This population-based prospective study on middle-aged Turkish adults seeking the direct and mediated effect of adiposity on cardiometabolic risk demonstrated following findings dependent on type of cardiometabolic condition and gender. A) BMI determined the development of type-2 diabetes at a 1.5- to 2-fold HR, more so in men than women, and was virtually not mediated by a combination of SBP, total cholesterol and glucose levels. B) Regarding incident CHD, overweight displayed a non-significant tendency to confer risk that was little modified in either gender by the 3 mediators. C) Compared with normal-weight, obesity imparted a significant ~2-fold CHD risk. In men, ¾ of this excess risk was mediated especially by SBP, and by total cholesterol and glucose. In women, in contrast, 60 % of the excess risk was retained by BMI, leaving the remainder to the mediation of the major risk factors. D) BMI, though a significant modest predictor of CHD mortality, was mediated by the conventional risk factors in males, but retained substantially greater independent risk in females. These findings, collectively, suggest that other determinant factors are mediated by BMI/obesity for the risk of diabetes and CHD and, in women, for the risk of CHD by obesity. CHD risk of obesity in men was largely conferred by SBP-total cholesterol, and little by obesity.
Noteworthy is that the overall obesity category was predominated by females whereas the referent “normal-weight” category was so by males (Additional file 2: Figure S1).
Adipose tissue, particularly tissue from visceral-fat deposits, secretes potential mediators in the development of chronic diseases. Obesity is characterized by abnormal adipokine production and the activation of several proinflammatory signaling pathways, resulting in the induction of several biological markers of inflammation [16]. Resistin and tumor necrosis factor TNF-α are implicated in inducing atherogenic adipokines, such as plasminogen activating inhibitor-1 and interleukin-6, and inhibiting adiponectin. TNF-α activates also nuclear factor-(NF-)kB which may mediate hypertension and endothelial dysfunction. In obese patients, macrophage and lymphocyte infiltration in adipose tissue may strongly contribute to obesity-related metabolic dysfunction and chronic inflammation [17].
Diabetes risk is overwhelmingly determined by BMI and little by glucose
Age-standardized adult diabetes prevalence globally rose since 1980 more rapidly in women than men [18]. The development of diabetes is recognized to be largely co-determined by BMI with which our findings concur. Noteworthy is that added adjustment for fasting glucose hardly attenuated the HR of BMI for diabetes in either or both sexes. This may be related to lipoprotein[Lp}(a)-activated autoimmunity [19] which determines glycemia and concomitantly mediates rise in BMI. In the meta-analysis by Singh et al. [20] RRs for 5 kg/m2 higher BMI for ages 55–64 was 2.32 (2.04–2.63) for diabetes and ranged for all adult ages from 3 to 1.4. RRs for the estimated effect of BMI were larger in Western cohorts as compared with Asian cohorts in adults <55 years old. Of interest was that the effect of BMI on incident diabetes in Turkish women was only half that found in men. This may be related to the gender difference existing on Lp(a)-induced autoimmunity [19]. Of further interest was that the mediation of systolic BP and total cholesterol (alike of glucose) was virtually negligible.
CHD risk of overweight little modified by the three mediators
Elevated peripheral vascular resistance and renal salt retention due to higher sympathetic nervous system activity, angiotensin-aldosterone activity and insulin levels [21] can lead to hypertension in people with adiposity which leads also to dyslipidemia. Moreover, enhanced low-grade inflammation may render insulin resistance and diabetes [22]. We concur with the global meta-analysis [7] that the association between adiposity and CHD is not completely explained by the three mediators in men and underline that it is far from being explained in women.
Overweight imparted modest age-adjusted CHD risk (1.33-fold the “normal” weight); and this was attenuated mainly by systolic BP. The attenuation via BP and serum total cholesterol was 45 % in the meta-analysis of the BMI-CHD Collaborators [6] and was one-half (of the unadjusted RR 1.26) via the three mediating risk factors in the meta-analysis of the Chronic Diseases Collaboration [7]. RR of the age-adjusted CHD risk in the current study was also close to the former meta-analysis.
The two-fold CHD risk of obesity is mediated by risk factors largely in men, modestly in women
Excess CHD risk, compared with normal weight, showed a steep rise in the obesity category relativeto the overweight one; sex-, age- and smoking-adjusted RRs in combined gender were, namely, 2.24 and 1.40, respectively. In comparison to the meta-analysis on global cohorts [7], this basic excess risk displayed gender difference insofar as the RR was by one-third higher in men, but nearly two-fold in women. Though mediation by the 3 risk factors (with 55 % of the excess risk) was closely similar to that in the global cohorts, gender disparity in the current study was more prominent in the mediation by the 3 risk factors: whereas 70 % of the excess BMI risk was thus mediated in men, 60 % was retained by BMI in women. A gender difference of the BMI-mediated risk was not reported in three meta-analyses [5–7] in which sex-stratified analysis was, however, not reported.
The retained CHD risk by BMI may be due to pathways of systemic inflammation, endothelial dysfunction, and thrombogenic factors. Alike the meta-analysis findings, the largest mediation was found for systolic BP, followed by total cholesterol and least for fasting glucose. Obesity mediation by the individual risk factors was markedly different across sexes inasmuch as glycemia did not mediate any BMI risk in men, in contrast to demonstrating the largest mediation (with 14 %) in women. This distribution of obesity-mediated risk across the sexes as well as the retention of the majority of the obesity risk in women support the notion of autoimmune process activated by obesity being far more common in females than males [19]. It is the autoimmune activation (induced by oxidative stress) and thrombo-embolic events rather than BP or cholesterolemia that lead to fatal and non-fatal CHD.
BMI modest determinant of CHD mortality
The sex- and age-adjusted continuous BMI variable was a significant modest contributor to HR for CHD mortality; yet this risk was fully abolished by mediation of systolic BP in men, indicating this factor assumed the main determinant of CHD mortality. In contrast, the HR was strengthened to over two-fold in women through mediation of fasting glucose, implicating that impaired fasting glucose (IFG) protected Turkish women against CHD death. This is in agreement with our previous report [23] that IFG status in non-diabetic people without MetS is associated with a less adverse cardiovascular risk profile and reduced future CHD risk, lest modulated by the developed MetS, especially in women in whom serum Lp(a), linked inversely to HOMA, is the likely modulator.
The modest magnitude of HR herein is in line with no effects of overweight on cardiovascular mortality [24], or with overall mortality in a meta-analysis [25]. In contrast, in the Prospective Studies Collaboration [26] 5 units of BMI revealed 40 % excess vascular mortality risk above the optimal BMI 22.5-25 kg/m2; below this range, BMI was inversely related to overall mortality.
Sex-modulated risk of fatal and nonfatal CHD imparted by obesity
Excess risk of age- and smoking-adjusted obesity was larger by one-half in women than men. This is at some variance from the findings of a large pooled analysis on 1.4 million individuals [20] in which effects by age, sex or global region of major metabolic risk factors on cardiovascular disease and diabetes were evaluated. At the age group 55–64 years, the RR was largest for systolic BP with respect to hypertensive HD or stroke, for BMI regarding diabetes or CHD, and at much lower effect size for fasting glucose in regard to CHD or stroke. Proportional effects declined with age, were generally consistent by sex, and differed little by region. However, effects of BMI on diabetes were larger in Western compared with Asian cohorts in younger adults [20].
In regard to BMI-mediated CHD risk of fasting glucose and systolic BP, a clear sex disparity was evident: Women had a significant risk through glucose (by 15 % higher than men), while men had such through systolic BP (by 20 % higher). We have evidence that these features are largely gene-dependent. The TT genotype of the CYP19A1 polymorphism encoding the aromatase enzyme involved in the final step of estrogen synthesis showed, namely, interaction with narrow waist girth for hypertension only in men, independent of age and BMI [27]. In Caucasian US women, an interaction between the risk allele of the FTO rs8050136 polymorphism mediated by BMI and low physical activity yielded increased cardiovascular disease risk [28].
Implications relate both to the prevention of CHD and DM. Coronary prevention programs should take into account the role of sex and be modified for sex. While addressing the mediators with measures including antihypertensive and lipid-lowering medication may largely be effective in men, addressing the mediators in women will alleviate only slightly the prevention problem. Major improvement in obesity and related proinflammatory state is required for the CHD prevention. As regards prevention of type-2 diabetes, our findings indicate that the overwhelming portion of the risk can be reduced only by weight loss and improvement in the related oxidative stress (mediated by Lp(a)-activated autoimmunity), regardless of gender.
Limitations and strength
Our basic regression models did not adjust for certain confounding factors such as socioeconomic state, physical activity grade, or diet; this might have affected the BMI-mediated CHD risk, though not to a great extent. Analysis stratified to sex which substantially generated novel knowledge constitutes a major strength. Despite the fact that, due to lack of an oral glucose tolerance test, some cases of actual diabetes may have been missed, analyzing the BMI-mediated effects also for diabetes and CHD mortality in the same cohort represents further strength.