Citations

To determine whether the sensitivity of adipose tissue lipolysis to catecholamines is increased in poorly controlled insulin-dependent diabetes, the lipolytic response to epinephrine was measured in seven nondiabetic volunteers and seven poorly controlled diabetic subjects with use of [1-(14)C]palmitate as a tracer. Subjects received sequential 1-h infusions of epinephrine, which produced epinephrine concentrations of approximately 1,000, approximately 1,750, approximately 3,500, and approximately 6,000 pmol/l. A pancreatic clamp was used to maintain constant plasma hormone levels. Concentration-response curves were constructed for each subject from the integrated lipolytic response during each epinephrine infusion. There was no difference in maximal lipolytic response (117 +/- 19 vs. 152 +/- 11 mumol.kg-1.h-1) or in maximally effective (3,171 +/- 267 vs. 3,357 +/- 349 pmol/l) or half-maximally effective (1,081 +/- 109 vs. 1,015 +/- 120 pmol/l) epinephrine concentrations between nondiabetic and diabetic subjects, respectively (all P = NS). In control subjects, maximum beta-hydroxybutyrate concentrations were achieved at lower epinephrine concentrations than those required for a maximum lipolytic effect. Thus, under pancreatic clamp conditions, the lipolytic response to epinephrine in nondiabetic and diabetic subjects was similar.

We previously found that epinephrine, a mixed beta- and alpha-adrenoreceptor agonist, stimulates systemic and nonsplanchnic upper body free fatty acid (FFA) release but not lower body FFA release in healthy nonobese women. To evaluate the role of beta-adrenergic-mediated effects on this regional difference in lipolysis, we measured systemic, leg, and splanchnic FFA kinetics ([3H]palmitate) in seven healthy nonobese women before and during an intravenous isoproterenol infusion. Isoproterenol increased systemic palmitate flux (87 +/- 12 vs. 100 +/- 10 mumol/min, P < 0.05) but failed to affect leg [10.8 +/- 1.2 vs. 11.4 +/- 2.3 mumol/min, P = not significant (NS)] or splanchnic (10.8 +/- 3.2 vs. 10.0 +/- 1.8 mumol/min, P = NS) palmitate release. Upper body nonsplanchnic palmitate release increased from 56 +/- 14 to 71 +/- 10 mumol/min. Systemic O2 consumption increased (227 +/- 11 to 241 +/- 10 ml/min, P = 0.006) during isoproterenol infusion, as did leg (318 +/- 42 vs. 404 +/- 53 ml/min, P < 0.01) and splanchnic (827 +/- 104 vs. 970 +/- 108 ml/min, P < 0.05) plasma flow. These results suggest that lower body adipose tissue lipolysis in women is less sensitive or responsive than nonsplanchnic upper body adipose tissue to beta-adrenergic stimulation and that regional differences in alpha 2-adrenergic-receptor responses were not responsible for the similar regional differences we observed previously with epinephrine.

These studies were conducted to determine whether there are gender-specific regional differences in meal triglyceride fatty acid uptake. Systemic and regional oleate ([3H]oleate) kinetics were measured in nine nonobese men and eight nonobese women before and at the end of a 6-h meal, administered as small frequent feedings to achieve steady-state chylomicronemia. Chylomicron uptake in the splanchnic bed accounted for 71 +/- 15% of meal triglyceride disappearance in men and 20 +/- 7% in women (P < 0.01), whereas leg chylomicron uptake could only account for 12 +/- 2 and 8 +/- 4% (P not significant in men vs. women) of meal triglyceride disappearance. Meal ingestion suppressed (P < 0.05) systemic and regional free fatty acid release in both men and women. Splanchnic nonchylomicron triglyceride release and leg nonchylomicron triglyceride uptake were not significantly different in men and women. In summary, the largest quantitative difference between men and women in fatty acid kinetics during meal ingestion is a substantially greater splanchnic uptake of meal triglyceride fatty acids in men. This could represent greater meal fatty acid storage in visceral adipose tissue.

Upper-body and lower-body adipocytes respond differently to physiological catecholamines in vitro. It is not known whether this is true in vivo or whether gender differences exist in the regional adipose tissue responses to epinephrine. These studies were therefore conducted to examine free fatty acid (FFA) release ([3H]palmitate) from lower-body (leg), splanchnic, and upper-body adipose tissue in normal-weight adult men (n = 8) and women (n = 7). In response to intravenous epinephrine (10 ng.kg-1.min-1), palmitate release increased (P < 0.01) in both men (168 +/- 10 to 221 +/- 15 mumol/min) and women (177 +/- 12 to 234 +/- 18 mumol/min). Basal leg palmitate release was similar in women and men (16.8 +/- 2.9 and 12.4 +/- 1.3 mumol/min, P = not significant) but doubled (P < 0.01) in response to epinephrine in men and was virtually unchanged in women. Splanchnic palmitate release increased (P < 0.05) in men (n = 6) but not in women (n = 6), whereas nonsplanchnic upper-body palmitate release increased more in women than in men. Upper-body (splanchnic and nonsplanchnic) palmitate release increased (P < 0.05) in both men and women in response to epinephrine. In summary, lower-body adipose tissue FFA release increased in response to epinephrine in men but not women, whereas upper-body palmitate release increased in both groups. These findings are consistent with some in vitro findings and suggest that catecholamine action may play a role in determining gender-based differences in body fat distribution.

We tested for gender differences in dietary fatty acid metabolism in 12 nonobese men and 12 nonobese women using the meal fatty acid tracer/adipose tissue biopsy study design. In addition to determining body composition, measurements of regional adipose tissue lipoprotein lipase activity, blood flow, and fat cell size were performed to place the meal fatty acid kinetic studies in perspective. Twenty-four hours after ingesting the test meal, the concentration of meal fatty acids was greater ( P < 0.05) in abdominal subcutaneous than in thigh adipose tissue in both men (0.61 ± 0.12 vs. 0.45 ± 0.09 mg/g) and women (0.59 ± 0.10 vs. 0.43 ± 0.05) but was not different between men and women. A greater percentage of dietary fat was stored in subcutaneous adipose tissue in women than in men (38 ± 3 vs. 24 ± 3%, respectively, P < 0.05), and a greater portion of meal fatty acid disposal was unaccounted for in men. Significant gender differences in regional adipose tissue blood flow after meal ingestion were noted; the differences were in the direction that could support greater nutrient storage in lower body fat in women.

The adipose tissue uptake of dietary fat has been studied using fatty acid radiotracers incorporated into a meal, followed by adipose tissue biopsies. A number of experimental design issues, including the use of isotopic tracers to measure meal fatty acid oxidation and plasma appearance of tracer, as well as the heterogeneity of adipose tissue fatty acid uptake, have been addressed. We examined these questions in a study of 24 volunteers (12 men and 12 women) who consumed a meal containing [3H]triolein and [14C]triolein. Slight differences in the purity of [3H]triolein vs. [14C]triolein were found, which could affect the apparent adipose tissue uptake of meal fatty acids. The adipose tissue triglyceride specific activity from bilateral biopsy sites agreed well, implying that a unilateral biopsy is satisfactory for measuring tracer uptake. Meal fatty acid oxidation measured using [3H]triolein and [14C]triolein was well correlated ( r = 0.79, P < 0.0001). The peak tracer appearance in plasma chylomicrons occurred 1 h after the ingestion of a second, unlabeled meal. Our findings have implications for the experimental design of future meal fatty acid tracer/adipose tissue biopsy studies.

We previously reported that epinephrine stimulates leg free fatty acid (FFA) release in men but not in women. The present studies were conducted to determine whether the same is true during exercise. Six men and six women bicycled for 90 min at 45% of peak O2 consumption, during which time systemic and leg FFA kinetics ([9,10-3H]palmitate) were measured. The catecholamine and hormonal responses to exercise were not different in men and women. The baseline systemic and leg palmitate release was 94 ± 15 vs. 114 ± 5 μmol/min and 16 ± 2 and 20 ± 3 μmol/min, respectively, in men and women [ P = nonsignificant (NS)]. Systemic and leg palmitate release increased (both P < 0.001) to 251 ± 18 vs. 212 ± 16 μmol/min and 73 ± 19 vs. 80 ± 12 μmol/min in men and women, respectively, during the last 30 min of exercise ( P = NS, men vs. women). We conclude that the systemic and leg adipose tissue lipolytic response to exercise is not different in nonobese men and women.

We measured splanchnic and leg glycerol [and free fatty acid (FFA)] uptake and release in 11 healthy volunteers before and after meal ingestion to assess whether regional FFA-to-glycerol release ratios mirror systemic release ratios. Basal splanchnic triglyceride release was also assessed. Although basal splanchnic glycerol uptake (111 ± 18 μmol/min) accounted for most of systemic glycerol rate of appearance (156 ± 20 μmol/min), leg glycerol uptake was also noted. The basal, systemic FFA-to-glycerol release ratio was less (2.6 ± 0.2, P < 0.05) than the splanchnic ratio of 6.1 ± 1.3, and the leg FFA-to-glycerol release ratio under fed conditions was less than the systemic ratio (0.9 ± 0.1 vs. 1.6 ± 0.2, respectively, P< 0.05). Basal splanchnic triglyceride production rates were 74 ± 20 μmol/min, which could produce equimolar amounts of glycerol in the peripheral circulation via lipoprotein lipase action. In summary, 1) regional FFA-to-glycerol release ratios do not mirror systemic ratios, 2) leg glycerol uptake occurs in humans, and 3) splanchnic triglyceride production rates are substantial relative to systemic glycerol appearance. Glycerol appearance rates may not be a quantitative index of whole body lipolysis.

Controversy exists regarding whether plasma glucose concentrations are independently involved in the regulation of adipose tissue lipolysis. In the present study, six subjects with insulin-dependent diabetes and six nondiabetic volunteers were studied during infusion of somatostatin, growth hormone, and insulin at rates designed to maintain basal rates of lipolysis, which was traced using a constant infusion of [1-14C]palmitate. A euglycemic (approximately 5 mmol/l) clamp was performed for 3 h, followed by 3 h of hyperglycemia (approximately 9 and approximately 11 mmol/l in nondiabetic and diabetic subjects, respectively). Ten nondiabetic subjects were studied during 6 h of euglycemia to exclude time-dependent changes in lipolysis. The results showed that palmitate concentrations did not change between euglycemia and hyperglycemia in either group [118 +/- 10 vs. 132 +/- 14 mumol/l and 145 +/- 21 vs. 134 +/- 15 mumol/l in nondiabetic and diabetic subjects, respectively; both P = not significant (NS)]. Similarly, palmitate rate of appearance (Ra) did not change during hyperglycemia (1.0 +/- 0.1 and 1.7 +/- 0.4 mumol.kg-1.min-1 in nondiabetic and diabetic subjects, respectively) compared with euglycemia (1.0 +/- 0.1 and 1.6 +/- 0.4 mumol.kg-1.min-1 in nondiabetic and diabetic subjects, respectively; P = NS). Palmitate concentrations and Ra did not change during 6 h of euglycemia in nondiabetic volunteers. Thus hyperglycemia per se has no effect on free fatty acid turnover. Changes in lipolysis that occur coincident with hyperglycemia are probably due to changes in other circulating substrates or hormones known to affect lipolysis.

The accuracy of non-steady-state equations for measuring changes in free fatty acid rate of appearance (Ra) is unknown. In the present study, endogenous lipolysis (traced with [14C]-linoleate) was pharmacologically suppressed in six conscious mongrel dogs. A computer-responsive infusion pump was then used to deliver an intravenous oleic acid emulsion in both constant and linear gradient infusion modes. Both non-steady-state equations with various effective volumes of distribution (V) and steady-state equations were used to measure oleate Ra [( 14C]oleate). Endogenous lipolysis did not change during the experiment. When oleate Ra increased in a linear gradient fashion, only non-steady-state equations with a large (150 ml/kg) V resulted in erroneous values (9% overestimate, P less than 0.05). In contrast, when oleate Ra decreased in a similar fashion, steady-state and standard non-steady-state equations (V = plasma volume = 50 ml/kg) overestimated total oleate Ra (18 and 7%, P less than 0.001 and P less than 0.05, respectively). Overall, non-steady-state equations with an effective V of 90 ml/kg (1.8 x plasma volume) allowed the most accurate estimates of oleate Ra.