The results of this study confirmed our previous observation in postmenopausal women (7
) that leg fat mass was associated with reduced CVD risk, independent of the increased risk attributable to trunk fat mass. The primary new finding of this study was that the favorable associations of leg fat with CVD risk factors did not persist, with the exception of TG, after adjusting for abdominal visceral adiposity. The relation between trunk fat mass and the risk factors was independent of abdominal sc, but not visceral, fat volume, suggesting that the associations of trunk fat with risk factors were mediated by abdominal visceral adiposity.
There has been debate over which adipose tissue regions confer the greatest increase in morbidity and mortality. Early evidence that upper-body adiposity conferred more risk than overall adiposity or lower-body adiposity came from epidemiological studies that compared waist-to-hip circumference ratio, or simply waist girth, and body mass index (6
). In such studies, waist-to-hip circumference ratio and waist size emerged as superior indices of disease risk compared with body mass index. The development of DXA to measure body composition allowed for a regional separation of body fat into trunk and appendicular (arm and leg) fat, and trunk fat emerged as a better correlate of disease risk compared with appendicular or whole-body adiposity (7
). Furthermore, delineation of central abdominal adiposity by DXA (i.e.
region within the trunk) (24
) and delineation of visceral and sc adiposity by CT or magnetic resonance imaging revealed central abdominal or visceral adiposity as the best correlate of disease risk (13
). Evidence from body composition studies suggests a hierarchy among regional fat depots and their relation to disease risk such that lower-body or appendicular adiposity appears less harmful, and upper-body or abdominal (particularly visceral) adiposity appears more harmful.
There is some evidence that lower-body adiposity is actually protective against disease risk, rather than simply less harmful. Previous studies demonstrated inverse correlations of thigh or hip girth with select CVD risk factors (8
), and reduced risk for ischemic heart disease (10
) and type 2 diabetes mellitus (26
). Appendicular skinfold thicknesses were also found to have an inverse relation with CVD risk (11
). We (7
) and others (13
) previously observed an inverse relation between DXA-measured leg fat mass and select risk factors in women. Because the majority of fat in the legs is stored sc (27
), we postulated that increased leg fat mass was simply indicative of a propensity to store fat sc and away from the abdominal visceral compartment. Further, we thought it was unlikely that sc fat would confer metabolic protection after controlling for the highly detrimental effects of abdominal visceral adiposity. However, we were unable to evaluate this in our previous study because we did not have measurements of abdominal visceral and sc fat (7
Therefore, the primary aim of the current study was to determine whether the favorable independent associations of leg fat with CVD risk factors that we observed after controlling for trunk fat (7
) persisted after adjusting for abdominal visceral or sc adiposity. We confirmed our previous finding of a favorable association of leg fat mass with risk factors, independent of trunk fat mass. However, leg fat mass was not an independent determinant of any of the risk factors after adjustment for abdominal sc adiposity, and was an independent determinant only of TG after adjustment for abdominal visceral adiposity. This suggests that abdominal fat accumulation, in either sc or visceral regions, is a potent determinant of CVD risk and that the storage of fat in non-abdominal regions does not counter these effects, with the possible exception of serum TG.
The inverse association of leg fat with TG that we observed, independent of trunk fat or visceral adiposity, remains intriguing. Although speculative, there is evidence to suggest that gluteal-femoral adipose tissue may be a fat sequestering storage depot. That is, femoral adipocytes, compared with abdominal adipocytes, have increased insulin sensitivity and increased expression of α
-2 adrenergic receptors (28
), which would act to promote storage of TG and inhibit lipolysis (i.e.
reduced turnover favoring fat storage). Furthermore, in vivo
measures of lipolysis (basal free fatty acid release) indicated a lower lipolytic rate in lower-body, compared with upper-body, adipose tissue (31
). If gluteal-femoral adipocytes are less lipolytic and act to sequester TG, this might theoretically contribute to a reduced circulating TG. In contrast, abdominal visceral adipocytes appear to have reduced insulin sensitivity (28
) and increased β
-adrenergic sensitivity (32
), which would potentially attenuate the suppression of lipolysis by insulin and increase the stimulation of lipolysis by catecholamines (i.e.
increased turnover favoring fat mobilization). Moreover, free fatty acid release has been shown to be reduced in lower-body obese women, despite greater upper-body adiposity, when compared with nonobese women (31
), supporting the possibility that gluteal-femoral fat protects against or counters free fatty acid release from upper-body fat regions.
The current study had limitations that should be noted. First, because we did not measure thigh fat by CT, we do not know whether the favorable association of lower-body adiposity with TG is specifically related to sc or im fat depots. Second, correlations do not imply causality. Thus, it is not known whether an independent increase in leg fat would promote a decrease in TG. However, there is evidence in rodents that removal (lipectomy) of sc fat promotes an increase in TG (33
). Third, generalizability of the findings is limited due to the homogeneity of the study cohort. The participants were all healthy postmenopausal women; non-smokers; and not using hormones or lipid-lowering or glucose-lowering medications. It is not known whether the results are applicable to men, to younger adults, or to a less healthy population.
In summary, leg fat mass was favorably associated with serum TG, HDL-cholesterol, and markers of insulin resistance independent of trunk fat mass in healthy postmenopausal women. The lack of an association between leg fat and most of the CVD risk factors, after adjusting for abdominal visceral or sc fat, suggests an overriding deleterious influence of abdominal adiposity on CVD risk. Nevertheless, our finding that regional adipose tissue depots have apparent independent and opposing effects on serum TG supports the need for further research into the physiological mechanisms governing these effects. If leg fat does have a cardioprotective role, selective reduction of fat from this region (i.e. lipectomy) could adversely affect CVD risk.