In this study, we observed that concentration of insulin and insulin resistance that evaluated by HOMA-IR index were significantly increased in women with NWO compared to the control women who had normal BMI and FM. Our primary outcomes were significant higher blood concentration of leptin in women with NWO compared to women in control group. Despite the higher level of vapin in NWO group, it was statistically significant in NWO group compared to controls.
In previous studies, the prevalence of cardiometabolic abnormalities in patients with NWO have reported compared to normal and obese counterparts. The results of Huang et al. study conducted on young Japanese female demonstrated that NWO women had higher fasting insulin levels than lean women or those with normal weight normal obesity (NWNO) (non-significant) but had lower level of fasting insulin levels compared to obese women (P =0.003). The same results were reported about the HOMA-IR, but the HOMA-β cell in NWO women was higher than lean and or NWNO women ,while it was lower in these women compared to the obese women.
The result of this study was important for us because this study performed on Asian women. Body fat mass deposition and distribution are influenced by race. The prevalence of fat mass accumulation in the upper body region is higher in Asian women compared to Caucasian whites in the same BMI. For this reason, Asian women with normal BMI are more susceptible to NWO. In our study, similar to the Huang study conducted on Japans women, body fat mass≥ 30 % of body weight was considered as excess body fat.
Madeira et al. conducted a study on 1222 men and women in Brazil and found that normal weight obesity was associated with HOMA-IR, low insulin sensitivity, and high insulin secretion.
The positive association between increased body fat tissue and cardiomatabolic disorders, despite having normal body weight, has reported among adolescences. Heijden et al. have shown that in Hispanic adolescent girls with normal BMI (<85th percentile) and high body fat (≥27%), abdominal and hepatic fat content, insulin resistance, plasma leptin and Hs-CRP concentrations significantly increased compared to those with normal BMI and BF.
Previous studies have shown that individuals with NWO are susceptible to metabolic syndrome and cardiovascular disease due to the increased prevalence of hyperglycemia, insulin resistance, low grade of pro-inflammation status, increased oxidative stress, hyperlipidemic disorders in NWO, which increased by increasing the percentage of body fat tissues in adults and adolescents [14-16].
The relationship between the abdominal fat depositions and other components of metabolic syndrome was confirmed in numerous previous studies in various populations such as subjects with overweight/obesity or type 2 diabetes or syndrome metabolic and or postmenopausal women[17-19].
Wei et al. study reported the distributed adipokines profile in obese patients with newly diagnosed type 2 diabetes (T2DM) compared to diabetic patients with normal BMI. It was shown that obese T2DM patients had increased level of leptin and reduced concentration of adiponectin compared to non-obese T2DM patients. The results obtained from this study and previous studies may explain the relationship between fat mass, adipokines as a paracrine and endocrine secretion of fat tissues and cardiometabolic abnormalities as a three components of the triangle with multiple interactions and feedbacks. However, more studies are needed to demonstrate the cellular and molecular mechanism of interaction between adipokines at cellular level and endocrine disorder in clinical level.
One of the theories to describe the association between the excessive body fat tissues and components of metabolic syndrome is related to adipokine secretion. The results of the present study showed that serum levels of leptin and vaspin in NWO women were higher than those in controls. Our results indicating an increase in the concentration of leptin were consistent with previous studies. Romero-Corral et al. reported increased concentration of leptin among American individuals with NWO which was consistent with our results . Another study conducted on Swiss population showed that leptin concentration in women with NWO was higher than that in women with normal BMI and FM%.
It was confirmed that the obese patients had higher level of leptin compared to the individuals with normal weight, which might be due to the leptin resistance in obesity.
Leptin is one of the primary hormones used to diagnose adipocytokine secreted from adipose tissues. Therefore, according to the previous studies, there is positive relationship between blood level of leptin and percentage of body fat. We observed similar results in our study among women with NWO (r = 0.36, P = 0.02). Our secondary outcomes were a positive association between concentration of leptin with fasting levels of FBS and insulin and HOMA-IR.
According to the past investigations, leptin shows paradox actions which can increase atherogenesis and insulin resistance or may have antiatherogensis and increase insulin sensitivity. Koh et al. reported that the opposite effects of leptin are in balanced conditions in healthy individuals and disrupted in obesity. It seemed that the action of leptin increasing insulin resistance in subjects with NWO is similar to the patients with obesity.
Otherwise, leptin level has a positive correlation with the markers of pro-inflammatory and inflammatory status, which can describe the role of higher level of leptin in increasing the risk factors of cardiometabolic disorders[25, 26].
Similar to the leptin, our results showed there was a statistically significant association between vaspin concentration and fasting insulin level and HOMA-IR in women with NWO.
Vaspin, as a serine protease inhibitor, is another adipokine secreted from adipose tissue. A experimental study showed that injection of vaspin to obese mice can improve glucose tolerance by increasing insulin sensitivity.
Compared to the leptin and adiponectine, limited studies have performed about vaspin in humans and most studies have focused on animal models of obesity and type 2 diabetes.
Based on the physiological functions of adipokines, they are classified into two categories:“healthy” adipokines such as adiponectine and omentin and “unhealthy” adipokines. In addition to the TNF‐α, IL‐6, plasminogen activator inhibitor‐1, adipocyte fatty acid‐binding protein, lipocalin‐2, chemerin, visfatin and resistin, vaspin and leptin are considered as unhealthy adipokines.
Based on the results of Genske, et al. study conducted on 1825 participants of the study of Health in Pomerania, they found no clear conclusion with respect to the association between blood concentration of vaspin and distribution fat tissues including visceral adipose tissue (VAT), subcutaneous adipose tissue (SAT), or liver fat content (LFC).
In 3T3-L1 cells, it was shown that endogenous vaspin positively associated with insulin signaling which could be described by the role of vaspin in increasing insulin-stimulated phosphorylation of the key mediator protein kinase B.
On the other hand, the results of experimental study in mice, reported that injection of insulin in fasting status positively increased the hepatic expression of vaspin.
Previous studies have indicated that the serum concentration of vaspin was increased with worsening insulin resistance in children and impaired glucose tolerance and obesity in adults[32-34].
Our results are consistent with those of previous studies and we found a positive significant association between serum levels of vaspin and insulin in women with NWO. Therefore, it suggested that serum levels of vaspin are increased as a compensatory response to elevated concentration of insulin and insulin resistance. Vaspin mRNA expression is higher in patients with type 2 diabetes and in addition in obese patients due to the higher percentage of FM. Patients with NWO phenotypically have both impaired glucose intolerance and higher FM%. Regarding to the compensatory effect of vaspin, Heiker et al. proposed that increasing insulin sensitivity through the reduction of kallikrein 7 (hk7) induced insulin degradation. They demonstrated hk7 as the target protease of vaspin in human tissues. On the other hand, obesity due to the higher body fat mass induced the chronic low-grade inflammation. Previous studies have shown that vaspin may inhibit inflammatory processes under the control of peroxisome proliferator-activated receptor (PPAR). More studies are needed to find the mechanism of adipokines effects on the glycemic responses in NWO patients.
To our knowledge, this is the first study on the changes in serum level of vaspin in individuals with NWO. More studies are needed to investigate the changes in the serum concentration of adipokines and their interaction between each other and component of metabolic syndrome.
Comparing the results of studies regarding normal weight obesity is difficult because of the ethnic differences in the study subjects, tools used to assess body composition (bioelectrical impedance vs. DXA) and diverse cutoff points for diagnosis of NWO by considering ethnics and gender.