Animal Models

Effect of resveratrol on visceral white adipose tissue inflammation and insulin sensitivity in a mouse model of sleep apnea

Abstract

Background:

Sleep fragmentation (SF) increases food intake and the risk of obesity, and recruits macrophages to visceral white adipose tissue (VWAT) promoting tissue inflammation and insulin resistance. Administration of resveratrol (Resv) has been associated with significant improvements in high-fat diet-induced obesity, inflammation and insulin resistance.

Methods:

Male mice were subjected to SF or sleep control conditions for 8 weeks, and treated with either Resv or vehicle (Veh). Fasting plasma levels of glucose, insulin and leptin were obtained and VWAT insulin sensitivity tests were performed (phosphorylated AKT/total AKT), along with flow-cytometric assessments for VWAT macrophages (M1 and M2) and T-cell lymphocytes (CD4+, CD8+ and T regulatory cell (Treg)).

Results:

SF-Veh and SF-Resv mice showed increased food consumption and weight gain. However, although SF-Veh mice exhibited increased fasting insulin and leptin levels, and reduced VWAT p-AKT/AKT responses to insulin, such alterations were abrogated in SF-Resv-treated mice. Increases in M1, reduced M2 counts and increased tumor necrosis factor-α release emerged in SF-Veh macrophages compared with all other three groups. Similarly, increased CD8+ and reduced Treg lymphocyte counts were apparent in SF-Veh.

Conclusions:

Resveratrol does not reverse the SF-induced increases in food intake and weight gain, but markedly attenuates VWAT inflammation and insulin resistance, thereby providing a potentially useful adjunctive therapy in the context of sleep disorders manifesting metabolic morbidity.

Introduction

Fragmented sleep (SF) is a very frequent occurrence among many highly prevalent disorders such as sleep apnea, and leads to excessive daytime sleepiness and cognitive, mood and neurobehavioral deficits. SF also imposes adverse metabolic consequences such as increased appetite and food intake that ultimately promote the emergence of obesity.1,2 However, even before the increases in somatic weight gain occur, evidence of altered insulin sensitivity is apparent in adipose tissues and has been ascribed to increased SF-induced oxidative stress.3

Sleep disturbances have been previously implicated in eliciting an increased oxidant and inflammatory burden. Indeed, SF substantially increases free radical burden and promotes inflammation in several end-organs,4, 5, 6, 7 leading to glucose intolerance in humans.8 Similarly, the role of oxidative stress and inflammation, in general, and more specifically of sirtuin genes in obesity and diabetes, has emerged in patient cohorts, suggesting a potential role for anti-oxidants or sirtuin activity regulators as therapeutic options.9,10

In the last decade, resveratrol (Resv) has emerged as potent anti-obesogenic compound that appears to induce sirtuin activity and affords protection against high-fat-diet-induced obesity and insulin resistance.11, 12, 13, 14, 15 Although the mechanisms underlying Resv-induced beneficial effects on systemic and tissue-specific insulin sensitivity remain to be fully delineated, we reasoned that treatment with this compound would potentially reduce the increased food consumption associated with SF, as well as attenuate systemic and visceral white adipose tissue (VWAT) insulin resistance in adipocytes.

Materials and methods

Animals

Adult male C57BL/6 J mice from Jackson Laboratories (8-week-old, ~22 g; Bar Harbor, ME, USA) were housed in groups of five (to prevent isolation stress) in standard clear polycarbonate cages and allowed to acclimatize to their surroundings. Mice were fed normal chow diet (cat#5001*, LabDiet, St Louis, MO, USA; diet content: http://www.labdiet.com/cs/groups/lolweb/@labdiet/documents/web_content/mdrf/mdi4/~edisp/ducm04_028021.pdf) and water ad libitum and maintained in a 12-h light/dark cycle (light on 0700 hours to 1900 hours) at a constant temperature (24±1 °C). Mice were randomly assigned to SF exposures or sleep control (SC) conditions, and to treatment with Resv or vehicle (Veh; control) for 8 weeks. Owing to blood volume limitations, separate sets of mice were used to test systemic glycemic and leptin responses and inflammatory cell responses with SF being performed for 12 h/day during daylight, and consisting of mechanically induced arousals at 2-min intervals using a custom-automated device as previously described.4, 5, 6,16

Mice received drinking water containing 0.01% Resv (Sigma-Aldrich, St Louis, MO, USA). This amount of Resv is ~10 times the amount found in 1 l of red wine. Resv was first dissolved in 0.4 ml of absolute ethanol and added to 100 ml of drinking water. The Veh group received the same volume of drinking water containing 0.4% ethanol. All mice had free access to the drinking solution. The mice consumed 3–4 ml of the drinking fluid daily, with the daily consumption of Resv being 0.3–0.4 mg per mouse.

Animal experiments were performed according to the protocols approved by the Institutional Animal Committee University of Chicago and are in close agreement with the National Institutes of Health Guide in the Care and Use of Animals. All efforts were made to minimize animal suffering and to reduce the number of animals used.

Sleep fragmentation

The SF device used to induce sleep disruption events has been previously described.4, 5, 6,16 Briefly, it employs intermittent tactile stimulation using a near-silent motorized horizontal bar sweeping just above the cage floor from one side to the other. Since on average, 30 episodes of arousal per hour occur in patients with severe obstructive sleep apnea (that is, every 2 min), our aim was to mimic closely the severe disease condition, and thus, a 2-min interval between each sweep was implemented during the light period (0700 hours to 1900 hours). SF was performed by switching on the sweeper to a timer mode in the cage. In this mode, the sweeper required around 9 s to sweep the floor of the cage one way. When it reached the end of the cage, a relay engaged the timer, which paused for ~110 s before enabling the sweeper to move in the opposite direction. Between the two intervals, the animal remained undisturbed. During sweeper motion, animals would need to step over the sweeper, and then continue with their unrestrained behavior. SF exposure lasted for 8 weeks during which mice had ad libitum access to food and water. Of note, this method prevents the need for human contact and intervention, minimizes physical activity during the entire sleep disruption procedure, does not require social isolation, and is associated with unchanged levels of stress hormones.4, 5, 6,16

Food consumption and body weight

Food consumption per cage was registered daily, always at the same time of the day (middle of the light period). Animal food consumption was then calculated by dividing the daily cage chow utilization by the number of mice in the cage. Body weight was measured every other day always at the same time of the day (middle of the light cycle period). Body weight gain was determined by subtracting the body weight on first day of SF exposure from the body weight on subsequent days.

ELISA and insulin sensitivity assays

Mice were fasted for 3 h (0400 hours till 0700 hours) with water available ad libitum, and were then euthanized. Venous blood was collected into EDTA-containing tubes, immediately centrifuged in at 4 °C and frozen at −80 °C till further analyses. Blood glucose was immediately assessed using an OneTouch Ultra2 glucometer (Life Scan, Inc., Milpitas, CA, USA). Insulin and leptin assays were carried out using ELISA kits (Millipore, St Charles, MO, USA) according to the manufacturer's protocol. The linear range of the insulin assay was 0.2–10 ng ml−1, with the limit of sensitivity at 0.2 ng ml−1 (35 pM), and intra- and interindividual coefficients of variation up to 8.4% and 18%, respectively, at lower concentrations (that is, 0.32 ng ml−1). Similarly, for the leptin assay, the linear range was 0.2–30 ng ml−1 with the sensitivity threshold at 0.05 ng ml−1 (3.13 pM). The intra-assay variation coefficient was up to 1.8% at high concentrations of leptin (17.60 ng ml−1), and 4.6% of interindividual coefficient of variation at low concentrations (that is, 1.66 ng ml−1).

Adipocyte insulin sensitivity was assessed in adipocytes derived from epidydimal fat tissue as described previously.17 Briefly, primary adipocytes were isolated by collagenase digestion and flotation centrifugation. They were then incubated with insulin at various concentrations at 37 °C for 10 min with gentle vortexing every 2 min. After two washes with cold Krebs–Ringer buffer, cells were lysed in Laemmli buffer and assessed using western blotting analysis for phosphorylated and total Akt (anti-phospho-Akt (Ser473) and anti-Akt; Cell Signaling Technology, Danvers, MA, USA).

Isolation of stromal-vascular fraction (SVF) and flow cytometry analysis

Epididymal fat pads and mesenteric adipose tissues were minced in Krebs–Ringer buffer supplemented with 1% bovine serum albumin and incubated with collagenase (1 mg ml−1; Worthington Biochemical Corporation, Lakewood, NJ, USA) at 37 °C for 45 min with shaking. Cell suspensions were filtered through a 100-μm mesh and centrifuged at 500 g for 5 min to separate floating adipocytes from the SVF pellet. SVF pellets were then resuspended in fluorescence-activated cell sorting buffer (phosphate-buffered saline plus 2% fetal bovine serum) and 106 cells were used for staining with fluorescence-conjugated primary antibodies or control IgGs at 4 °C for 30 min. Cells were then washed twice and analyzed with a flow cytometer (Canto II; BD Biosciences, San Jose, CA, USA). Data analysis was performed using the FlowJo software (Tree Star, Ashland, OR, USA). Adipose tissue macrophages) were defined as F4/80+ and CD11b+ cells, from which M1 and M2 macrophages were identified as CD11c+ or CD206+ cells, respectively. T regulatory cell (Treg) lymphocytes were identified as CD3+/CD4+/FOXP3+ cells. All antibodies were from Biolegend (San Diego, CA, USA). In a subset of the experiments, macrophages from the SVF were isolated using the EasySep Mouse CD11b Positive Selection Kit (StemCell Technologies, Vancouver, BC, Canada), cultured for 12 h, cell culture supernatants were then collected and centrifuged to remove any debris, and frozen till assay. Tumor necrosis factor (TNF)-α concentration in medium was measured using a commercially available ELISA assay per manufacturer’s instructions (Ready-SET-Go! Mouse TNF-a Kit; eBioscience, San Diego, CA, USA).

Statistical analysis

All values are expressed as mean±standard deviation. Analyses of variance procedures followed by post-hoc tests and Student's t-tests were used to compare the results between four treatment groups. In all cases, two-tailed P value of <0.05 was considered to achieve statistical significance.

Results

Food intake and weight gain

As previously reported,1 mice exposed to SF exhibited increased food intake that began within a few days after the initiation of SF, and was sustained throughout the duration of SF exposures (Figure 1). There were no differences in Resv-treated and Veh-treated mice as far as food intake, or weight gain at the end of the 8-week period, with SF-exposed mice displaying increased weight gain (Figure 1; n=18/group; P<0.001).

Figure 1
figure1

Food intake and weight gain in SF- and SC-exposed mice treated with either resveratrol or vehicle for 8 weeks. n=18/treatment group; *P<0.001 SF-Veh or SF-Resv vs two other treatment groups.

Resv prevents hyperleptinemia and systemic and visceral fat insulin resistance

Overall, fasting glycemic levels were similar across the four treatment groups; however, in SF-Veh mice, higher fasting homeostasis model assessment levels due to higher insulin levels emerged after 8 weeks of SF, with such changes being abrogated in SF-Resv-treated mice (Figure 2). Similarly, increased plasma leptin levels were apparent in SF-Veh mice when compared with all other three treatment groups (Figure 2a).

Figure 2
figure2

Metabolic effects of resveratrol in mice. (a) Plasma levels of glucose, insulin and leptin in SF and SC-exposed mice after fasting for 3 h and treated with either resveratrol or vehicle for 8 weeks. (b) Example of adipose tissue insulin sensitivity assay as demonstrated by changes in phosphorylated Akt (p-AKT) and total Akt (T-AKT) after adding 0 or 5 nM insulin to the medium (upper panel). Lane 1: SC-Veh; Lane 2: SC-Resv; Lane 3: SF-Veh; Lane 4: SF-Resv; Lane 5: SC-Veh; Lane 6: SF-Resv; Lane 7: SC-Veh; Lane 8: SF-Veh; Lane 9: SF-Resv; Lane 10: SF-Veh; Lane 11: SF-Resv; Lane 12: SC-Resv. Lower panel illustrates the summary of six separate experiments for p-AKT/T-AKT ratios between 0 and 5 nM insulin. *P<0.01 SF-Veh vs three other treatment groups.

Insulin sensitivity in VWAT, as assessed by Akt phosphorylation in response to insulin, indicated reduced insulin sensitivity after 8 weeks of SF but only in Veh-treated mice. In contrast, there were no changes in adipose tissue insulin sensitivity in SF-exposed mice treated with Resv (Figure 2b; n=8/treatment group).

Resv protects from SF-associated increases in macrophage number and polarization in VWAT

SF for a period of 8 weeks induced marked increases in the global number of macrophages present in the SVF of VWAT (Figure 3). Such increases consisted primarily of increases in the proportion of macrophages exhibiting the pro-inflammatory M1 phenotype (CD11c+; n=8/group; P<0.01; Figure 3) and reciprocal reductions in macrophages with M2 polarity (CD206+; n=8/group; P<0.01; Figure 3), such that the M1/M2 ratio was markedly increased following SF (n=8/group; P<0.01; Figure 3). SF-induced changes in VWAT macrophages were markedly attenuated in Resv-treated mice exposed to SF. In addition, when compared with SF-Veh mice, macrophages harvested from visceral fat in mice exposed to SF and treated with Resv exhibited reduced release of TNF-α to the media (SF-Veh macrophages: 134.5±23.6 pg ml−1; SF-Resv: 45.6±14.7 pg ml−1; SC-Veh: 37.2±11.9 pg ml−1; n=6/group; P<0.005 ANOVA) at levels that were similar to those of SC-exposed mice.

Figure 3
figure3

Macrophage cell recruitment in SVF of visceral white adipose tissue in SF- and SC-exposed mice treated with either resveratrol or vehicle for 8 weeks. (a) Total macrophage count expressed as percentage of cells isolated from SVF; (b) M1 macrophage count expressed as percentage of total macrophages; (c) M2 macrophage count expressed as percentage of total macrophage count; (d) M1/M2 ratio. N=8/experimental group; *P<0.01 SF-Veh vs three other treatment groups.

Resv abrogates SF-induced changes in T-cell lymphocytes in the SVF

SF exposures were associated with significant increases in the number and proportion of CD8+ lymphocytes (n=6/treatment group; P<0.01; Figure 4b) as well as in reductions in Treg lymphocytes within the SVF of VWAT (n=6/group; P<0.01; Figure 4c), but no changes in the overall number of CD3+ or CD4+ lymphocyte subsets occurred (Figure 4a).

Figure 4
figure4

T-cell lymphocyte changes in SVF of visceral white adipose tissue in SF- and SC-exposed mice treated with either resveratrol or vehicle for 8 weeks. (a) Total CD4+ cell count expressed as percentage of CD3+ cells in SVF. (b) Total CD8+ cell count expressed as percentage of CD3+ cells in SVF. (c) Total Treg cell count expressed as percentage of CD4+ cells in SVF. N=6/experimental group; *P<0.01 SF-Veh vs three other treatment groups.

Discussion

This study confirms our previous findings that chronic SF exposures imposed during the predominant sleep period in mice lead to the emergence of increased caloric intake, accelerated weight accrual, systemic insulin and leptin resistance, reduced VWAT insulin sensitivity and increased VWAT inflammation. Furthermore, we now show that although treatment with Resv did not affect orexigenic patterns or weight gain, it restored insulin and leptin responsiveness while normalizing the inflammatory processes within VWAT.

Before we discuss some of the major implications of our findings, some methodological issues deserve specific mention. First, we have implemented a SF experimental paradigm that provides highly reproducible findings, and most importantly is void of major effects on stress hormones, sleep duration and social setting, while allowing for completely unrestricted food and water access.4, 5, 6,16 In this context, the increased food consumption exhibited by SF mice appears to be mediated by SF-mediated sustained activation of the unfolded protein response in the hypothalamus, which translates into the generation of leptin receptor resistance,18 the latter likely accounting for the increases in plasma leptin concentrations reported herein. Notably, Resv treatment did not alter SF-mediated increases in food consumption or the emergence of accelerated weight increases during the duration of the experiments, suggesting that the potential central pathways modulated by SF are not likely to be affected by this compound. However, chronic SF induces increases in central nervous system levels of TNF-α,6 such that it is likely that the increases in macrophage release of this pro-inflammatory cytokine in SF-exposed mice may reflect an overall systemic inflammatory response induced by the disrupted sleep paradigm. In this setting, Resv administration normalized TNF-α VWAT macrophage release, suggesting that this compound exerts anti-inflammatory effects on adipose tissue, as previously inferred by several investigators.19, 20, 21, 22, 23 Second, we opted not to impose a high-fat diet regimen or to employ transgenic mice with heightened susceptibility to obesity, as we wished to examine the isolated effects of Resv on SF-induced metabolic dysfunction and obesogenic behaviors. Third, we selected a relatively standard dose of Resv that had previously shown favorable activity profile in either metabolic or low-grade chronic inflammatory processes.24, 25, 26, 27 Finally, the observational nature of the present study design obviously precludes any specific inferences on mechanisms underlying the biologically pertinent effects of Resv in our animal model, and such causal pathways will definitely have to be explored in the future.

As mentioned, although Resv treatment did not alter the accrued food intake and weight gain associated with SF, it either improved or completely reversed both systemic and insulin resistance. Thus, it is possible that use of Resv as a dietary supplement in sleep disorder patients manifesting metabolic dysfunction may improve the latter via its anti-oxidant properties,28 as increased oxidative stress is clearly elicited by SF and promotes insulin resistance.2,3 However, the beneficial impact of Resv on the inflammatory phenotype of VWAT would suggest that the increased activation of inflammatory pathways elicited by SF3 was reversed by Resv. We here not only explored a previously described inflammatory pathway, namely macrophages and their polarity shifts,3 but further investigated potential changes in T-cell lymphocytes, and more particularly Tregs. The compelling evidence supporting a major role for adipose tissue macrophage infiltration in the context of obesity and metabolic derangements is mimicked by chronic SF in the absence of obesogenic diet, and the magnitude of such primarily M1 macrophage infiltration along with M2 macrophage reduction is closely associated with the degree of adiposity, as well as with insulin resistance.29, 30, 31 Indeed, concurrent with the increased presence of macrophages in SF-exposed adipose tissues, there was also a shift in their phenotypes, such that increased populations of M1 macrophages along with reduced M2 macrophage cell counts occurred, with all these changes being reversed by Resv. Furthermore, our data show for the first time that SF induces concomitant changes in T-cell lymphocyte populations, with increased CD8+ pro-inflammatory lymphocytes and reciprocal reductions in the proportion of circulating Tregs, and that Resv treatment normalized these major alterations. Similar changes in T-cell lymphocytes within adipose tissue have been previously reported in the context of high-fat diet and also aging, with increased CD8+ cells and reductions in Tregs.32, 33, 34 The reduced Treg cell count in SF-exposed mice treated with Veh could reflect increased methylation of FOXP3, the major transcriptional regulator of Treg cell fate, thereby facilitating a pro-inflammatory phenotype.35,36 It is possible that Resv may reduce the activity of methyl-transferases and thus prevent the increased and overall deleterious methylation of FOXP3 and other metabolic genes.37,38 In this context, we have previously shown that children with sleep apnea, a disease characterized by disrupted sleep, is accompanied by increased methylation of FOXP3, and leads to reduced numbers of circulating Tregs.39,40

Thus, current experiments conclusively confirm that chronic SF, a frequent occurrence in multiple sleep disorders, and more particularly in obstructive sleep apnea, is not only an important contributor to the metabolic dysfunction of these conditions via effects on visceral adipose tissue, but that it may also promote obesity by increasing food intake. Furthermore, concurrent administration of resveratrol does not abrogate the increase food intake and weight gain, but clearly ameliorates the metabolic disturbances induced by SF via reductions in adipose tissue inflammation. Thus, dietary supplements such as Resv may offer therapeutic value as adjunct therapies aimed at reducing the metabolic morbidity of sleep disorders.

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Acknowledgements

This work was supported by the Herbert T. Abelson Endowed Chair in Pediatrics to DG.

Author Contributions

AC participated in the conceptual framework of the project, performed experiments, analyzed data and drafted components of the manuscript. SXZ, EP, ZQ, IA performed experiments. YW analyzed data and served as blinded observer. DG conceptualized the project, provided critical input in all phases of the experiments, analyzed data, drafted the ulterior versions of the manuscript and is responsible for the financial support of the project and the manuscript content. All authors have reviewed and approved the final version of the manuscript.

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Correspondence to D Gozal.

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Carreras, A., Zhang, S., Peris, E. et al. Effect of resveratrol on visceral white adipose tissue inflammation and insulin sensitivity in a mouse model of sleep apnea. Int J Obes 39, 418–423 (2015). https://doi.org/10.1038/ijo.2014.181

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