Correlation of renin angiotensin and aldosterone system activity with subcutaneous and visceral adiposity: the framingham heart study

Obesity, and in particular central obesity, is associated with hypertension, increased cardiovascular risk, diabetes mellitus and chronic kidney disease [1]. Risk estimates from population-based studies indicate that over 65% of hypertension cases may be directly attributable to obesity [2]. Recent increases in the US prevalence of diabetes and chronic kidney disease parallel similar increases in obesity rates, and observational studies demonstrate an association between increasing body mass index (BMI) and these diseases [3–5]. Furthermore, it is proposed that different adipose compartments are associated with varying degrees of metabolic risk [6] and that visceral adipose tissue (VAT) in particular may confer increased risk [7].

The renin-angiotensin-aldosterone system (RAAS) is a cascade of hormones that play a central role in fluid homeostasis and the regulation of vascular resistance, classically activated by the release of renin from the juxta-glomerular apparatus in response to a variety of stimuli, such as renal hypoperfusion [8]. Upregulation of the RAAS has been shown to promote the development of hypertension, hypertension-related end organ damage, atherosclerosis, diabetic end organ damage and chronic kidney disease [9]. Many diverse pathophysiologic mechanisms are implicated, including the production of pro-sclerotic and pro-fibrotic cytokines such as transforming growth factor-β, the promotion of endothelial dysfunction and hypertrophy of vascular beds, the induction of glomerular hypertension [8] and bi-directional interaction with hyperglycemia-induced maladaptive pathways [9].

Adipose tissue, and VAT in particular, may be an important source of non-classical RAAS activity. For example, visceral fat expression of angiotensinogen approximates that of the liver, classically considered the main source of this enzyme [10], and concentrations of angiotensinogen increase with increasing BMI [11]. Non-classical RAAS activation may result from the activity of lipid derived mediators (adipokines) such as complement-C1q TNF-related protein 1 (CTRP1) or adiponectin [12]. For example, CTRP1 is expressed at high levels in adipose tissue and has been shown to induce aldosterone production and partially mediate angiotensin II-induced aldosterone secretion in the obese Zucker rat [12]. In humans, CTRP1 levels are increased in the serum of hypertensive patients, as well as being highly expressed in obese subjects [12]. BMI has also been shown to predict plasma aldosterone concentrations in hypertensive subjects [13], normotensive individuals on a high-salt diet [14], and visceral adiposity is strongly associated with increased blood pressure and hypertension [15].

In light of these observations, we hypothesized that RAAS activity may be related to variation in regional adiposity. To investigate this, we examined relations of RAAS activity, as assessed by circulating plasma renin activity (PRA), serum aldosterone level and aldosterone:renin ratio (ARR), with specific regional adiposity measures in a large, community-based sample. Specifically, we calculated correlations of waist circumference (WC), BMI, VAT and subcutaneous adipose tissue (SAT) with PRA, aldosterone and ARR, and calculated partial correlations adjusted for factors known to be associated RAAS activity.

Contrary to our original hypothesis, we did not observe an association between any specific adiposity measure and activity of the RAAS system in overall, sex-stratified or multivariable-adjusted analyses.

Angiotensinogen, renin (or peptides with renin-like activity), angiotensin converting enzyme (ACE), and AT₁ and AT₂ receptors are all secretory products of the rodent adipocyte [26], and the expression of some are increased in obesity [27, 28]. Although their primary function is not known, autocrine/paracrine tissue effects on adipocyte function are well described [29, 30]. In addition, studies in transgenic mice demonstrate that adipose-derived angiotensinogen may also contribute to the systemic RAAS pool, and the relationship between obesity and hypertension may be directly explained by angiotensinogen secretion by the rodent adipocyte [31].

As in rodents, multiple lines of evidence support the existence of adipocyte RAAS in humans [30], and the present findings do not preclude the existence of significant local RAAS activity in our sample. However, evidence that the human adipose RAAS makes a significant contribution to systemic activity has not been convincingly demonstrated, and the literature in this area is conflicting. For example, a study in lean, healthy, young men (n = 91) did demonstrate a correlation between plasma angiotensinogen levels and BMI (r = 0.33, P < 0.05), whereas no significant correlation with PRA or circulating aldosterone levels was observed [11]. In a second study of 38 obese vs. lean postmenopausal women, circulating levels of angiotensinogen, renin, aldosterone and angiotensinogen converting enzyme (ACE) were significantly higher in the obese women, and plasma levels of several RAAS peptides decreased after weight loss [32]. However, in contrast to our population-based study, morbidly obese cases were selected for this analysis (mean BMI 38 kg/m²), making direct comparison with our study difficult. It is possible that unaccounted factors may have influenced RAAS levels in that study; for example, there was evidence of substantial insulin resistance in cases, which has been shown to be independently associated with RAAS activity in many studies [33–37]. A third study also detected a correlation between BMI and plasma aldosterone concentrations in overweight and obese patients with essential hypertension [13]. However, this was conducted in a tertiary referral hypertension clinic, and is not directly comparable with the present analysis. Furthermore, several studies in obese individuals with hypertension have not detected an association between obesity and circulating RAAS components [38–40].

The present work extends the literature in several ways. In contrast to evidence from animal models, where adipocyte RAAS exerts substantial physiologic action beyond the local environment of the adipocyte [29], our findings suggest that adipose RAAS does not make a substantial contribution to the systemic RAAS pool in the general population. There are several potential reasons for this. First, substantial inter-species differences in fat deposits and metabolism exist between rodents and humans [41]. For example, whereas angiotensin II promotes adipocyte growth and pre-adipocyte recruitment in rodents, it is anti-adipogenic in human adipose tissue [41]. Furthermore, in contrast to rodent models of diet-induced obesity, angiotensinogen mRNA expression in the adipose tissue of obese, hypertensive females is not greater than that of non-obese controls [30]. Fundamental inter-species differences in adipocyte biology such as these may preclude the extension of observations made in the rodent to humans. Equally, even if observations made in obese rodents are reflective of human pathophysiology, the cross-sectional design of our study may fail to capture dynamic changes in RAAS components due to active weight gain. For example, changes in the expression of RAAS components following sudden, controlled weight gain in rodents may not be observed during chronic, stable obesity, which may be more representative of the participants in our study. As discussed, significant changes in circulating RAAS components have been demonstrated in response to acute weight loss in humans [32]. Finally, it may be that adipose RAAS functions primarily in a paracrine/autocrine manner, and systemic levels are not reflective of local tissue activity in humans.

Several avenues for further study are suggested by the present analysis. In particular, efforts to delineate the relative importance of adipocyte-derived (as compared to classically-derived) RAAS components, and their relative contribution to circulating levels, are required; adipocyte-specific RAAS component knockout models would be most helpful in this regard. Human studies comparing tissue mRNA expression of RAAS components during weight gain as compared to chronic obesity and lean controls may also prove illuminating.

The use of an unselected, community-based sample, the highly reproducible volumetric method of assessing SAT and VAT, and the sample size sufficient to power multivariable analyses comparing the relative magnitudes of association strengthen our study. However, several limitations should also be acknowledged. Ambulatory RAAS measurements were drawn from individuals on a free-living sodium diet, while taking their usual antihypertensive medications, potentially biasing our results toward the null. As sodium balance is a major determinant of renin and aldosterone, the absence of data on sodium intake and urinary excretion is an important limitation. However, it should be noted that results were similar to the primary analysis in participants not taking anti-hypertensive treatment. Furthermore, samples were drawn after only 10 minutes in the supine position, and not after 1 h of rest as recommended in research unit protocols, which are impractical in the setting of a large, longitudinal observational cohort. Our analysis would be enhanced by directly measuring markers of local RAAS activation in adipose tissue. However, this is unfortunately not technically feasible in a large, observational epidemiologic study. Finally, our results may not be generalizable to all racial/ethnic groups or age groups, as our sample was primarily white and middle-aged, and racial differences in serum aldosterone and renin values have been reported [42].

In conclusion, regional adiposity measures were not associated with systemic RAAS activity, as determined by plasma renin activity, serum aldosterone concentration and aldosterone to renin ratio, in this large population-based study. Further studies are required to establish whether adipose-derived RAAS components contribute to systemic activity in humans.