It has been hypothesized that many of the metabolic abnormalities associated with obesity are caused by excessive FFA release from adipose tissue into plasma. However, the relationship between body fat and FFA metabolism has been confusing because of conflicting data from different studies and potential sex-related differences in FFA metabolism. By studying more than 100 non-diabetic men and women, the results from the present study have clarified several issues regarding the influence of adiposity and sex on FFA kinetics. First, our data demonstrate that sexual dimorphism in FFA kinetics is primarily due to differences in body composition between men and women. We found that the rate of FFA release into plasma per unit of FM is the same in men and women, but total FFA Ra in relationship to FFM is greater in women than men, because women have more body fat than men. Second, total FFA Ra and FFA Ra expressed per unit of FFM increase with increasing adiposity whereas FFA release per unit of FM decreases in a curvilinear fashion with increasing body fat. Therefore, obesity is associated with a decrease in the rate of FFA release from adipose tissue. However, this downregulation in the rate of FFA release per unit of body fat does not completely compensate for the increase in total body fat, so total FFA Ra and FFA availability in relation to FFM are increased. Third, abdominal fat distribution does not have an important independent influence on FFA kinetics. These data underscore the importance of total body fat mass in regulating the basal FFA flux.
Total body adiposity was an important predictor of the rate of FFA release into plasma, independent of sex and body fat distribution. The progressive increase in FFA Ra with increasing FM helps explain the reason for the conflicting results from previous studies, which reported that the rate of FFA release into plasma, expressed per unit of FFM, is increased (11
) or the same (5
) in obese compared with lean subjects. The apparent discrepancy between these studies could be due to differences in the relationship between body FM and FFM and the inherent variability in FFA kinetics at any given amount of body FM. In addition, our data suggest the reason for sexual dimorphism in FFA kinetics, i.e., greater basal FFA Ra relative to either FFM (33
) or resting energy expenditure (34
) in women than in men, is because women generally have more body fat and less FFM than men (18
). In a previous study, Nielson et al. (34
) found there was a linear relationship between FFA release and resting energy expenditure (REE), and that REE predicted most of the inter-individual variation in the rate of FFA release. We also observed a direct liner relationship between FFM, which is closely related to REE (34
); however, the relationship between FM and FFA Ra was stronger and FM was a better predictor of FFA Ra in our study.
Our data contradict the current dogma that adipose tissue lipolytic activity, and the rate of FFA release into the circulation, are abnormal in obesity (35
). This notion is based, in large part, on data from studies that found FFA Ra expressed per unit of FFM was increased in obese subjects (11
). However, the use of ratios to determine whether FFA Ra is “normal” can be misleading when used to compare groups of subjects who have marked differences in body composition, because the relationship between FFA kinetics and all components of body composition have y and x intercepts that are significantly different from zero (e.g. , top panel). Therefore, FFA kinetics normalized by body composition (e.g., FFA Ra per kg FM or FFA Ra per kg FFM) will be different between groups who differ in body composition because of mathematical bias rather than true differences in FFA metabolism (41
). The most appropriate approach for evaluating whether FFA kinetics are “abnormal” in obesity is by using regression curves among subjects who have a large range in percent body fat mass. The data from the present study demonstrate that basal FFA Ra correlated closely with body FM in lean, overweight and obese subjects, and data from obese subjects followed the same regression curve as data from overweight and lean subjects. Therefore, FFA Ra is “normal” (i.e., as expected) in overweight and obese men and women, even though FFA Ra in relationship to FM decreases and FFA Ra in relationship to FFM increases with increasing amounts of body fat.
The rate of FFA release into plasma per unit of FM progressively decreased with increasing FM. This downregulation has beneficial effects because it helps prevent excessive FFA release into plasma, which could have adverse metabolic consequences (1
). However, the decrease in FFA release is not able to completely compensate for the increase in total FM, so total FFA Ra increased with increasing amounts of body fat. The increase in FFA delivery to the liver and skeletal muscle can contribute to insulin resistance in these organs because excessive FFA uptake impairs insulin mediated suppression of glucose production by the liver (1
) and insulin-mediated glucose uptake by skeletal muscle (1
The relative suppression of FFA Ra with increasing adiposity seems surprising, because insulin is the major regulator of basal adipose tissue lipolytic rates and FFA Ra (42
) and obesity is associated with adipose tissue insulin resistance (13
). Therefore, other regulatory mechanisms must exist that inhibit FFA release from adipose tissue TG, which more than offset the increase in lipolysis induced by insulin resistance. It is unlikely that the differences in FFA Ra we observed between our lean and obese subjects were due to differences in intracellular adipocyte fatty acid re-esterification which would prevent FFA release into plasma, because data from arteriovenous balance studies across adipose tissue in human subjects found re-esterification does not occur during basal, postabsorptive conditions (46
). The data obtained in vivo
from the present study are consistent with data obtained from ex vivo
studies conducted in adipocytes prepared from adipose tissue biopsies obtained from lean and obese subjects. Although lipolytic rate per cell was greater in large adipocytes from obese subjects than in small adipocytes from lean subjects, lipolytic rate in relationship to cell volume (i.e., total TG content) was lower in large than small adipocytes (47
Abdominal (upper body) obesity is associated with a greater risk of metabolic diseases than femoral/gluteal (lower body) obesity (49
). It has been hypothesized that the relationship observed between visceral fat and peripheral insulin resistance is due to increased rates of FFA release into plasma (50
). However, in our subjects, intra-abdominal fat mass itself was not an important determinant of FFA flux. Although multivariate regression analysis identified intra-abdominal fat mass as the best predictor of both total FFA Ra and FFA Ra per kg FFM in women, this was most likely a reflection of the inherent instability in multivariate analyses when there are correlated predictors, such as intra-abdominal fat and total body fat mass. Nielson and colleagues (51
) found the contribution of FFA derived from lipolysis of visceral adipose tissue to systemic FFA flux was only ~6% in lean and ~14% in obese subjects. Therefore, increased visceral fat mass, itself, is not an important contributor to whole-body FFA flux, and FFA release from visceral fat is unlikely to be responsible for insulin resistance in skeletal muscle.
The results from the present study provide a comprehensive evaluation of the relationship between body composition and FFA kinetics in human subjects. Our data demonstrate that total body fat mass is an important determinant of the rate of FFA release into plasma in both men and women during basal conditions. In addition, the rate of FFA release from adipose tissue decreases with increasing body FM. However, the downregulation of FFA release is unable to completely compensate for the increase in FM, so total FFA Ra is greater in women than in men and in obese than in lean subjects. These findings provide additional insights into the mechanisms responsible for metabolic complications associated with obesity, and provide a framework for interpreting data from other studies evaluating the pathophysiology of FFA kinetics in human subjects.