The principal findings of the present study are 3-fold. First, circulating N-BNP concentrations are inversely related to abdominal adipose tissue mass. Second, circulating N-BNP is more strongly related to visceral adiposity than subcutaneous adiposity. Third, the association between plasma N-BNP and VAT is attenuated by adjustment for HOMA-IR, suggesting that hyperinsulinemia could be a mediator of the link between visceral adiposity and lower natriuretic peptide levels. Taken together, these findings offer novel insights into possible mechanisms underlying the relation of obesity with natriuretic peptides and, in turn, cardiovascular risk.
The natriuretic peptides play an important role in the regulation of vascular tone, sodium balance, and cardiovascular remodeling. Although it is well recognized that obese individuals have lower circulating natriuretic peptide levels,1
the mechanisms underlying this relationship have been unclear. Obese individuals have both higher fat mass and higher lean body mass. A report from the Dallas Heart Study found that lean body mass, as measured by DEXA, was more strongly associated with N-BNP than fat mass.1
Although DEXA scans do not distinguish subcutaneous from visceral adipose tissue, the majority of fat mass assessed by DEXA is thought to comprise of SAT.4
Accordingly, we found that the association of N-BNP with SAT was attenuated in multivariable models, particularly in men. In contrast to our findings with SAT, we observed a robust inverse association of N-BNP with VAT, even in analyses restricted to non-obese individuals.
In a smaller study of individuals with advanced type II diabetes, visceral fat mass was also observed to be associated with lower N-BNP.15
However, the role of fat depots on natriuretic peptide levels in ambulatory adults has not been investigated previously. The results of our analysis in a large community-based sample suggest that the distribution of adiposity contributes to variation in natriuretic peptide levels, with fat in the visceral compartment being a stronger correlate than subcutaneous fat.
Our findings are consistent with a growing body of evidence linking the natriuretic peptides and insulin resistance. We and others have previously observed an association of the metabolic syndrome with low natriuretic peptide levels.11,16
Interestingly, the association of N-BNP with visceral adiposity in the present study was attenuated by adjustment for HOMA-IR but not by adjustment for metabolic syndrome. These results support the hypothesis that metabolic syndrome, as a clinical entity, does not completely capture the metabolic abnormality associated with elevated HOMA-IR.17,18
It is possible that insulin resistance is more closely related than metabolic syndrome to pathways that promote cardiovascular risk, via mechanisms that have yet to be unidentified. Visceral adiposity is a well-known correlate of hyperinsulinemia, and hyperinsulinemia has been shown in some physiologic studies to suppress natriuretic peptide secretion and activity.19,20
Thus, one model is that visceral adiposity leads to hyperinsulinemia, which suppresses circulating N-BNP. However, other experimental studies have investigated results of acute insulin administration and found either increased21
or no significant change22
in natriuretic peptides. The physiologic effects of acute and chronic hyperinsulinemia on natriuretic peptide secretion and activity remain an important area for future study.
There is accumulating evidence that the natriuretic peptides themselves have effects on glucose and insulin related pathways, including the ability to facilitate glucose transport via cyclic-GMP23,24
and stimulate lipolysis.25
Experimental models suggest that natriuretic peptides increase expression of PGC-1α,26
a transcriptional coactivator that plays a central role in maintaining glucose, lipid, and energy homeostasis.27
In fact, a recent study in mice showed that over-expression of BNP led to upregulation of PGC-1α and less accumulation of abdominal adiposity on a high fat diet;26
this finding appeared more pronounced for visceral than subcutaneous adiposity. In addition, a recent meta-analysis of genetic data indicated that BNP promoter variants associated with higher BNP concentrations were also related to lower risk of type 2 diabetes.28
Together, these data suggest a complex, possibly bi-directional interplay between low natriuretic peptides, visceral adiposity, and insulin resistance.
Several limitations of this study merit consideration. The use of cross-sectional data precludes inference of a causal relation between regional adiposity and low natriuretic peptide levels. Further research is needed to elucidate possible underlying biological mechanisms. The results of our study may not be generalizable to all racial/ethnic groups or age groups, because our sample was primarily white and young to middle-aged. Furthermore, adiposity measures were limited to those who weighed <350 pounds. Since we did not subdivide subcutaneous fat into superficial and deep compartments, we cannot comment on the relative importance of these compartments with respect to variation in N-BNP. HOMA-IR is a surrogate measure of insulin resistance. It is less precise than measures obtained from the hyperinsulinemic euglycemic glucose clamp technique or the insulin suppression test. Nonetheless, it is regarded as a reasonably reliable surrogate in individuals without severely impaired pancreatic beta-cell function and it is practical for epidemiological studies.29
Notwithstanding the above limitations, the present study had several strengths. Our community-based sample was not selected on the basis of adiposity-related traits, cardiovascular disease risk factors, or natriuretic peptide levels. For assessing regional adiposity, we used a highly reproducible volumetric method of measuring SAT and VAT,30
which accounts for the heterogeneity of fat distribution throughout the abdomen. Finally, our large sample size provided adequate power for performing multivariable analyses and comparing strengths of association.