Omental adipocyte hypertrophy relates to coenzyme Q10 redox state and lipid peroxidation in obese women
2015; Elsevier BV; Volume: 56; Issue: 10 Linguagem: Inglês
10.1194/jlr.p058578
ISSN1539-7262
AutoresThomas Grenier–Larouche, Anne Galinier, Louis Casteilla, André C. Carpentier, André Tchernof,
Tópico(s)Antioxidant Activity and Oxidative Stress
ResumoOccurrence of oxidative stress in white adipose tissues contributes to its dysfunction and the development of obesity-related metabolic complications. Coenzyme Q10 (CoQ10) is the single lipophilic antioxidant synthesized in humans and is essential for electron transport during mitochondrial respiration. To understand the role of CoQ10 in adipose tissue physiology and dysfunction, the abundance of the oxidized and reduced (CoQ10red) isoforms of the CoQ10 were quantified in subcutaneous and omental adipose tissues of women covering the full range of BMI (from 21.5 to 53.2 kg/m2). Lean women displayed regional variations of CoQ10 redox state between the omental and subcutaneous depot, despite similar total content. Obese women had reduced CoQ10red concentrations in the omental depot, leading to increased CoQ10 redox state and higher levels of lipid hydroperoxide. Women with low omental CoQ10 content had greater visceral and subcutaneous adiposity, increased omental adipocyte diameter, and higher circulating interleukin-6 and C-reactive protein levels and were more insulin resistant. The associations between abdominal obesity-related cardiometabolic risk factors and CoQ10 content in the omental depot were abolished after adjustment for omental adipocyte diameter. This study shows that hypertrophic remodeling of visceral fat closely relates to depletion of CoQ10, lipid peroxidation, and inflammation. Occurrence of oxidative stress in white adipose tissues contributes to its dysfunction and the development of obesity-related metabolic complications. Coenzyme Q10 (CoQ10) is the single lipophilic antioxidant synthesized in humans and is essential for electron transport during mitochondrial respiration. To understand the role of CoQ10 in adipose tissue physiology and dysfunction, the abundance of the oxidized and reduced (CoQ10red) isoforms of the CoQ10 were quantified in subcutaneous and omental adipose tissues of women covering the full range of BMI (from 21.5 to 53.2 kg/m2). Lean women displayed regional variations of CoQ10 redox state between the omental and subcutaneous depot, despite similar total content. Obese women had reduced CoQ10red concentrations in the omental depot, leading to increased CoQ10 redox state and higher levels of lipid hydroperoxide. Women with low omental CoQ10 content had greater visceral and subcutaneous adiposity, increased omental adipocyte diameter, and higher circulating interleukin-6 and C-reactive protein levels and were more insulin resistant. The associations between abdominal obesity-related cardiometabolic risk factors and CoQ10 content in the omental depot were abolished after adjustment for omental adipocyte diameter. This study shows that hypertrophic remodeling of visceral fat closely relates to depletion of CoQ10, lipid peroxidation, and inflammation. The metabolic consequences of excess fat accumulation, especially in intra-abdominal adipose tissue compartments, are closely related to white adipose tissue dysfunction. This phenomenon is characterized by adipocyte hypertrophy, inflammatory cytokine secretion, and altered postprandial lipid fluxes (1.Carpentier A.C. Labbé S.M. Grenier-Larouche T. Noll C. Abnormal dietary fatty acid metabolic partitioning in insulin resistance and type 2 diabetes.Clin. Lipidol. 2011; 6: 703-716Crossref Scopus (19) Google Scholar). A growing body of evidence suggests that oxidative stress might be involved early in this pathological state. In white adipocytes, reactive oxygen species (ROS) production is mainly driven by NADPH oxidase activity instead of xanthine oxidase or mitochondrial respiration (2.Furukawa S. Fujita T. Shimabukuro M. Iwaki M. Yamada Y. 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Moreover, the reduced isoform displays direct or indirect antioxidant properties by scavenging lipid peroxyl radical or by reducing α-tocophenol (12.Mohr D. Bowry V.W. Stocker R. Dietary supplementation with coenzyme Q10 results in increased levels of ubiquinol-10 within circulating lipoproteins and increased resistance of human low-density lipoprotein to the initiation of lipid peroxidation.Biochim. Biophys. Acta. 1992; 1126: 247-254Crossref PubMed Scopus (255) Google Scholar). Depletion of CoQ10 content was found in subcutaneous adipose tissue of obese subjects and mice (13.Bour S. Carmona M.C. Galinier A. Caspar-Bauguil S. Van Gaal L. Staels B. Pénicaud L. Casteilla L. Coenzyme Q as an antiadipogenic factor.Antioxid. Redox Signal. 2011; 14: 403-413Crossref PubMed Scopus (25) Google Scholar). Overexpression of COQ2 in 3T3-F442A preadipocytes decreased the CoQ redox state and promoted ROS synthesis by the mitochondria (13.Bour S. Carmona M.C. Galinier A. Caspar-Bauguil S. Van Gaal L. Staels B. Pénicaud L. Casteilla L. Coenzyme Q as an antiadipogenic factor.Antioxid. Redox Signal. 2011; 14: 403-413Crossref PubMed Scopus (25) Google Scholar). Interestingly, the adipogenic potential of these cells was almost completely blunted, suggesting an important role of CoQ content and redox state during adipogenesis and adipose tissue expansion. However, the variation in CoQ10 content and redox state in subcutaneous and omental adipose tissues has not been investigated in humans. Moreover, the potential contribution of these parameters to white adipose tissue dysfunction and obesity-related metabolic complications remains unclear. In the present study, we have explored physiological variations in CoQ10 content and redox state in omental and subcutaneous adipose tissue of lean, overweight, and obese women. We hypothesized that CoQ10red content is lower in omental fat of obese individuals and is associated with lipid peroxidation. The loss of lipophilic antioxidant capacity of this molecule could be an important mechanism. We also postulate that this phenomenon could link visceral adipose tissue hypertrophy to systemic low-grade inflammation and insulin resistance. Women undergoing elective hysterectomy (n = 29) without (n = 17) or with unilateral (n = 4) or bilateral (n = 8) salpingo-oophorectomy were recruited at the gynecologic unit of the Laval University Medical Center. Surgery was performed for the following reasons: menorrhagia/menometrorrhagia (n = 9), myoma/fibroids (n = 15), incapacitating dysmenorrhea (n = 1), pelvic pain (n = 1), benign cyst (n = 5), endometriosis (n = 2), pelvic adhesions (n = 1), hypermenorrhea (n = 1), excessive anemia-causing uterine bleeding (n = 1), endometrial hyperplasia (n = 2), or polyp (n = 2). All scientific protocols were approved by the Research Ethics committee of Laval University Medical Center. Subjects provided written informed consent before their inclusion in the study. Subcutaneous adipose tissue samples were collected at site of the surgical incision (lower abdomen), while omental samples were removed from the distal part of the greater omentum. Fresh samples were immediately carried to the laboratory and used for adipocyte isolation. A portion of each sample was flash frozen in liquid nitrogen and stored at −80°C. Tissue samples were digested with collagenase type I in Krebs-Ringer-Henseleit buffer for 45 min at 37°C according to a modified version of the Rodbell method (14.Michaud A. Drolet R. Noel S. Paris G. Tchernof A. Visceral fat accumulation is an indicator of adipose tissue macrophage infiltration in women.Metabolism. 2012; 61: 689-698Abstract Full Text Full Text PDF PubMed Scopus (64) Google Scholar, 15.Michaud A. Pelletier M. Noël S. Bouchard C. Tchernof A. Markers of macrophage infiltration and measures of lipolysis in human abdominal adipose tissues.Obesity (Silver Spring). 2013; 21: 2342-2349Crossref PubMed Scopus (23) Google Scholar, 16.Rodbell M. Metabolism of isolated fat cells. I. effects of hormones on glucose metabolism and lipolysis.J. Biol. Chem. 1964; 239: 375-380Abstract Full Text PDF PubMed Google Scholar). Cell suspensions were filtered through nylon mesh and washed three times with Krebs-Ringer-Henseleit buffer. To determine adipocyte diameter, pictures of 250 cells were taken with a phase contrast microscope and analyzed with Scion Image software. The collagenase digestion was not performed for three samples because of the limited amount of tissue. The determination of body fat and lean body mass was performed by dual-energy X-ray absorptiometry (DEXA) using a Hologic QDR-2000 densitometer and the enhanced array whole-body software V5.73A (Hologic, Bedford, MA). Regional adipose tissue distribution was measured by computed tomography (CT) as previously described (14.Michaud A. Drolet R. Noel S. Paris G. Tchernof A. Visceral fat accumulation is an indicator of adipose tissue macrophage infiltration in women.Metabolism. 2012; 61: 689-698Abstract Full Text Full Text PDF PubMed Scopus (64) Google Scholar, 17.Deschênes D. Couture P. Dupont P. Tchernof A. Subdivision of the subcutaneous adipose tissue compartment and lipid-lipoprotein levels in women.Obes. Res. 2003; 11: 469-476Crossref PubMed Scopus (74) Google Scholar) using a GE Light Speed 1.1 CT scanner (General Electric Medical Systems, Milwaukee, WI). Briefly, the cross-sectional scan was performed at the L4–L5 vertebrae level in supine position with arms over the head. The exact scanning position was determined using a scout image. Adipose tissue areas of interest including visceral and subcutaneous adipose tissue areas, the latter included superficial and deep subcutaneous adipose tissues, were highlighted and computed with attenuation ranging from −190 to −30 Hounsfield units with ImageJ 1.33u software (National Institutes of Health, Bethesda, MD). Two obese volunteers exceeded the CT scanner field of view, and only the visceral adipose tissue area was determined. One of these women also exceeded the upper limit of weight allowed for the DEXA table and did not undergo this test. Lipid hydroperoxides (LPOs) were quantified using an LPO assay kit purchased from Cayman Chemical (Ann Arbor, MI), performed according to supplier recommendations with minor modifications. Briefly, 50 mg of omentum and subcutaneous adipose tissues were homogenized in methanol. Lipid extraction was achieved by adding 500 µl of water and 1 ml of chloroform. The mixture was centrifuged at 1,500 g, and the organic phase was collected. An aliquot was used to perform the colorimetric reaction, and absorbance was read at 500 nm with a 96-well plate reader. The quantification of both isoforms was performed by reverse-phase HPLC with electrochemical detection as previously described (18.Galinier A. Carriere A. Fernandez Y. Bessac A.M. Caspar-Bauguil S. Periquet B. Comtat M. Thouvenot J.P. Casteilla L. Biological validation of coenzyme Q redox state by HPLC-EC measurement: relationship between coenzyme Q redox state and coenzyme Q content in rat tissues.FEBS Lett. 2004; 578: 53-57Crossref PubMed Scopus (37) Google Scholar). The HPLC-EC system is composed of a Gilson 307 pump, a Rheodine injector, an analytical column, and an ESA Coulochem 2 Electrochemical Detector (Model 5200 A) with a computer/controller with EuroChrom 2000 Integration Package. The analytical cell (ESA Model 5010 porous graphite) consisted of a series of two coulometric electrodes and was connected in series to the analytical column: the first electrode (E2) was for reduction of CoQs, and the second electrode (E3) was for detection of these reduced CoQs. The identification of the different forms was set by the chromatographic separation with an analytical column, a reverse-phase Hypersil BDS C18 column (4 mm × 25 cm, 5 µm bead). The mobile phase for the isocratic elution of internal standard from ChromSystem and CoQ10s containing sodium acetate, acetic acid and 2-propanol, methanol and hexane, suited for EC detector. The standards of CoQ10ox were obtained from Sigma. Identification and quantification of oxidized and reduced forms of CoQs were performed using in-house external standards. The concentration of the working solution was confirmed by measuring absorbance at a wavelength of 275 nm and by reference to known coefficients (E 1%1cm 185 for CoQ9 and 165 for CoQ10). Then the conditioned solution of oxidized standard was reduced in loop to −1,000 mV in the system pump-guard cell. The determination of the concentration of each form was compared with the QA program organized by the National Institute of Standard Technology on lyophilized serums. Calibration curves were performed with a mix of three different diluted working CoQ10s stock solutions. Before injection, each standard solution was prepared as the biological samples in propanol. A highly linear relationship was observed between the area of the peak (mV/min) and the molecular concentration ratios of each compound over a wide concentration from 10–15 nM to 3,000 nM (r = 0.99). Acceptable repeatability was obtained for CoQs with a coefficient of variation below 5%, respectively 3.5% and 3.7% for CoQ10red and CoQ10ox. The limits of detection per injected quantity were 21 pmol for CoQred and 15 pmol for CoQox. To perform CoQ10 extraction, frozen tissues (100 mg) were added to 0.9 ml of 2-propanol and homogenized with an Ultraturax blender. One hundred microliters of this homogenate was mixed with 500 µl of 2-propanol during 30 s and then centrifuged (10,000 rpm for 3 min). Fifty microliters of the supernatant was directly injected in the system. This extraction procedure with only propanol was chosen because it was simple to perform and avoid oxidation of reduced CoQ forms as it was demonstrated and validated using various molecules well known to modify electron flow at different levels of the respiratory chain. As expected, CoQ redox state was significantly decreased in the presence of antimycin A and significantly increased in the presence of rotenone and carbonyl cyanide m-chlorophenyl hydrazine. The details of the validation were reported by Galinier et al. (18.Galinier A. Carriere A. Fernandez Y. Bessac A.M. Caspar-Bauguil S. Periquet B. Comtat M. Thouvenot J.P. Casteilla L. Biological validation of coenzyme Q redox state by HPLC-EC measurement: relationship between coenzyme Q redox state and coenzyme Q content in rat tissues.FEBS Lett. 2004; 578: 53-57Crossref PubMed Scopus (37) Google Scholar). The total coenzyme Q10 (CoQ10tot) pool was described as the sum of CoQ10ox and CoQ10red concentrations. Results were expressed as nmol/g of tissue. The redox state was calculated as follows: [CoQ10ox]/[CoQ10tot] × 100. Dietary intake was assessed using a food frequency questionnaire validated by Goulet et al. (19.Goulet J. Nadeau G. Lapointe A. Lamarche B. Lemieux S. Validity and reproducibility of an interviewer-administered food frequency questionnaire for healthy French-Canadian men and women.Nutr. J. 2004; 3: 13Crossref PubMed Google Scholar) that was interviewer administered by the same investigator within 2 weeks preceding or following the surgery and was structured to represent food habits throughout the previous month. The questionnaire was based on foods available in the Quebec City area and reflected Canadian food habits. The participants were questioned about the quantity and frequency intake of each item among different food groups: vegetables, fruits, legumes, nuts and seeds, cereals and grain products, milk and dairy products, meat/processed meat, poultry, fish, eggs, sweets, oil and fats, fast foods, and drinks. The content in CoQ10 by portion of each food groups was estimated using the compiled by Pravst et al. (20.Pravst I. Zmitek K. Zmitek J. Coenzyme Q10 contents in foods and fortification strategies.Crit. Rev. Food Sci. Nutr. 2010; 50: 269-280Crossref PubMed Scopus (151) Google Scholar) and is reported in supplementary Fig. 1. Total daily consumption of CoQ10 was calculated as the sum from each food source. All tables show mean ± standard error of the mean. Each graph shows dots as a single observation and horizontal lines as the mean of the distribution. Differences among body weight categories and adipose tissue depots were analyzed by two-way ANOVA, followed by Tukey's post hoc test. The stratification of CoQ10 content in the omental and subcutaneous depot was performed using a cutoff value of 14.0 and 15.0 nmol/g of tissue, respectively. These values were selected from a previous publication (13.Bour S. Carmona M.C. Galinier A. Caspar-Bauguil S. Van Gaal L. Staels B. Pénicaud L. Casteilla L. Coenzyme Q as an antiadipogenic factor.Antioxid. Redox Signal. 2011; 14: 403-413Crossref PubMed Scopus (25) Google Scholar). Differences between women with low and high concentrations of CoQ10 were analyzed by Student's t-test or Mann-Whitney test. Multiple univariate Pearson's linear correlations were performed to find associations between adiposity measurements and the concentrations of the CoQ10 isoforms for both depots. Log10 and Box-Cox transformations were used for correlations with nonnormally distributed residuals. Statistically significant correlations (in omental depot) between body fat distribution parameters and CoQ10 isoforms were adjusted for omental fat cell diameter to investigate the confounding effect of visceral fat hypertrophy. Statistical analyses were performed with the JMP 11.0 (SAS Institute, Cary, NC) and GraphPad Prism 6 (GraphPad, a Jolla, CA) software. Twenty-nine Caucasian women aged between 40.4 and 55.5 years (mean of 48.1 ± 4.1) were recruited. Their anthropometric and metabolic characteristics are shown in Table 1. They were characterized by a wide range of BMI values (from 21.5 to 51.3 kg/m2) with an average around the class I obesity threshold (30.0 ± 6.8 kg/m2). Of the 29 volunteers, 7 were lean (BMI 30.0 kg/m2). Twelve of the 29 subjects were insulin resistant based on a HOMA-IR value >2.5, but none of them had type 2 diabetes. This sample was specifically designed to identify cardiometabolic risk factors and adipose tissue dysfunction, features that relate to obesity and fat distribution in women.TABLE 1Anthropometric characteristics (n = 29)VariablesMean ± SDRange (Minimum–Maximum)Age and anthropometricsAge (years)48.1 ± 4.140.4–54.5Weight (kg)76 ± 1753–133Height (cm)159 ± 5151–170BMI (kg/m2)30.0 ± 6.821.5–51.3Waist circumference (cm)an = 28.97.2 ± 15.572.5–147.0Total body fat mass (kg)an = 28.28.8 ± 8.912.4–50.4Total lean body mass (kg)an = 28.43.8 ± 6.129.3–55.2% fatan = 28.37.6 ± 5.823.3–48.6Adipose tissue areas (cm2)Totalbn = 27.448 ± 151192–773Subcutaneousbn = 27.340 ± 128129–555Visceral111 ± 6444–266Adipocyte diameter (µm)Subcutaneousan = 28.104.0 ± 11.477–131Omentalbn = 27.90.7 ± 14.865–117Cholesterol (mM)an = 28.Total5.2 ± 1.13.2–6.9VLDL0.5 ± 0.20.4–0.6LDL3.3 ± 0.91.3–4.7HDL1.4 ± 0.30.8–2.1Triglycerides (mM)an = 28.Total1.4 ± 0.60.7–2.5VLDL0.9 ± 0.50.3–1.8LDL0.2 ± 0.10.1–0.6HDL0.2 ± 0.10.2–0.3Glucose homeostasisGlucose (mM)5.9 ± 0.74.8–7.1Insulin (µU/ml)11.4 ± 4.43.3–45.3HOMA-IR2.4 ± 1.30.7–13.7HOMA-IR, homeostasis model assessment-insulin resistance.a n = 28.b n = 27. Open table in a new tab HOMA-IR, homeostasis model assessment-insulin resistance. Using a food frequency questionnaire, we found that women included in our study consumed an average of 4.6 mg of CoQ10 per day with a range from 2.0 to 8.0 mg/day. BMI of the volunteers did not influence their daily consumption of CoQ10 from diet (supplementary Fig. 1A). We also found that vegetal sources (oils, nuts, vegetables, and fruits) were the main sources of CoQ10 in this French Canadian population (supplementary Fig. 1C). In this study, CoQ10 consumption did not influence the total levels and redox state of this molecule in the omental (supplementary Fig. 2A–C) or the subcutaneous (supplementary Fig. 2 B–D) adipose tissue compartment. Only four volunteers were smokers and were distributed among BMI subgroups. We did not observe any specific pattern of CoQ10 content or redox state in adipose tissues of these individuals (data not shown). We were able to quantitatively assess the levels of CoQ10ox and CoQ10red in 24 omental and 22 subcutaneous samples. We excluded data from five omental (overweight, n = 3; obese, n = 2) and seven subcutaneous (lean, n = 2; overweight, n = 4; obese, n = 1) samples because of complete oxidation of the CoQ10red isoform during the extraction process. We considered the CoQ10ox levels as the CoQ10tot pool for these samples. However, only women with available data of CoQ10ox, CoQ10red, and CoQ10tot within the same depot were included in this set of analysis. We first analyzed the regional variation of CoQ10 content in lean, overweight, or obese patients. We did not observe a difference in CoQ10tot content between the omental and subcutaneous adipose tissue of women within the same BMI category (Fig. 1A). However, we observed a depletion of the CoQ10 pool in omental adipose tissue of overweight and obese women, as well as in subcutaneous adipose tissue of obese women (BMI effect: P = 0.001; Fig. 1A). In lean individuals, we measured higher concentrations of the CoQ10red isoform in the omental depot compared with subcutaneous tissue (P = 0.003; Fig. 1B). However, we found higher levels of CoQ10ox isoform in subcutaneous adipose tissue of these women (P = 0.01; Fig. 1C). As expected, they displayed greater CoQ10 redox state in the subcutaneous depot (depot effect: P = 0.0003; Fig. 2A), suggesting that omental and subcutaneous adipose tissues have distinct CoQ10 redox statuses in healthy volunteers. The content in CoQ10red was decreased specifically in omental adipose tissue of obese women (P = 0.007; Fig. 1B). A reduction in CoQ10ox concentrations was also observed in subcutaneous adipose tissue of overweight and obese volunteers (Fig. 1C). Because of these differences, regional variations in CoQ10 redox state were not significant (Fig. 2A).Fig. 2Redox state of CoQ10 (A) and LPO levels (B) in the OM and SC compartment. Spearman correlation between LPO levels, CoQ10 redox state (C), and CoQ10 content (D) in the OM depot. The horizontal bar is the mean of the distribution. & P ≤ 0.05 body weight versus lean, # P = 0.06, † P ≤ 0.05, †† P ≤ 0.01, ††† P ≤ 0.001, OM versus SC adipose tissues. Dark gray and light gray dots respectively represent OM and SC adipose tissues samples. Redox state: OM (n = 24), SC (n = 22). LPO: OM (n = 16), SC (n = 18). OM, omental; SC, subcutaneous.View Large Image Figure ViewerDownload Hi-res image Download (PPT) For samples with valid CoQ10 redox state data, 16 omental and 18 subcutaneous fat samples were available for LPO levels quantification as a marker of oxidative stress. The omental depot had higher levels of LPO than the subcutaneous compartment (depot effect: P < 0.0001; Fig. 2B). We also observed a significant increase in the omental LPO content of obese women compared with lean and overweight volunteers (P = 0.01 and 0.02 respectively; Fig. 2B). A positive association was found between the CoQ10 redox state and LPO content in omental adipose tissue (r = 0.67, P = 0.005; Fig. 2C), supporting a role of the CoQ10 redox state in the regulation of redox status and oxidative stress in visceral fat. However, the association between CoQ10tot and LPO levels was not statically significant in this sample of patients (r = −0.41, P = 0.11). LPO concentration in subcutaneous adipose tissue was similar for all groups (Fig. 2B) and was not linked with the CoQ10 redox state (data not shown). Table 2 provides the Pearson and Spearman Rho values describing the correlations between adipose tissue areas measured by axial tomography and the abundance of CoQ10 isoforms in subcutaneous and omental adipose tissues. We found significant negative associations between visceral (r = −0.63, P = 0.0009), subcutaneous (r = −0.49, P = 0.02), and total adipose tissue areas (r = −0.58, P = 0.005) with CoQ10red levels in omental adipose tissue. Moreover, the CoQ10tot pool negatively correlated with visceral (r = −0.50, P = 0.006), superficial subcutaneous (r = −0.40, P = 0.04), and total (r = −0.43, P = 0.02) adipose tissue areas. The presence of the CoQ10ox isoform in omentum was not associated with visceral or subcutaneous adiposity. The CoQ10 redox state of the visceral depot was also weakly associated with visceral adipose tissue area (r = 0.37, P = 0.08) and deep subcutaneous adipose tissue area (r = 0.39, P = 0.07). To test the hypothesis that visceral adipocyte hypertrophy is a major contributor to CoQ10 depletion in obesity, we adjusted the previous correlations for omental fat cell diameter. The association between omental CoQ10red content and adipose tissue areas was no longer significant. Adjustment also abolished the relationship between the CoQ10tot pool and visceral adipose tissue area, although the correlation with subcutaneous adipose tissue areas remained statistically significant (r = −0.40, P = 0.05).T
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