Abdominal obesity exhibits distinct effect on inflammatory and anti-inflammatory proteins in apparently healthy Japanese men

National Cholesterol Education Program (NCEP)-Adult Treatment Panel (ATP) III, and American Heart Association (AHA)/National Heart Lung and Blood Institute (NHLBI) proposed definitions of the metabolic syndrome (MetS) as a cluster of at least 3 of 5 following risk factors, abdominal obesity, raised blood pressure, hyper-triglyceridemia, hypo-HDL-cholesterolemia, and raised fasting blood glucose [1, 2]. The primary mechanism for clustering of metabolic abnormalities has yet to be elucidated, but insulin resistance or accumulation of visceral fat is believed as an encouraging candidate [3, 4]. As for visceral fat, the International Diabetes Federation (IDF) newly recommended a definition in which abdominal obesity is the essential component of MetS [5, 6].

Recent studies have proposed an association between MetS and inflammatory markers [7‐10]. Abdominal obesity, especially a visceral fat, may play a key role in these situations, because adipose tissue is known to secrete many bioactive substances, including inflammatory and anti-inflammatory proteins [11, 12]. However, only few studies have precisely examined the significance of abdominal obesity in the inflammatory changes observed in MetS [13, 14].

In the present study, we examined inflammatory and anti-inflammatory proteins in Japanese middle-aged men, and investigated whether presence of abdominal obesity has an impact on the inflammatory responses. We here describe unique associations among abdominal obesity, clustering of MetS components, and inflammatory and anti-inflammatory markers.

Profiles of the study subjects are shown in Table 1. Traditional risk factors were exacerbated and HOMA-IR was increased in abdominal obesity group as compared with non-abdominal obesity group. Abdominal obesity group presented significantly higher hs-CRP and IL-6 levels, and a lower adiponectin level than non-abdominal obesity group.

The effects of clustering MetS components on inflammatory status were compared between these two groups. Interestingly, in non-abdominal obesity group, serum levels of hs-CRP and IL-6 changed a little in association with clustering of MetS components (Figure 1A). However, serum levels of hs-CRP and IL-6 significantly increased in association with clustering of MetS components in abdominal obesity group (Figure 1B). On the other hand, serum adiponectin level exhibited a little change with clustering of MetS components in abdominal obesity group (Figure 1B), while it was significantly decreased in non-abdominal obesity group. These findings suggest that abdominal obesity may be a key factor in modulating the inflammatory reactions observed in MetS.

We next examined whether these changes of inflammatory markers associate with traditional risk factors. The mean value of risk factor in the subjects either with low or high level of inflammatory marker was compared. Significance of difference was summarized in Table 2. The mean values of waist, TG, and HDL-C showed significant changes associated with classification of adiponectin and hs-CRP levels. FPG was significantly changed between subjects with high and low adiponectin levels. SBP, and DBP levels were significantly changed between subjects with high and low hs-CRP levels. Moreover, stepwise regression analysis revealed waist circumference was a significant determinant for the levels of adiponectin, IL-6, and hs-CRP (Standard regression co-efficient: -0.237, 0.115, and 0.256; F value: 18.6, 4.1, and 20.9; respectively)

Networks of inflammatory and anti-inflammatory proteins may be altered by the presence of abdominal obesity. Therefore, we next examined the correlation of these markers both in the subjects with abdominal obesity and in obese subjects defined by body mass index (BMI) ≥ 25. As shown in Table 3, correlation was not observed between serum adiponectin and hs-CRP levels in obese subjects (BMI ≥ 25), and even in those with two or more MetS components. However, there was a significant negative correlation between serum adiponectin and hs-CRP levels in abdominal obesity group (r = -0.23 [95%CI, -0.37 to -0.08]). In addition, significant correlation was detected in the subjects with abdominal obesity with two or more MetS components, i.e. MetS (r = -0.29 [95%CI, -0.53 to -0.01]). No significant correlation was observed between adiponectin and IL-6 in both obese and abdominal obese subjects (data not shown).

It is considered that clustering of metabolic abnormalities presents synergistic effects on cardiovascular complications beyond the sum of effects of individual abnormalities [19]. Therefore, to elucidate the mechanism in clustering of metabolic abnormalities is an important issue. In the present study, percentage of the subjects with two or more MetS components was markedly higher in the abdominal obesity group (30.1%) than the non-abdominal obesity group (11.0%) (data not shown). Abdominal obesity, therefore, might play a pivotal role among various MetS components in the practical definition of MetS. When abdominal obesity was absent, inflammatory proteins, such as hs-CRP and IL-6, did not increase significantly with clustering of MetS components (Figure 1A), despite the fact that previous studies found an association between CRP and MetS [7, 20]. Our results clearly demonstrated association between hs-CRP/IL-6 levels and clustering of MetS components predominantly in the presence of abdominal obesity. Although BMI might also alter inflammatory status, classification by BMI did not present clear association between inflammation and clustering of MetS components (data not shown).

Inflammation may be an important underlying etiology of MetS [8] through its various effects mediated by adipose tissue-derived factors, such as leptin, adiponectin, IL-6, IL-10 and etc. [12]. Many studies demonstrated associations between inflammatory proteins and MetS, abdominal obesity, or insulin resistance. Our results also demonstrate the importance of waist circumference in the changes of inflammatory markers (Table 2). However, abdominal obesity has usually been evaluated as one of the components of MetS. In the present study, we clearly showed that abdominal obesity exhibits distinct association with inflammatory and anti-inflammatory proteins in clustering of MetS components in apparently healthy subjects.

Adiponectin, an anti-inflammatory protein [21], has been demonstrated to be insulin-sensitizing and anti-atherogenic factor, and is considered a key component of MetS [11, 22, 23]. Serum adiponectin level was significantly lower in the subjects with abdominal obesity than those without it, and a marked decrease was observed with clustering of MetS components only in the subjects without abdominal obesity. In agreement with previous reports, low level of serum adiponectin is a potent risk for MetS, and elevation of serum hs-CRP and IL-6 concentration enhances the incidence of MetS in the subjects with abdominal obesity.

Previously, an inverse correlation between expression levels of CRP and adiponectin in adipose tissue from the patients with coronary artery disease had been demonstrated [24]. In the present study, a significant negative correlation was observed between serum adiponectin and hs-CRP levels in the subjects with abdominal obesity, but not in obese subjects. These results suggest that abdominal obesity may exhibit distinct effect on inflammatory and anti-inflammatory proteins. Recently, it is reported that portal concentration of IL-6 is higher than peripheral concentration of it, and visceral fat is identified as an important site for IL-6 secretion [25]. Thus, portal IL-6 from visceral fat might directly induce the production of CRP in the liver. In addition, macrophages infiltrating into visceral fat is another possibility for inflammatory networks specific to the abdominal obesity. It has been reported that macrophage is a source of adipose tissue-derived proteins [26]. The increased number of macrophages infiltrating the visceral fat tissue in individuals with abdominal obesity suggests that adipose tissue itself is a source and site of inflammation [27]. Thus, the inflammatory networks associated with abdominal obesity were distinct from those associated with mere "obesity". Després and Lemienx proposed visceral fat as a dysfunctional adipose tissue [4], and our results support this idea.

In conclusion, without abdominal obesity, inflammatory status is not exaggerated by clustering of MetS components in apparently healthy middle-aged men. Abdominal obesity may exhibit distinct effect on inflammatory and anti-inflammatory proteins and modulates inflammatory network in MetS.