Greater systemic lipolysis in women compared with men during moderate-dose infusion of epinephrine and/or norepinephrine.

Women have lower circulating catecholamine levels during metabolic perturbations, such as exercise or hypoglycemia, but similar rates of systemic lipolysis. This suggests women may be more sensitive to the lipolytic action of catecholamines, while maintaining similar glucoregulatory effects. The aim of the present study, therefore, was to determine whether women have higher rates of systemic lipolysis compared with men in response to matched peripheral infusion of catecholamines, but similar rates of glucose turnover. Healthy, nonobese women (n = 11) and men (n = 10) were recruited and studied on 3 separate days with the following infusions: epinephrine (Epi), norepinephrine (NE), or the two combined. Tracer infusions of glycerol and glucose were used to determine systemic lipolysis and glucose turnover, respectively. Following basal measurements of substrate kinetics, the catecholamine infusion commenced, and measures of substrate kinetics continued for 60 min. Catecholamine concentrations were similarly elevated in women and men during each infusion: Epi, 182-197 pg/ml and NE, 417-507 pg/ml. There was a significant sex difference in glycerol rate of appearance and rate of disappearance with the catecholamine infusions (P < 0.0001), mainly due to a significantly greater glycerol turnover during the first 30 min of each infusion: glycerol rate of appearance during Epi was only 268 +/- 18 vs. 206 +/- 21 micromol/min in women and men, respectively; during NE, only 173 +/- 13 vs. 153 +/- 17 micromol/min, and during Epi+NE, 303 +/- 24 vs. 257 +/- 21 micromol/min. No sex differences were observed in glucose kinetics under any condition. In conclusion, these data suggest that women are more sensitive to the lipolytic action of catecholamines, but have no difference in their glucoregulatory response. Thus the lower catcholamine levels observed in women vs. men during exercise and other metabolic perturbations may allow women to maintain a similar or greater level of lipid mobilization while minimizing changes in glucose turnover.

Effects of short-term sex steroid suppression on dietary fat storage patterns in healthy males.

Hypogonadism in males is associated with increased body fat and altered postprandial metabolism, but mechanisms remain poorly understood. Using a cross-over study design, we investigated the effects of short-term sex hormone suppression with or without testosterone add-back on postprandial metabolism and the fate of dietary fat. Eleven healthy males (age: 29 ± 4.5 year; BMI: 26.3 ± 2.1 kg/m2 ) completed two 7-day study phases during which hormone levels were altered pharmacologically to produce a low sex hormone condition (gonadotropin releasing hormone antagonist, aromatase inhibitor, and placebo gel) or a testosterone add-back condition (testosterone gel). Following 7 days of therapy, subjects were administered an inpatient test meal containing 50 µCi of [1-14 C] oleic acid. Plasma samples were collected hourly for 5 h to assess postprandial responses. Energy metabolism (indirect calorimetry) and dietary fat oxidation (14 CO2 in breath) were assessed at 1, 3, 5, 13.5, and 24 h following the test meal. Abdominal and femoral adipose biopsies were taken 24 h after the test meal to determine uptake of the labeled lipid. Postprandial glucose, insulin, free-fatty acid, and triglyceride responses were not different between conditions (P > 0.05). Whole-body energy metabolism was also not different between conditions at any time point (P > 0.05). Dietary fat oxidation trended lower (P = 0.12) and the relative uptake of 14 C labeled lipid into femoral adipose tissue was greater (P = 0.03) in the low hormone condition. Short-term hormone suppression did not affect energy expenditure or postprandial metabolism, but contributed to greater relative storage of dietary fat in the femoral depot. ClinicalTrials.gov Identifier: NCT03289559.

Short-term overfeeding increases resting energy expenditure in patients with HIV lipodystrophy.

BACKGROUND: HIV lipodystrophy and other lipodystrophy syndromes are characterized by extensive loss of subcutaneous adipose tissue. Lipodystrophy syndromes are also associated with increased resting energy expenditure (REE). This hypermetabolism may be an adaptive response to an inability to store triacylglycerol fuel in a normal manner. OBJECTIVE: This study was done to determine whether REE increases significantly after short-term overfeeding in patients with HIV lipodystrophy. DESIGN: REE was measured in HIV-infected patients with lipodystrophy (n = 9) and in HIV-infected (n = 10) and healthy (n = 9) controls after 3 d on a eucaloric diet and again after 3 d on a diet of similar composition but increased in calories by 50%. RESULTS: After 3 d of eucaloric feeding, REE was significantly higher in patients with HIV lipodystrophy [33.2 +/- 0.27 kcal/kg lean body mass (LBM)] than for both HIV-infected and healthy controls (29.9 +/- 0.26 and 29.6 +/- 0.27 kcal/kg LBM, respectively; P < 0.01). Furthermore, after 3 d of overfeeding, REE increased significantly in patients with HIV lipodystrophy but not in the control groups (33.2 +/- 0.27 vs 34.7 +/- 0.27 kcal/kg LBM; P < 0.01). Finally, postprandial thermogenesis did not differ among the groups after a "normal" test meal but tended to be higher in patients with HIV lipodystrophy than in healthy controls after a large test meal. CONCLUSIONS: Adaptive thermogenesis in the resting component of total daily energy expenditure and in the postprandial period may be a feature of the HIV lipodystrophy syndrome and may be due to an inability to store triacylglycerol fuel in a normal manner.

Short-term energy restriction reduces resting energy expenditure in patients with HIV lipodystrophy and hypermetabolism.

We have previously shown that resting energy expenditure (REE) is increased in patients with HIV lipodystrophy. This hypermetabolism could be the result of an inadequate storage capacity for lipid fuel secondary to atrophy of the subcutaneous adipose tissue depot. Therefore, energy restriction may be able to alleviate this hypermetabolism. To test this hypothesis, we measured REE in HIV-infected patients with lipodystrophy and hypermetabolism and in HIV-infected and healthy controls. Measurements were taken during the overnight fasted state after 3 days on a eu-energetic diet and again after 3 days on a diet of similar composition but reduced in energy by 50%. After 3 days of eu-energetic feeding, REE was significantly higher in HIV-infected patients with lipodystrophy compared with healthy controls (139.5 +/- 1.3 vs 117.2 +/- 1.3 kJ/kg lean body mass, P < .001) and tended to be higher compared with HIV-infected subjects without lipodystrophy (139.5 +/- 13 vs 127.3 +/- 1.4 kJ/kg lean body mass, P = .06). Furthermore, energy restriction caused a significant decline in REE in patients with HIV lipodystrophy (P < .001). This dietary manipulation did not lead to a significant reduction in REE in either HIV-infected or healthy controls. This suggests that energy intake and REE may be uniquely coupled in patients with lipodystrophy as a means to dissipate energy that cannot be stored in a normal manner. A better understanding of this coupling would have important implications for weight regulation in general.

No effect of menstrual cycle phase on glycerol or palmitate kinetics during 90 min of moderate exercise.

The systemic flux of glycerol and palmitate [a representative nonesterified free fatty acid (NEFA)] was assessed in three different phases of the menstrual cycle at rest and during moderate-intensity exercise. It was hypothesized that circulating glycerol and NEFA turnover would be greatest in the midfollicular (MF) phase of the menstrual cycle, when estrogen is elevated but progesterone low, followed by the midluteal phase (ML; high estrogen and progesterone), and lowest in the early follicular (EF) phase of the menstrual cycle (low estrogen and progesterone). Subjects included moderately active, eumenorrheic, healthy women. Testing occurred after 3 days of diet control and after an overnight fast (12-13 h). Resting and exercise (50% maximal oxygen uptake, 90 min) measurements of tracer-determined glycerol and palmitate kinetics were made. There was a significant increase in both glycerol and palmitate turnover from rest to exercise in all phases of the menstrual cycle (P<0.0001). No significant differences, however, were observed between cycle phases in the systemic flux of glycerol or palmitate, at rest or during exercise. Maximal peripheral lipolysis during exercise, as represented by glycerol rate of appearance at 90 min, equaled 8.45+/-0.96, 8.35+/-1.12, and 7.71+/-0.96 micromol.kg-1.min-1 in the EF, MF, and ML phases, respectively. Circulating free fatty acid utilization also peaked at 90 min of exercise, as indicated by the palmitate rate of disappearance (3.31+/-0.35, 3.17+/-0.39, and 3.47+/-0.26 micromol.kg-1.min-1) in the EF, MF, and ML phases, respectively. In conclusion, systemic rates of glycerol and NEFA turnover (as represented by palmitate flux) were not significantly affected by the cyclic fluctuations in estrogen and progesterone that occur throughout the normal menstrual cycle, either at rest or during 90 min of moderate exercise.

Glucose kinetics differ between women and men, during and after exercise.

As exercise can improve the regulation of glucose and carbohydrate metabolism, it is important to establish biological factors, such as sex, that may influence these outcomes. Glucose kinetics, therefore, were compared between women and men at rest, during exercise, and postexercise. It was hypothesized that glucose flux would be significantly lower in women than men during both the exercise and postexercise periods. Subjects included normal weight, healthy, eumenorrehic women and men, matched for habitual activity level and maximal oxygen uptake per kilogram lean body mass. Testing occurred following 3 days of diet control, with no exercise the day before. Subjects were tested in the overnight-fasted condition with women studied in the midluteal phase of the menstrual cycle. Resting (120 min), exercise (85% lactate threshold, 90 min), and postexercise (180 min) measurements of glucose flux and substrate metabolism were made. During exercise, women had a significantly lower rate of glucose appearance (Ra) (P<0.001) and disappearance (Rd) (P<0.002) compared with men. Maximal values were achieved at 90 min of exercise for both glucose Ra (mean+/-SE: 22.8+/-1.12 micromol.kg body wt-1.min-1 women and 33.6+/-1.79 micromol.kg body wt-1.min-1 men) and glucose Rd (23.2+/-1.26 and 34.1+/-1.71 micromol.kg body wt-1.min-1, respectively). Exercise epinephrine concentration was significantly lower in women compared with men (P<0.02), as was the increment in glucagon from rest to exercise (P<0.04). During the postexercise period, glucose Ra and Rd were also significantly lower in women vs. men (P<0.001), with differences diminishing over time. In conclusion, circulating blood glucose flux was significantly lower during 90 min of moderate exercise, and immediately postexercise, in women compared with men. Sex differences in the glucagon increase to exercise, and/or the epinephrine levels during exercise, may play a role in determining these sex differences in exercise glucose turnover.

Gender differences in insulin action after a single bout of exercise.

Effects of a single exercise bout on insulin action were compared in men (n = 10) and women (n = 10). On an exercise day, subjects cycled for 90 min at 85% lactate threshold, whereas on a rest (control) day, they remained semirecumbent. The period of exercise, or rest, was followed by a 3-h hyperinsulinemic-euglycemic clamp (30 mU.m(-2).min(-1)) and indirect calorimetry. Glucose kinetics were measured isotopically by using an infusion of [6,6-2H2]glucose. Glucose infusion rate (GIR) during the clamp on the rest day was not different between the genders. However, GIR on the exercise day was significantly lower in men compared with women (P = 0.01). This was mainly due to a significantly lower glucose rate of disappearance in men compared with women (P = 0.05), whereas no differences were observed in the endogenous glucose rate of appearance. Nonprotein respiratory quotient (NPRQ) increased significantly during the clamp from preclamp measurements in men and women on the rest day (P < 0.01). Exercise abolished the increase in NPRQ seen during the clamp on the rest day and tended to decrease NPRQ in men. Our results indicate the following: 1) exercise abolishes the usual increase in NPRQ observed during a hyperinsulinemic-euglycemic clamp in both genders, 2) men exhibit relatively lower whole body insulin action in the 3-4 h after exercise compared with women, and 3) gender differences in insulin action may be explained by a lower glucose rate of disappearance in the men after acute exercise. Together, these data imply gender differences in insulin action postexercise exist in peripheral tissues and not in liver.

No effect of menstrual cycle phase on lactate threshold.

No previous exercise studies in women have assessed the effects of the normal menstrual cycle on the lactate threshold (LT) measured during a graded, maximal exercise test. This is relevant to our understanding of exercise training and metabolism in eumenorrheic women. The present study, therefore, examined the effect of menstrual cycle phase on the LT. Eight moderately active, eumenorrheic women performed three maximal exercise tests with simultaneous determination of LT. Tests were performed in the early follicular (low estrogen and progesterone), midfollicular (elevated estrogen and low progesterone), and midluteal (elevated estrogen and progesterone) phases of the menstrual cycle. No significant differences were observed in LT measured across phases of the menstrual cycle whether data were expressed in absolute terms (1299 +/- 70, 1364 +/- 80, and 1382 +/- 71 ml O(2)/min, respectively) or relative to maximal oxygen uptake (V(o2 max); 52.1 +/- 1.7, 54.7 +/- 1.7, and 55.7 +/- 1.6%, respectively). In addition, there were no significant cycle phase differences in V(o2 max), maximal heart rate, heart rate at LT, or final lactate concentration. With data combined across all phases of the menstrual cycle, there was a significant correlation between the LT and the epinephrine breakpoint (r = 0.91, P < 0.0002) and norepinephrine breakpoint (r = 0.94, P < 0.0001). For epinephrine only, there was close correspondence between the epinephrine breakpoint (ml O(2)/min) and the LT. In conclusion, LT as well as V(o2 max) and other measures of cardiorespiratory fitness are not significantly affected by the changing sex steroid levels observed across the normal menstrual cycle. Data suggest that the onset of the steep increase in epinephrine determines the LT during graded exercise.

Effect of exercise intensity on 24-h energy expenditure and nutrient oxidation.

The aim of this study was to determine the effects of exercise at different intensities on 24-h energy expenditure (EE) and substrate oxidation. Sixteen adults (8 men and 8 women) were studied on three occasions [sedentary day (Con), a low-intensity exercise day (LI; 400 kcal at 40% of maximal oxygen consumption) and a high-intensity exercise day (HI; 400 kcal at 70% of maximal oxygen consumption)] by using whole room indirect calorimetry. Both 24-h EE and carbohydrate oxidation were significantly elevated on the exercise days (Con < LI = HI), but 24-h fat oxidation was not different across conditions. Muscle enzymatic profile was not consistently related to 24-h fat or carbohydrate oxidation. With further analysis, it was found that, compared with men, women sustained slightly higher rates of 24-h fat oxidation (mg x kg FFM(-1) x min(-1)) and had a muscle enzymatic profile favoring fat oxidation. It is concluded that exercise intensity has no effect on 24-h EE or nutrient oxidation. Additionally, it appears that women may sustain slightly greater 24-h fat oxidation rates during waking and active periods of the day.

Adrenergic control of lipolysis in women compared with men.

Data suggest women are more sensitive to the lipolytic action of epinephrine compared with men while maintaining similar glucoregulatory effects (Horton et al. J Appl Physiol 107: 200-210, 2009). This study aimed to determine the specific adrenergic receptor(s) that may mediate these sex differences. Lean women (n = 14) and men (n = 16) were studied on 4 nonconsecutive days during the following treatment infusions: saline (S: control), epinephrine [E: mixed ß-adrenergic (lipolytic) and α2-adrenergic (antilipolytic) stimulation], epinephrine + phentolamine (E + P: mixed ß-adrenergic stimulation only), and terbutaline (T: selective ß2-adrenergic stimulation). Tracer infusions of glycerol, palmitate, and glucose were administered to determine systemic lipolysis, free fatty acid (FFA) release, and glucose turnover, respectively. Following basal measurements, substrate and hormone concentrations were measured in all subjects over 90 min of treatment and tracer infusion. Women had greater increases in glycerol and FFA concentrations with all three hormone infusions compared with men (P < 0.01). Glycerol and palmitate rate of appearance (Ra) and rate of disappearance (Rd) per kilogram body weight were greater with E infusion in women compared with men (P < 0.05), whereas no sex differences were observed with other treatments. Glucose concentration and kinetics were not different between sexes with any infusion. In conclusion, these data support the hypothesis that the greater rate of lipolysis in women with infusion of E was likely due to lesser α2 antilipolytic activation. These findings may help explain why women have greater lipolysis and fat oxidation during exercise, a time when epinephrine concentration is elevated.

The effects of sex, metabolic syndrome and exercise on postprandial lipemia.

OBJECTIVE: Exercise has been suggested to have cardioprotective benefits due to a lowering of postprandial triglycerides (PPTG). We hypothesized that a morning exercise bout would significantly lower PPTG measured over a full day, in response to moderate fat meals (35% energy) in men more so than women, and in metabolic syndrome (MetS) relative to normal weight (NW) individuals. MATERIALS/METHODS: Participants completed two randomized study days; one control and one exercise day (60 min of morning exercise, 60% VO(2peak)). Meals were consumed at breakfast, lunch and dinner with the energy expended during exercise replaced on the active day. The areas (AUC) and incremental areas (IAUC) under the curve were calculated for total triglycerides, total cholesterol and other metabolites. RESULTS: Exercise did not significantly change the PPTG AUC & IAUC overall, or within, or between, each sex or group (NW and MetS). Exercise induced a 30% decrease in total cholesterol IAUC (p=0.003) in NW subjects. Overall, women had a lower IAUC for PPTG compared to men (p=0.037), with the greatest difference between MetS women and MetS men, due to a sustained drop in TG after lunch in the women. This suggests that PP, rather than fasting, lipid analyses may be particularly important when evaluating sex differences in metabolic risk. CONCLUSIONS: With energy replacement, moderate morning exercise did not result in a significant decrease in PPTG excursions. Exercise did elicit a significant decrease in PP cholesterol levels in NW subjects, suggesting a potential mechanism for the cardioprotective effects of exercise.

Skeletal muscle munc18c and syntaxin 4 in human obesity.

BACKGROUND: Animal and cell culture data suggest a critical role for Munc18c and Syntaxin 4 proteins in insulin mediated glucose transport in skeletal muscle, but no studies have been published in humans. METHODS: We investigated the effect of a 12 vs. 48 hr fast on insulin action and skeletal muscle Munc18c and Syntaxin 4 protein in lean and obese subjects. Healthy lean (n = 14; age = 28.0 +/- 1.4 yr; BMI = 22.8 +/- 0.42 kg/m2) and obese subjects (n = 11; age = 34.6 +/- 2.3 yr; BMI = 36.1 +/- 1.5 kg/m2) were studied twice following a 12 and 48 hr fast. Skeletal muscle biopsies were obtained before a 3 hr 40 mU/m2/min hyperinsulinemic-euglycemic clamp with [6,6-2H2]glucose infusion. RESULTS: Glucose rate of disappearance (Rd) during the clamp was lower in obese vs. lean subjects after the 12 hr fast (obese: 6.25 +/- 0.67 vs. lean: 9.42 +/- 1.1 mg/kgFFM/min, p = 0.007), and decreased significantly in both groups after the 48 hr fast (obese 3.49 +/- 0.31 vs. lean: 3.91 +/- 0.42 mg/kgFFM/min, p = 0.002). Munc18c content was not significantly different between lean and obese subjects after the 12 hour fast, and decreased after the 48 hr fast in both groups (p = 0.013). Syntaxin 4 content was not altered by obesity or fasting duration. There was a strong positive relationship between plasma glucose concentration and Munc18c content in lean and obese subjects during both 12 and 48 hr fasts (R2 = 0.447, p = 0.0015). Significant negative relationships were also found between Munc18c and FFA (p = 0.041), beta-hydroxybutyrate (p = 0.039), and skeletal muscle AKT content (p = 0.035) in lean and obese subjects. CONCLUSION: These data indicate Munc18c and Syntaxin 4 are present in human skeletal muscle. Munc18c content was not significantly different between lean and obese subjects, and is therefore unlikely to explain obesity-induced insulin resistance. Munc18c content decreased after prolonged fasting in lean and obese subjects concurrently with reduced insulin action. These data suggest changes in Munc18c content in skeletal muscle are associated with short-term changes in insulin action in humans.

Effects of fasting on insulin action and glucose kinetics in lean and obese men and women.

The development of insulin resistance in the obese individual could impair the ability to appropriately adjust metabolism to perturbations in energy balance. We investigated a 12- vs. 48-h fast on hepatic glucose production (R(a)), peripheral glucose uptake (R(d)), and skeletal muscle insulin signaling in lean and obese subjects. Healthy lean [n = 14; age = 28.0 +/- 1.4 yr; body mass index (BMI) = 22.8 +/- 0.42] and nondiabetic obese (n = 11; age = 34.6 +/- 2.3 yr; BMI = 36.1 +/- 1.5) subjects were studied following a 12- and 48-h fast during 2 h of rest and a 3-h 40 mUxm(-2)xmin(-1) hyperinsulinemic-euglycemic clamp (HEC). Basal glucose R(a) decreased significantly from the 12- to 48-h fast (lean 1.96 +/- 0.23 to 1.63 +/- 0.15; obese 1.23 +/- 0.07 to 1.07 +/- 0.07 mgxkg(-1)xmin(-1); P = 0.004) and was equally suppressed during the HEC after both fasts. The increase in glucose R(d) during the HEC after the 12-h fast was significantly decreased in lean and obese subjects after the 48-h fast (lean 9.03 +/- 1.17 to 4.16 +/- 0.34, obese 6.10 +/- 0.77 to 3.56 +/- 0.30 mgxkg FFM(-1)xmin(-1); P < 0.001). After the 12- but not the 48-h fast, insulin-stimulated AKT Ser(473) phosphorylation was greater in lean than obese subjects. We conclude that 1) 48 h of fasting produces a marked decline in peripheral insulin action, while suppression of hepatic glucose production is maintained in lean and obese men and women; and 2) the magnitude of this decline is greater in lean vs. obese subjects.

No effect of menstrual cycle phase on glucose kinetics and fuel oxidation during moderate-intensity exercise.

Resting and exercise fuel metabolism was assessed in three different phases of the menstrual cycle, characterized by different levels of estrogen relative to progesterone: early follicular (EF, low estrogen and progesterone), midfollicular (MF, elevated estrogen, low progesterone), and midluteal (ML, elevated estrogen and progesterone). It was hypothesized that exercise glucose utilization and whole body carbohydrate oxidation would decrease sequentially from the EF to the MF to the ML phase. Normal-weight healthy females, experiencing a regular menstrual cycle, were recruited. Subjects were moderately active but not highly trained. Testing occurred after 3 days of diet control and after an overnight fast (12-13 h). Resting (2 h) and exercise (50% maximal O(2) uptake, 90 min) measurements of whole body substrate oxidation, tracer-determined glucose flux, and substrate and hormone concentrations were made. No significant difference was observed in whole body fuel oxidation during exercise in the three phases (nonprotein respiratory exchange ratio: EF 0.84 +/- 0.01, MF 0.85 +/- 0.01, ML 0.85 +/- 0.01) or in rates of glucose appearance or disappearance. There were, however, significantly higher glucose (P < 0.05) and insulin (P < 0.001) concentrations during the first 45 min of exercise in the ML phase vs. EF and MF phases. In conclusion, whole body substrate oxidation and glucose utilization did not vary significantly across the menstrual cycle in moderately active women, either at rest or during 90 min of moderate-intensity exercise. During the ML phase, however, this similar pattern of substrate utilization was associated with greater glucose and insulin concentrations. Both estrogen and progesterone are elevated during the ML phase of the menstrual cycle, suggesting that one or both of these sex steroids may play a role in this response.

Gender differences in lipoprotein lipase activity after acute exercise.

OBJECTIVE: To determine whether gender differences exist in lipoprotein lipase (LPL) activity in response to exercise and/or insulin. Exercise and insulin are known modulators of LPL activity in men, but this is less clear in women. LPL activity may predict propensity for obesity; therefore, understanding its modulators is of considerable importance. RESEARCH METHODS AND PROCEDURES: Gender differences in skeletal muscle and adipose tissue LPL activity were determined after a single bout of exercise followed by a hyperinsulinemic/euglycemic clamp and compared with an identical rest day in healthy lean men (n = 10) and women (n = 10). Muscle and adipose tissue biopsies were obtained pre- (post-exercise vs. rest) and post-clamp. RESULTS: Basal levels of muscle and adipose tissue LPL activity were not different between men and women. There was, however, a significant gender by day interaction for muscle LPL activity (p = 0.023) and adipose tissue LPL activity (p = 0.013). In muscle, this was because of a significant increase in LPL activity on the exercise vs. rest day in men (p < 0.001) but not women. Adipose tissue LPL activity also increased significantly in men on the exercise day relative to rest day (p = 0.04) but decreased in women (p = 0.10). The hyperinulinemic/euglycemic clamp had no independent effect on tissue LPL activity, in either gender, after rest or exercise. DISCUSSION: In the 3 to 4 hours after exercise, muscle and adipose tissue LPL activity increased significantly in men, whereas LPL activity remained unchanged in women.

Postprandial leg uptake of triglyceride is greater in women than in men.

The postprandial excursion of plasma triglyceride (TG) concentration is greater in men than in women. In this study, the disposition of dietary fat was examined in lean healthy men and women (n = 8/group) in either the overnight-fasted or fed (4.5 h after breakfast) states. A [14C]oleate tracer was incorporated into a test meal, providing 30% of total daily energy requirements. After ingestion of the test meal, measures of arteriovenous differences in TG and 14C across the leg were combined with needle biopsies of skeletal muscle and adipose tissue and respiratory gas collections to define the role of skeletal muscle in the clearance of dietary fat. The postprandial plasma TG and 14C tracer excursions were lower (P = 0.04) in women than in men in the overnight-fasted and fed states. Women, however, had significantly greater limb uptake of total TG compared with men on both the fasted (3,849 +/- 846 vs. 528 +/- 221 total micro mol over 6 h) and fed (4,847 +/- 979 vs. 1,571 +/- 334 total micromol over 6 h) days. This was also true for meal-derived 14C lipid uptake. 14C content of skeletal muscle tissue (micro Ci/g tissue) was significantly greater in women than in men 6 h after ingestion of the test meal. In contrast, 14C content of adipose tissue was not significantly different between men and women at 6 h. The main effect of nutritional state, fed vs. fasted, was to increase the postmeal glucose (P = 0.01) excursion (increase from baseline) and decrease the postmeal TG excursion (P = 0.02). These results support the notion that enhanced skeletal muscle clearance of lipoprotein TG in women contributes to their reduced postprandial TG excursion. Questions remain as to the mechanisms causing these sex-based differences in skeletal muscle TG uptake and metabolism. Furthermore, nutritional state can significantly impact postprandial metabolism in both men and women.