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Association between deposit of abdominal adipose tissues and metabolic abnormality in a Chinese population

Previous studies indicated that deposit of abdominal adipose tissue associated with the abnormalities of cardiometabolic components. However, the results were inconsistent on the effects of subcutaneous adipose tissue (SAT) and difference between men and women. The aim of this study was to examine the associations of VAT, SAT with metabolic status and the different effects between male and female. 1388 eligible subjects were recruited from the baseline investigation of metabolic syndrome investigation in China. Areas of abdominal VAT and SAT were determined by nuclear magnetic resonance imaging (MRI). Total triglycerides (TG), high-density lipoprotein cholesterol (HDL-C) were measured by biochemical auto-analyzer. Metabolic abnormality (MA) was dened more than one of abnormally metabolic components, which were based on the denition of metabolic syndrome (IDF 2005). Multiple logistic regression was used to calculate the odds ratios (ORs) and 95% condence intervals (95%CI). The predictive values were assessed with area under the curve (AUC), net reclassication improvement (NRI), and integrated discrimination improvement (IDI), respectively.


Introduction
Obesity, especially central obesity, is a strong risk factor for a variety diseases, such as dyslipidemia, type 2 diabetes, cardiovascular diseases, and all-cause mortality (1,2). Body mass index (BMI) and waist circumference (WC) are two commonly used indicators of obesity. However, BMI by itself does not fully characterize adiposity, it is limited by differences in body adiposity for a given BMI across age, gender and ethnicity (3). Asians are generally more likely to have metabolic abnormalities with a lower BMI than Caucasians (4). Although WC re ected central obesity and readily available, do not adequately re ect actual body fat tissue distribution and thus fail to distinguish between abdominal subcutaneous adipose tissue (SAT) and visceral adipose tissue (VAT), and SAT and VAT have different metabolic consequences (5). While reports on the effects of SAT on metabolic abnormality are still inconclusive and even contradictive (1,(6)(7)(8). Some studies have found that SAT is a bene cial fat depot for type 2 diabetes and metabolic syndrome(8, 9), however, other studies have not found a signi cant correlation between SAT and some metabolic abnormal components (6,7,10). In addition, because of sex-difference in fat depot accumulation between the sexes, they have different effects on metabolic abnormalities. The conclusion that VAT increased the risk of metabolic abnormalities is consistent, but the extent to which it affects different genders is unclear. Some studies have found that higher VAT has a causal relationship with cardiometabolic risk factors, with a larger effect on women (11). While other studies indicated that VAT contributes to a more absolute risk for metabolic factors in men than women (12), highlighting the gender difference in the contribution of regional fat distribution.
A possible reason for these sophisticated associations may due to the distinct fat distribution across ethnic groups (13,14). In addition, the way of measurement of SAT and VAT, and the adjustment of confounding factors were also likely reasons. Currently, accurate assessment of regional fat depots requires imaging with radiographic techniques such as computed tomography (CT) and magnetic resonance imaging (MRI) (15). MRI-based adipose tissue measurements that directly quantify abdominal fat compartments, such as VAT and SAT. In the Chinese population, limited studies had probed into the effect of MRI-measured SAT, VAT on metabolic disorders in different sex. Therefore, we explored the relationship between SAT, VAT and metabolic abnormalities in men and women, respectively.

Subjects
The subjects were recruited from our previous baseline investigation of metabolic syndrome investigation in China in 2010. The detailed information was previously described(16). In this study, a subpopulation from two communities in Hangzhou (n=1170) and Chengdu (n=761) was included. Subjects were excluded if they had (1) severe chronic diseases including cardiovascular diseases, cancers, kidney dysfunction and other chronic wasting diseases, (2) missing data on anthropometric information, SAT and VAT, a total of 1388 eligible subjects were included at last. This study was approved by the institutional review board at Zhejiang University, Zhejiang, China. All participants were given their written informed consents.

SAT and VAT measurements
Abdominal adipose tissue was measured by nuclear magnetic resonance imaging (MRI) using a wholebody imaging system (SMT-100, Shimadzu Co, Japan) with TR-500 and TE-200 of SE. MRI scan was performed at the level of umbilicus between L4 and L5 with the subject in the supine position. The areas of subcutaneous and visceral abdominal adipose tissue were calculated using sliceOmatic software (version 4.2).

Covariant assessment
With a standard questionnaire, the information including age, gender, smoking (current, former, and never), alcohol drinking behaviors (never, moderate, and heavy), and menstrual history (for women) were collected. Current smoking was de ned as smoking at least one cigarette per day and lasting for one year. Former smoking was considered as quitting smoking for at least one year. According to the frequency of drinking, they were classi ed as heavy drinking, moderate drinking and never: more than three times per week was categorized as heavy drinking. Anthropometric variables were collected by trained investigators with a standard protocol, including weight, height, WC, systolic blood pressure, and diastolic blood pressure. Body mass index (BMI) was calculated as weight (in kilograms) divided by the square of height (in meters). Waist circumference (WC) was measured at the midpoint between the iliac crest and lowest rib. Blood pressure was surveyed in a sitting position with a mercury sphygmomanometer. Systolic blood pressure (SBP) and diastolic blood pressure (DBP) were measured as the average of three repeat measurements with at least 30-s intervals.
The overnight fasting blood samples were collected for each subject. Total triglycerides (TG), total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C) were measured by biochemical auto-analyzers (Hitachi 7060, Tokyo, Japan). Fasting plasma glucose (FPG) was analyzed with a glucose oxidase method with the Beckman Glucose Analyzer (Beckman Instruments, Irvine, CA, USA).
The abnormal metabolic components were de ned by the metabolic syndrome de nition of the International Diabetes Federation (IDF) criteria in 2005, including elevated TG ≥1.7mmol/L, low HDL-C<1.03mmol/L (in men), <1.29mmol/L (in women); elevated FPG ≥5.6 mmol/L or have a history of diabetes, or using drugs of anti-diabetes; elevated SBP >130mmHg, or DBP<85 mmHg or using antihypertensive drug therapy. Metabolic abnormality (MA) was de ned as more than one abnormally metabolic components, metabolic normality (MN) was de ned as zero or only one metabolic component with abnormality(16).

Statistical analysis
Continuous variable was presented as mean ± standard deviation or median (inter-quartiles range).
Categorical variable was shown as number (%). Student's t-test or the Wilcoxon rank-sum test was used to compare continuous variables. Chi-square test was used to compare categorical variables. The subjects were divided into four groups by quartiles of SAT and VAT, respectively, with the rst quartile (Q1) as the reference group. The ORs and 95%CIs for each quartile by sex were calculated using multiple logistic regression, adjusted for age, BMI (for overall), smoke, drink, menstrual history (for women). Considering different distributions between men and women, further analysis was performed by stratifying sex. The signi cant level was set at P<0.05. The main two packages of "Predict ABEL" and "pROC" were used to calculate the net reclassi cation improvement (NRI), integrated discrimination improvement (IDI), area under curve (AUC) and so on. The software IBM SPSS Statistics version 25.0 and R 3.6.3 were used to analyze the data.

Results
The baseline characteristics of subjects Levels of SAT, VAT in different metabolic status strati ed by sex and BMI  only VAT in women irrespectively of BMI levels. In women, borderline signi cance was found for SAT in BMI ≥ 24kg/m 2 (P = 0.066) and no signi cance in BMI < 24kg/m 2 (P > 0.05).
The associations of different levels of SAT, VAT with metabolic abnormality strati ed by sex and BMI Table 3 shows the associations of SAT, VAT with metabolic abnormality strati ed by sex and BMI after adjusted for age, BMI (for overall), smoke, drink, and menstrual history (for women). In men and women, levels of VAT were signi cantly correlated with higher risks for MA (p for trend < 0.05). Comparing with the reference group of the rst quartile (Q1), OR in fourth quartile (Q4) was 6.537 (95% CI = 3.394-12.591) in men and 3.364 (95% CI = 1.898-5.962) in women, however, no signi cance was found in SAT.   The Predictive Ability Of Vat On Metabolic Abnormality Table 4 describes the predictive ability of VAT on metabolic abnormality. In men, the AUC of VAT was 0.727, which was signi cantly higher than that of BMI (0.658, 95%CI = 0.614-0.701) and WC (0.688, 95%CI = 0.646-0.730) (all the P values < 0.05). When compared with BMI or WC, VAT improved the predictive value of MA, NRI (95%CI) were 0.139(0.070, 0.208) and 0.106(0.038, 0.173), respectively; IDI (95%CI) were 0.074(0.053-0.095) and 0.046(0.026-0.066), respectively.

Discussion
In this cross-sectional study, we found that higher VAT rather than SAT increased risk for MA in men, and for women, the correlation of SAT only existed in BMI ≥ 24kg/m 2 . Higher VAT showed a signi cant positive association with MA in men and women, independent of BMI. VAT improved the predictive ability of MA comparing with BMI and WC. Deposit of abdominal adipose tissue associated with the risk of MA.
There are some differences between SAT and VAT in anatomical, cellular, molecular, physiological, clinical and so on (17). VAT has been considered the more pathogenic adipose tissue compartment compared with SAT(18). This may be related to the biological function of VAT, VAT was a metabolically active organ, which included more non-adipocytes including macrophages, immune cells, preadipocytes and broblasts, and could secrete amounts of in ammation mediators to induce metabolism impairments (17,(19)(20)(21). In addition, the high lipolytic activity of VAT and its accompanied in ammation response also contribute to abnormal lipogenesis, glucose homeostasis, and vascular health (22,23). Therefore, it is plausible that higher VAT increased the risk for the metabolic abnormalities. With regards to the contribution of VAT in different sex, inconclusive results were reported (11,12,(24)(25)(26). Several Caucasian population studies showed the associations of VAT with type 2 diabetes, hypertension and hyperlipidemia were stronger in women (11,24,27). In our supplemental table3(See Additional File 1), we observed that the effect of VAT on high TG and low-HDL were higher in men, indicating that VAT may have more striking effect on the lipid metabolism in men than women. Another possible reason was that only limited confounding factors were adjusted, which may have affected the results. Extending studies of the Chinese population needed to be expanded to determine gender differences in the contribution of VAT.
SAT is known to have adverse effects on a variety of metabolic risk factors and may have unique pathogenic properties independent of BMI (1,7,24,28), and the effects of different levels of SAT on cardiometabolic factors are inconsistent (1,7,14,18,24,29). In line with previous studies (29)(30)(31), our study (See Supplementary table 1 and 2, Additional File 1) showed higher SAT did not link to increased risk for hypertension, higher TG, and lower HDL-C independent of BMI, and SAT may be a protective factor for blood glucose. Several studies for European or African population found that SAT had independent associations with high blood pressure and HDL-C (1,15,25), suggesting the distinct effect of SAT across ethnics. A possible explanation for this gender difference in SAT was the distinct sex steroid hormone pro les since these sex hormones are important factors in regulating the adipose tissue distribution and energy metabolism (32,33). For the protective effect of SAT, there were also several hypotheses to explain this observation. One is with smaller adipocyte, SAT was more insulin sensitive, and have a larger capacity to uptake fatty acids and triglycerides, thus can act as a powerful buffer to prevent excess fat into non-adipose tissue (34). On the other hand, SAT could secrete more favorable adipokines such as adiponectin, which had anti-diabetes and antiatherogenic properties (17,22). Therefore, the different effects of SAT on metabolic outcomes may be related to its biological function.
Previous studies have shown that baseline and changes in VAT were independent predictors of future dyslipidemia, but BMI and SAT were not associated with future development of atherosclerotic dyslipidemia (35). The outcome was consistent to our study that VAT was a better indicator for predicting MA when compared to BMI and WC. Finally, VAT was more strongly associated with MA than BMI, WC, and SAT.
There are some advantages in our study. Areas of SAT and VAT were measured using MRI, which was the gold standard method of determining abdominal adipose tissue. The data, including anthropometric and questionnaire-based information, were collected by trained health professionals, and the biochemical measurements followed the standard protocols. Our study also has some limitations. First, we cannot infer causality between the fat indices and the metabolic abnormality because of the cross-sectional design. Second, limited confounding factors were included in this study, for example, regional fat distribution, such as deep SAT and super cial SAT, and drug use were not included, which may bias the results. Thirdly, the sample size of this study was relatively small. Finally, our data were based on only one single ethnic group, thus the results may not be applied to other ethnicities.

Conclusions
In brief, deposit of abdominal adipose tissue associated with the risk of MA. VAT positively increased risks for metabolic abnormality in both of men and women, different effects were found between men and women. In women, SAT only increased the risk of MA in BMI ≥ 24kg/m 2 ; VAT increased the predictive ability of on MA comparing with BMI and WC. Distribution of abdominal fat associates with its biological effects.