These studies were conducted to address two previously unsettled issues with respect to the relationship between adipose tissue fuel release and lean tissue fuel use. Our first concern was that the traditional means of comparing resting FFA release rates between groups — dividing by FFM — is inappropriate and misleading. The second major concern was the lack of information as to whether men and women could be compared using the same approach. In addition, by more accurately determining the average basal FFA release rate for each individual, we were able to examine additional factors that might relate to basal FFA release. Consistent with our hypothesis, REE was found to be a better predictor of basal palmitate release than FFM. Our inability to detect an association with FFM after adjusting for other variables could be because any independent relationship between FFA release and FFM was too slight to detect, rather than because there is no relationship at all. Our second concern, that comparing men and women directly could lead to problems in identifying “abnormal” FFA release, was also confirmed. The greater relative FFA release rates in women despite similar plasma concentrations can only be explained by greater clearance rates. Thus, understanding adipose tissue lipolysis will require that energy expenditure and sex, as well as body composition, be taken into account.
Despite the sex differences in FFA release and uptake there was no difference between men and women in FFA concentrations or in the proportion of energy expenditure accounted for by fatty acid oxidation. This is possible because not all FFAs removed from the circulation are immediately oxidized — significant proportions are re-esterified as tissue triglyceride (29
). It follows that at rest women shunt more circulating FFA into re-esterification pathways than do men. Recent studies (30
) have shown that lean women have almost double the VLDL-triglyceride production rates as lean men, despite comparable the VLDL-triglyceride concentrations. Thus, greater hepatic clearance, re-esterification, and export of the “excess” FFA back to adipose tissue could explain our findings.
This basic, physiological difference in FFA metabolism between men and women could be advantageous at times of increased energy requirements, such as exercise or stress. For example, adipose tissue lipolysis increases somewhat gradually in response to exercise, whereas energy expenditure and fat oxidation increase almost immediately (10
). Women should, therefore, be able to increase the proportion of FFA directed toward oxidation (with a concomitant reduction in FFA re-esterification) and better match circulating lipid fuel availability to lipid fuel needs as energy expenditure increases. The combination of greater availability and greater clearance may explain the ability of women to oxidize relatively more fat than do men during exercise (32
). This greater resting lipid fuel release rate is accomplished without exposing tissues to higher and potentially harmful FFA concentrations.
Excess accumulation of central fat is associated with adverse health consequences (33
), which have been linked to higher FFA concentrations (1
). In this study, indices of body fatness did not contribute significantly to FFA release rates after REE, sex, and epinephrine were considered. The number of individuals with upper-body obesity was small, however, compared with our previous studies (13
). As a way to assess whether the results of the present study were in conflict with previous studies we examined whether visceral fat area was associated with greater palmitate release rates after interindividual differences in REE were taken into account. There was an association with visceral adiposity in men, but we did not detect such an effect in women. We reported previously that FFA flux is increased in upper-body obesity when larger numbers of lean and obese women (matched for FFM and REE) were evaluated (13
). Therefore, we do not believe that the current data should be taken to indicate that centrally obese adults have the same rates of lipolysis as do lean adults. The narrower range of visceral fat area in women compared with men in the present study (Table ) may have limited our ability to detect an effect of visceral fat on FFA kinetics.
One cannot infer causal mechanisms from statistical analysis alone: that interindividual variances in REE drive FFA release rates. It might be argued that differences in FFA release rates determine REE. A number of observations lead us to doubt that FFA modulates REE, however. For example, experimental increases in plasma FFA do not raise REE (34
). In addition, REE is not reduced by suppression of FFA release and fatty acid oxidation using acipimox (35
) or insulin (36
), or by pharmacological blockade of fatty acid oxidation (37
). We conclude differences in REE seem to be the major, underlying factor influencing the rate at which adipose tissue releases its fuel into the circulation in resting humans. Of note, the intercept of the relationship between REE and FFA release rates was not zero. This indicates that dividing FFA release rates by a measure of energy expenditure is inappropriate. Regression analysis will be needed to compare groups with different mean REE values.
It is not known how REE influences adipose tissue fuel export function in the basal state and why this relationship is different in men and women. However, interpreting the present data within the framework of previously published studies, we would like to suggest a new concept in the regulation of adipose tissue lipolysis. Plasma FFA concentrations may themselves serve as a signal for the secretion of hormones that modulate lipolytic activity. Insulin, catecholamines, and growth hormone exert rapid effects on adipose tissue lipolysis and are the major regulators of systemic FFA release. High-plasma FFA concentrations enhance glucose-stimulated insulin secretion (38
), which can then feed back to inhibit lipolysis. High FFA also suppresses growth hormone secretion (39
), which in turn can reduce lipolysis. There is also evidence that FFAs may themselves directly inhibit adipose tissue FFA release (40
). In contrast, lowering plasma FFA concentrations decreases glucose-mediated insulin secretion (41
) and can increase plasma growth hormone concentrations (42
). Therefore, changes in plasma FFA concentrations influence the secretion of lipolytic and antilipolytic hormones in a counterregulatory fashion. The data from the present study suggest to us that energy expenditure (requirement) is an indicator of the need for FFA as an oxidative fuel. In general, even when individuals are in energy balance, greater energy requirements require greater plasma FFA uptake and oxidation, thereby lowering plasma FFA concentrations and setting in motion counterregulatory responses that maintain plasma FFA. Likewise, lesser energy requirements and fatty acid oxidation would require lesser FFA uptake and thus reduced lipolysis to maintain “normal” plasma FFA concentrations. This feedback loop provides a mechanism that allows energy demand to regulate the release of FFA, an oxidative fuel, into the circulation. The higher basal rate of lipolysis we observed in women can be explained by a higher rate of nonoxidative FFA clearance in women than in men.
In summary, these results have important implications for understanding endogenous fuel mobilization and how it may affect human health. We found that (a) FFA release rates are highly correlated with REE; (b) women have higher rates of FFA release in relationship to energy requirements than do men; (c) plasma FFA concentrations are not different in women and men, indicating greater nonoxidative FFA clearance in women; and (d) increased basal catecholamine concentrations are associated with greater resting FFA release rates. These findings suggest that new approaches will be required to assess how variations in lipolytic activity might impact on obesity-related disease. The study of adipose tissue lipolytic rates should account for REE and sex if the goal is to identify abnormalities in the regulation of adipose tissue lipolysis. The greater relative FFA availability in women compared with men at comparable FFA concentrations could be a distinct metabolic advantage at times of increasing needs for lipid fuel, such as during exercise, stress, or starvation.