue) was 22-fold greater [330.61 ± 77.01 vs. 14.82 ± 4.93 pg/mg protein, F (1,4) = 25.81, P < 0.005] in perigonadal WAT from HFD mice than ND mice. Liver from HFD and ND mice showed similar amounts of IL-1RA (54.33 ± 4.74 vs. 33.79 ± 22.03 pg/mg protein, HFD vs. ND). In brain, IL-1RA protein was not detectable. Supplemental Table 3 demonstrates the expression of IL-1RA, IL-1R2, IL-1α, and IL-1β mRNA expression in perigonadal, sc, perirenal, and mesenteric fat from ND and HFD mice. Because macrophages are a critical source of IL-1RA, we isolated AtMφs to examine their IL-1RA production. Figure 3C demonstrates that AtMφs from HFD mice produced 11-fold more IL-1RA than AtMφs from ND mice (103 ± 42 vs. 1129 ± 107 pg/mg protein per 3 h). PerMφ production of IL-1RA from HFD mice did not show a difference compared with ND mice (456.49 ± 168.01 vs. 572.38 ± 192.86 pg/mg protein per 3 h, HFD vs. ND). Finally, a hypoxic environment did not appear to significantly impact AtMφ or PerMφ IL-1RA production in either HFD or ND mice.

Figure 3.

Figure 3

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WAT in HFD mice is a key source of IL-1RA. A, IL-1RA protein was measured in WAT, liver, and brain tissue homogenates by ELISA. Results are expressed as means ± sem: n = 4. *, P < 0.05; **, P < 0.005, ND vs. HFD. B, IL-1RA protein produced by PerMφs and AtMφs cultured in vitro for 2 h in normoxic conditions was measured by ELISA. Results are expressed as means ± sem: n = 3. *, P < 0.05, ND vs. HFD. C, IL-1RA protein produced by PerMφs and AtMφs cultured in vitro for 2 h in hypoxic conditions was measured by ELISA. Results are expressed as means ± sem: n = 3. *, P < 0.05, ND vs. HFD.

Accelerated hypoxia recovery can be transferred from HFD mice to ND mice

SVF isolated from HFD mice and then transferred to the peritoneum of ND mice increased peritoneal and blood levels of IL-1RA in ND mice 20-fold (115 ± 19 vs. 2322 ± 432 pg/ml per 3 h) and 9-fold (29.58 ± 24.31 vs. 251.43 ± 86.41 pg/ml per 3 h), respectively (Fig. 4A). Figure 4B demonstrates that ND mice administered SVF from HFD mouse recovered faster from acute hypoxia than sham-transferred ND mice. Immediately after hypoxia, SVF and sham-transferred mice showed similar recovery (9.84 ± 3.49 vs. 9.39 ± 2.47%, SVF vs. sham). Two hours after hypoxia, SVF-transferred mice had recovered from hypoxia (72.71 ± 8.25 vs. 88.20 ± 5.49%, hypoxia vs. normoxia), whereas sham-transferred animals had not (53.44 ± 9.27 vs. 96.91 ± 6.43%, hypoxia vs. normoxia). This delay in recovery was still evident in sham-treated animals 6 h after hypoxia (64.01 ± 4.32 vs. 95.51 ± 5.41%, hypoxia vs. normoxia). Three-way ANOVA (phenotype × hypoxia × time) revealed a significant hypoxia × time interaction [F (2,36) = 45.29, P < 0.0001] but no treatment × hypoxia × time interaction.

Figure 4.

Figure 4

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Accelerated hypoxia recovery can be transferred from HFD mice to ND mice. A, ND mice were ip injected with (transfer) or without (sham) HFD mouse SVF. Serum and peritoneal fluid IL-1RA protein was measured by ELISA 3 h after transfer. Results are expressed as means ± sem: n = 3. *, P < 0.05 sham vs. transfer. B, ND mice were ip injected with (transfer) or without (sham) SVF mouse stromal vascular fraction 3 h before hypoxia exposure. Baseline behavior was measured in sham and transferred mice immediately before hypoxia exposure (−2 h). Mice were then placed in either a normoxic or hypoxic environment for 2 h. Behavioral recovery from hypoxia was measured 0, 2, 6, and 10 h after return of animals to normoxia. Results are expressed as means ± sem: n = 3–5. *, P < 0.05 normoxia vs. hypoxia.

Exogenous administration of IL-1RA improves recovery from hypoxia

To ensure that IL-1RA was important to hypoxia recovery, ND mice were administered anakinra (a derivatized recombinant IL-1RA) (32) 1 h before hypoxia. Figure 5A shows that IL-1RA-treated ND mice recovered faster from acute hypoxia than sham-treated ND mice. Immediately after hypoxia, IL-1RA-treated ND mice were less recovered (21.17 ± 5.77 vs. 5.24 ± 2.65%, IL-1RA vs. sham). At 2 h after hypoxia, IL-1RA-treated ND mice had recovered from hypoxia (81.29 ± 3.46 vs. 98.72 ± 4.32%, hypoxia vs. normoxia), whereas sham-treated mice were had not (34.07 ± 6.39 vs. 103.54 ± 3.91%, hypoxia vs. normoxia). At 6 h after hypoxia, both IL-1RA and sham-treated ND mice had recovered. Three-way ANOVA (phenotype × hypoxia × time) revealed a significant IL-1RA × hypoxia × time [F (2,32) = 4.21, P < 0.05], IL-1RA × hypoxia interaction [F (1,16) = 50.35, P < 0.0001], and a hypoxia × time interaction [F (2,32) = 116.51, P < 0.0001]. Figure 5B demonstrates the half-life of serum IL-1RA in ND mice administered IL-1RA. Before IL-1RA administration, ND mice had serum IL-1RA levels of 50.28 ± 38.11 pg/ml. At 1 and 3 h after IL-1RA, ND mouse IL-1RA was increased to 2239.67 ± 238.94and 953.77 ± 154.08 pg/ml, respectively. At 6 h after IL-1RA, serum IL-1RA had returned to normal (190.57 ± 55.67 pg/ml).

Figure 5.

Figure 5

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Exogenous administration of IL-1RA improves recovery from hypoxia. A, ND mice were injected sc with (IL-1RA) or without (sham) anakinra (1.4 mg/kg) 1 h before hypoxia exposure. Baseline behavior was measured in sham and anakinra (IL-1RA) administered to mice immediately before hypoxia exposure (−2 h). Mice were then placed in either a normoxic or hypoxic environment for 2 h. Behavioral recovery from hypoxia was measured 0, 2, 6, and 10 h after return of animals to normoxia. Results are expressed as means ± sem: n = 6. *, P < 0.05, hypoxia vs. normoxia; #, P < 0.05 IL-1RA vs. sham. B, ND mice were injected with IL-1RA, as in A, and serum IL-1RA protein was measured by ELISA, at the times indicated. Results are expressed as means ± sem: n = 3–4. *, P < 0.005 vs. 0 h.

Accelerated hypoxia recovery in HFD mice is reliant on IL-1RA

To determine the importance of IL-1RA to hypoxia recovery in HFD mice, HFD mice were administered IL-1RA antiserum to immune absorb IL-1RA. Figure 6A shows that HFD mice treated with IL-1RA antiserum 2 h before hypoxia exposure were delayed in their recovery compared with HFD mice treated with normal sheep serum. Immediately after hypoxia (0 h), IL-1RA antiserum and normal sheep serum-treated HFD mice were similarly impacted (0.34 ± 0.41 vs. 11.67 ± 7.82%, IL-1RA antiserum vs. normal sheep serum). At 2 h after hypoxia, HFD mice treated with IL-1RA antiserum were markedly delayed in their recovery compared with normal sheep serum-treated HFD mice (37.92 ± 10.54 vs. 80.16 ± 4.35%, IL-1RA antiserum vs. normal sheep serum). At 6 h after hypoxia, both IL-1RA antiserum and normal sheep serum-treated HFD mice had recovered. Two-way ANOVA (treatment × time) revealed a significant treatment × time interaction [F (3,12) = 16.91, P < 0.0001]. Figure 6B demonstrates that IL-1RA anti-serum was able to significantly reduce both serum and perigonadal WAT IL-1RA in HFD mice [serum 36.59 ± 9.84 pg/ml vs. nondetectable, normal sheep serum vs. IL-1RA antiserum and WAT 244.48 ± 61.80 vs. 77.65 ± 27.98 pg/mg protein, normal sheep serum vs. IL-1RA antiserum, F (1,4) = 9.07, P < 0.05].

Figure 6.

Figure 6

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Accelerated hypoxia recovery in HFD mice is reliant on IL-1RA. A, HFD mice were injected ip with IL-1RA antiserum or without nonimmune serum 1 h before hypoxia exposure. Baseline behavior was measured in nonimmune serum and IL-1RA antiserum administered to mice immediately before hypoxia exposure (−2 h). Mice were then placed in either a normoxic or hypoxic environment for 2 h. Behavioral recovery from hypoxia was measured 0, 2, 6, and 10 h after return of animals to normoxia. Results are expressed as means ± sem: n = 3. *, P < 0.05 nonimmune serum vs. IL-1RA antiserum: #, P < 0.05 vs. −2 h. B, IL-1RA protein was measured in serum and WAT from the mice in A immediately after the 10-h time point. Results are expressed as means ± sem: n = 3. *, P < 0.05.

Discussion

An obesity paradox was first described more than 7 yr ago by Horwich et al. (25), who noted that higher body mass index was not a risk factor for increased mortality in heart failure but was in fact associated with improved survival. Given today’s antifat cultural environment (36), this assertion by Horwich et al. is especially controversial, but recent work has supported an obesity paradox in heart failure (25,26). Whereas Habbu et al. (37) questioned the validity of an obesity survival advantage in heart failure, their counterargument is weakened by the poor prognosis seen in those who suffer from cardiac cachexia (38). Therefore, it is not entirely surprising that increased fatness, and hence energy stores, might mitigate demise in heart failure. Very few studies have looked at this paradox in severely obese populations, but even Habbu et al. (37) support the notion of a U-shaped outcomes curve in which overweight and mildly obese populations have the best outcomes.

In general, improved survival tied to body mass index is often explained by vague notions of heightened nutritional status, in which increased calorie consumption is linked to a greater intake of protein and other essential nutrients. An antagonistic finding to the obesity paradox is that, in mice, calorie restriction is associated with increased life span (39,40). Whether calorie restriction is beneficial to humans is unclear (41,42), especially in that weight loss occurring at 65 yr of age or older precipitates decreased health-related quality of life (43) and survival (44,45). Obesity ties in to this quandary because it is regarded as a proinflammatory state (15), and many of the leading causes of death in those 65 yr of age and older are associated with inflammation including heart disease, diabetes, Alzheimer’s disease, and nephritis (46). Fat from overweight and obese individuals tends to be infiltrated by macrophages (6) and serum proinflammatory cytokines like TNF-α, IL-1, and IL-6 can be elevated in obesity (3,47). We demonstrate that HFD mice were 38.5% heavier then our ND mice and had fasting blood glucoses and total cholesterols 57 and 46% than our ND mice, respectively. Interestingly, we did not see increases in serum TNF-α, IL-1, or IL-6 (in fact, IL-6 was down 51.5%). This is not suppressing because elevations in some or all of these cytokines in serum are variable (48,49). In addition, it appears that a proinflammatory serum cytokine profile is better correlated with degree of insulin resistance in diabetes than with the weight (47). We did, however, find brain-based and fat depot-based basal increases in both IL-1α and IL-1β mRNA in HFD mice. The brain findings are very interesting because obesity is associated with a variety of conditions that may be caused by brain-based proinflammation or brain-based proinflammatory cytokines, including depression (50) and Alzheimer’s disease (51).

As expected, HFD mice demonstrated an increase in serum leptin (52,53). Leptin, importantly, drives expression of IL-1RA in both monocytes (54) and macrophages (34). This ability of leptin to enhance IL-1RA production underscores the antiinflammatory potential of a HFD and the resulting fatness. Leptin-dependent up-regulation of IL-1RA appears to be a direct result of leptin in that leptin through its receptor long form uses the ERK/MAPK pathway and the nuclear factor-κB/PU.1 binding site of the IL-1RA promoter (55). In addition, Janus kinase-2 recruitment to Tyr985 may be pivotal to leptin-induced IL-1RA because Tyr985 plays an important role in leptin-induced full activation of ERK (56). In our study, feeding a HFD increased serum leptin by 38% but increased serum IL-1RA by nearly 1100%. IL-1RA was also increased in perigondal and perirenal WAT of HFD mice, likely due to a direct effect of WAT leptin on adipose tissue-based macrophages, as we recently reported (34). Interestingly, IL-1R2 mRNA was increased in perigonadal and perirenal WAT of HFD mice. Like IL-1RA, the IL-1 decoy receptor (IL-1R2) counteracts IL-1 signaling (57); however, it is not yet clear whether leptin directly drives expression of IL-1R2.

Acute hypoxia is potent activator of the IL-1 arm of the neuroimmune system (58), and loss of IL-1 production or signaling speeds recovery from acute hypoxia (33). Importantly, interruption of IL-1 signaling also protects the brain from ischemic necrosis induced by carotid artery ligation in mice (59). Also, disruption of IL-1 signaling via administration of IL-1RA to stroke victims may have a beneficial impact on stroke recovery (60). We found that HFD mice recovered faster from acute hypoxia than ND mice. This finding was somewhat surprising for two reasons. First, HFD mice had a basal up-regulation of IL-1α and IL-1β mRNA in the brain without a corresponding increase in basal IL-1R2 or IL-1RA. Second, we have previously shown that obese db/db mice, which have an increased basal up-regulation of IL-1β in the brain, have a marked recovery prolongation when exposed to acute hypoxia (33,34). A critical difference between db/db mice and HFD mice is functional leptin signaling and the failure of db/db mice to up-regulate either IL-1R2 or IL-1RA in response to hypoxia (33). Significantly, when ob/ob mice are administered leptin, systemic IL-1RA in response to hypoxia is restored, as is a normal recovery from acute hypoxia (34).

Finally, how important is IL-1RA to acute hypoxia recovery in HFD mice? We found that peripheral administration of anakinra to ND mice speeds ND mouse recovery from acute hypoxia. Interestingly, transfer of the WAT SVF from HFD mice to ND mice also speeds hypoxia recovery. The impact of the SVF transfer on hypoxia recovery was not as great as that seen with anakinra because of an inability to achieve a serum level of IL-1RA that matched that of anakinra administration. This limitation in achievable IL-1RA titer was due to the number of mice required. To generate a serum IL-1RA level of 2000 pg/ml (which was seen with anakinra), the SVF of about 24 HFD mice would have been needed because we found that the SVF of three HFD mice generated a serum IL-1RA level of 250 pg/ml. Therefore, to ensure that IL-1RA was important to accelerated hypoxia recovery in HFD mice, IL-1RA was immunoabsorbed in vivo with anti-IL-1RA antiserum. When HFD mice were administered anti-IL-1RA, they were 50% less recovered from acute hypoxia at 2 h after hypoxia than HFD mice administered nonimmune serum. In addition, IL-1RA antiserum reduced HFD mouse serum IL-1RA to undetectable. Taken together, our results indicate that, in acute hypoxia, HFD-associated up-regulation of IL-1RA is critical to accelerated recovery. Furthermore, because hypoxia is a key contributor to cardiac dysfunction and death in heart failure (61), it is likely that a significant component of the obesity paradox of Horwich et al. (25) is tied to obesity-dependent up-regulation of IL-1RA and the ability of IL-1RA to counterregulate IL-1 driven peripheral and neuroinflammation.

Supplementary Material

[Supplemental Data]
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Footnotes

This work was supported by grants from the American Heart Association (Predoctoral Fellowship to C.L.S), National Institutes of Health (DK64862 and NS58525 to G.G.F.) and University of Illinois Agricultural Experiment Station (to G.G.F.). This work was also supported in part by a grant from the United States Department of Homeland Security, Assistance to Firefighters Grants Office, Research and Development Grant EMW-2006-FP-02459.

Disclosure Summary: The authors have nothing to disclose.

First Published Online February 12, 2009

Abbreviations: AtMφ, Adipose tissue macrophage; HFD, high-fat diet-fed; IL-1RA, IL-1 receptor antagonist; ND, normal-diet-fed; PerMφ, peritoneal macrophage; SVF, stromal vascular fraction; WAT, white adipose tissue.

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