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Context: Sex differences in lipid metabolism result in a less proatherogenic plasma lipid profile in premenopausal women than men. The mechanisms responsible for this are unclear but are thought to be related to differences in the sex hormone milieu in men and women., Objective: Our objective was to evaluate the effect of endogenous sex hormones on very-low-density lipoprotein (VLDL) triglyceride (TG) and apolipoprotein B-100 (apoB-100) metabolism. EXPERIMENTAL DESIGN AND MAIN OUTCOME MEASURES: We measured basal VLDL-TG and VLDL-apoB-100 concentrations and kinetics by using stable isotope-labeled tracers., Setting and Participants: Eight premenopausal women [age, 43 + or - 8 yr; body mass index (BMI), 35 + or - 4 kg/m(2); mean + or - sd], eight postmenopausal women (age, 55 + or - 4 yr; BMI, 34 + or - 4 kg/m(2)), and eight men (age, 41 + or - 13 yr; BMI, 34 + or - 4 kg/m(2)) were studied at Washington University School of Medicine, St. Louis, MO., Results: VLDL-TG secretion rate was approximately double (P < 0.05) in postmenopausal women and men compared with premenopausal women but not different in postmenopausal women and men. The secretion rate of VLDL-apoB-100 was not different in pre- and postmenopausal women but was greater (P < 0.05) in men than in women., Conclusions: Endogenous ovarian sex steroids are responsible for sexual dimorphism in VLDL-TG secretion, whereas VLDL-apoB-100 secretion is not regulated by female reproductive hormones.

Insulin is an important regulator of glucose, lipid, and protein metabolism. It suppresses hepatic glucose and triglyceride production, inhibits adipose tissue lipolysis and whole-body and muscle proteolysis, and stimulates glucose uptake in muscle. In this review we discuss what is currently known about the control of substrate metabolism by insulin in men and women. The data available so far indicate that women are more sensitive to insulin with regards to glucose metabolism (both in the liver and in muscle), whereas there are no differences between men and women in insulin action on lipolysis. Potential differences exist in the regulation of plasma triglyceride concentration and protein metabolism by insulin and in changes in insulin action in response to stimuli (e.g., weight loss and exercise) that are known to alter insulin sensitivity. However, these areas have not been studied comprehensively enough to draw firm conclusions., (2010 Elsevier Inc. All rights reserved.)

The muscle protein fractional synthesis rate (FSR) is determined by monitoring the incorporation of an amino acid tracer into muscle protein during a constant-rate intravenous tracer infusion. Commonly two sequential muscle biopsies are obtained some time after starting the tracer infusion. However, other protocols, including those with an initial biopsy before starting the tracer infusion to measure the background enrichment and those with only a single biopsy after several hours of tracer infusion have been used. To assess the validity of these approaches, we compared the muscle protein FSR obtained by calculating the difference in [ring-(2)H(5)]phenylalanine and [5,5,5-(2)H(3)]leucine incorporation into muscle protein at approximately 3.5 h after starting the tracer infusion and 1) at 60 min; 2) before starting the tracer infusion (background enrichment); 3) a population average muscle protein background enrichment; and 4) by measuring the tracer incorporation into muscle protein at approximately 3.5 h assuming essentially no background enrichment. Irrespective of the tracer used, the muscle protein FSR calculated from the difference in the muscle protein labeling several hours after starting the tracer infusion and either the labeling at 60 min or the background enrichment were not different (e.g., 0.049 +/- 0.007%/h vs. 0.049 +/- 0.007%/h, respectively, with [(2)H(5)]phenylalanine; P = 0.99). However, omitting the initial biopsy and assuming no background enrichment yielded average FSR values that were approximately 15% (with [(2)H(5)]phenylalanine) to 80% (with [(2)H(3)]leucine) greater (P < or = 0.059); using a population average background enrichment reduced the difference to approximately 3% (P = 0.76) and 22% (P = 0.52) with [(2)H(5)]phenylalanine and [(2)H(3)]leucine, respectively. We conclude that during basal, postabsorptive conditions, valid muscle protein FSR values can be obtained irrespective of the timing of the initial biopsy so long as the protein labeling in two sequential biopsies is measured whereas the single biopsy approach should be avoided.

Background and Objective: The effect of exercise on the plasma concentration of high-molecular weight (HMW) adiponectin (i.e. the biologically active form of circulating adiponectin) and the possible role of HMW adiponectin in mediating the exercise-induced enhancement of insulin action are not known. The aim of this study was to evaluate the relationship between the post-exercise increase in insulin sensitivity and plasma HMW adiponectin concentration., Design and Methods: We measured total and HMW adiponectin concentrations in plasma using an ELISA kit, and insulin sensitivity using the updated homeostasis model assessment of insulin sensitivity (HOMA2-IS) score in the basal, overnight fasted state, once approximately 12 h after a single bout of moderate-intensity endurance exercise and once after an equivalent period of rest, in 27 healthy men and women (age: 29+/-1 years and body mass index: 24.7+/-0.8 kg/m(2))., Results: The HOMA2-IS score was 18+/-7% greater after exercise than after rest (229+/-20 and 196+/-17 respectively; P=0.006), whereas the concentrations of total adiponectin (7.8+/-0.5 and 7.7+/-0.5 mg/l respectively; P=0.597) and HMW adiponectin (3.0+/-0.3 and 3.0+/-0.3 mg/l respectively; P=0.625) were not different. The exercise-induced change in HOMA2-IS score was not related to changes in total and HMW adiponectin concentrations (P>0.3)., Conclusions: Changes in HMW adiponectin concentration are not involved in the acute exercise-induced enhancement of insulin action.

An increased release of free fatty acids (FFAs) into plasma likely contributes to the metabolic complications associated with obesity. However, the relationship between body fat and FFA metabolism is unclear because of conflicting results from different studies. The goal of our study was to determine the inter-relationships between body fat, sex, and plasma FFA kinetics. We determined FFA rate of appearance (Ra) in plasma, by using stable isotopically labeled tracer techniques, during basal conditions in 106 lean, overweight, and obese, nondiabetic subjects (43 men and 63 women who had 7.0-56.0% body fat). Correlation analyses demonstrated: (i) no differences between men and women in the relationship between fat mass (FM) and total FFA Ra (micromol/min); (ii) total FFA Ra increased linearly with increasing FM (r=0.652, P<0.001); (iii) FFA Ra per kg FM decreased in a curvilinear fashion with increasing FM (r=-0.806; P<0.001); (iv) FFA Ra in relationship to fat-free mass (FFM) was greater in obese than lean subjects and greater in women than in men; and (v) abdominal fat itself was not an important determinant of total FFA Ra. We conclude that total body fat, not regional fat distribution or sex, is an important modulator of the rate of FFA release into plasma. Although increased adiposity is associated with a decrease in fatty acid release in relationship to FM, this downregulation is unable to completely compensate for the increase in FM, so total FFA Ra and FFA Ra with respect to FFM are greater in women than in men and in obese than in lean subjects.

Men have more muscle than women, but most studies evaluating sex differences in muscle protein metabolism have been unable to discern sexual dimorphism in basal muscle protein turnover rates in young and middle-aged adults. We hypothesized that the anabolic response to nutritional stimuli (i.e., amino acids and insulin) would be greater in young/middle-aged men than women. We therefore measured the rates of muscle protein synthesis (MPS) in 16 healthy individuals [8 men and 8 women, matched for age (mean +/- SE: 37.7 +/- 1.5 yr) and body mass index (25.2 +/- 0.7 kg/m2)] after an overnight fast (plasma insulin approximately 5 microU/ml and plasma phenylalanine approximately 60 microM) and during a hyperinsulinemic-hyperaminoacidemic-euglycemic clamp (plasma insulin approximately 28 microU/ml; plasma phenylalanine approximately 110 microM; plasma glucose approximately 5.4 mM). The rates of MPS were not different between men and women (ANOVA main effect for sex; P = 0.49). During the clamp, the rate of MPS increased by approximately 50% (P = 0.003) with no difference in the increases from basal values between men and women (+0.019 +/- 0.004 vs. +0.018 +/- 0.010%/h, respectively; P = 0.93). There were also no differences between men and women in the basal concentrations of muscle phosphorylated Akt(Ser473), Akt(Thr308), mTOR(Ser2448), and p70s6k(Thr389) or in the hyperinsulinemia-hyperaminoacidemia-induced increases in phosphorylation of those signaling elements (P > or = 0.25). We conclude that there are no major differences in the rate of MPS and its intracellular control during basal conditions and during hyperinsulinemia-hyperaminoacidema between young and middle-aged adult men and women.

Free fatty acid (FFA) availability increases several-fold during exercise and remains significantly elevated for at least 3 to 6 hours after exercise cessation. Little, however, is known regarding the duration of the postexercise rise in FFA flux. In the present study, we used stable isotope-labeled palmitate infusion to examine fatty acid metabolism in 27 healthy untrained men and women (age, 29 +/- 7 years; body mass index, 25 +/- 4 kg/m2) between 13 to 16 hours and 21 to 24 hours after a single bout of moderate-intensity endurance exercise (1-2 hours at 60% of peak oxygen consumption), performed in the evening, and after a time-matched resting trial. Postabsorptive FFA rate of appearance (Ra) and FFA concentration in plasma were significantly greater after exercise than rest throughout the recovery period (P < .015), but the exercise-induced increases declined from approximately 40% at 13 to 16 hours to approximately 10% at 21 to 24 hours postexercise (P = .001). The magnitude of the exercise-induced increase in plasma FFA concentration was proportional to the increase in FFA Ra. Correlation analysis demonstrated that exercise-induced changes in plasma FFA Ra at 13 to 16 hours are (1) negatively associated with resting plasma FFA Ra and (2) positively associated with the net energy expenditure of exercise and the exercise-induced changes in whole-body fat oxidation rate (all P values < .05). In multivariate stepwise linear regression analysis, baseline plasma FFA Ra (P < or = .008) and net energy expenditure of exercise (P < or = .005) independently predicted the exercise-induced change in plasma FFA Ra at 13 to 16 hours. We conclude that the exercise-induced increase in FFA mobilization is (1) long-lived, persisting for 12 to 24 hours after exercise, with a progressive decline with time; (2) greater in subjects with low than high resting plasma FFA availability; and (3) greater after exercise with high than low energy demand.

There are many differences between men and women, and between lean and obese subjects, in fatty acid and very low-density lipoprotein triglyceride and apolipoprotein B-100 metabolism. Currently, observations in this area are predominantly descriptive. The mechanisms responsible for sexual dimorphism in lipid metabolism are largely unknown.

There are considerable differences in the plasma lipid profile between lean and obese individuals and between men and women. Little, however, is known regarding the effects of obesity and sex on the plasma concentration of enzymes involved in intravascular lipid remodeling. Therefore, we measured the immunoreactive protein mass of lipoprotein lipase (LPL), hepatic lipase (HL), cholesterol-ester transfer protein (CETP) and lecithin-cholesterol acyl transferase (LCAT) in fasting plasma samples from 40 lean and 40 obese non-diabetic men and premenopausal women. Women, compared with men, had approximately 5% lower plasma LCAT (p < 0.041), approximately 35% greater LPL (p = 0.001) and approximately 10% greater CETP (p = 0.085) concentrations. Obese, compared with lean individuals of both sexes, had approximately 30% greater plasma LCAT (p < 0.001), approximately 20% greater CETP (p < 0.001) and approximately 20% greater LPL (p = 0.071) concentrations. Plasma HL concentration was not different in lean men and women. Obesity was associated with increased (by approximately 50%) plasma HL concentration in men (p = 0.018) but not in women; consequently, plasma HL concentration was lower in obese women than obese men (p = 0.009). In addition, there were direct correlations between plasma lipid transfer enzyme concentrations and lipoprotein particle concentrations and sizes. There are considerable differences in basal plasma lipid transfer enzyme concentrations between lean and obese subjects and between men and women, which may be partly responsible for respective differences in the plasma lipid profile.

Understanding lipid metabolism and its regulation requires information on the rates at which lipids are produced within the body, absorbed (dietary lipids) into the body, transported within the body, and utilized by various tissues. This article focuses on the use of stable isotope-labeled tracers for the quantitative evaluation of major pathways of fatty acid and triglyceride metabolism in humans in vivo. Adipose tissue lipolysis and free fatty acid appearance in plasma, fatty acid tissue uptake and oxidation, and hepatic very low-density lipoprotein triglyceride secretion are among the metabolic pathways that can be studied by using stable isotope labeled tracers, and will be discussed in detail. The methodology has been in use for many years and is constantly being refined. A variety of tracers and analytical approaches are available and can be used; knowing the advantages, assumptions, and limitations of each is essential for the planning of studies and the interpretation of data, which can provide unique insights into human lipid metabolism.

Hypertriacylglycerolaemia is an important risk factor for cardiovascular disease. In men, we have shown that the effects of evening exercise on basal VLDL (very-low-density lipoprotein) metabolism are dose-dependent: a single prolonged bout of aerobic exercise [2 h at 60% of VO(2 peak) (peak oxygen consumption)] reduces fasting plasma TAG [triacylglycerol (triglyceride)] concentrations, via enhanced clearance of VLDL-TAG from the circulation, whereas the same exercise performed for 1 h has no effect on VLDL-TAG metabolism and concentration. We hypothesized that women are more sensitive to the TAG-lowering effect of exercise because they reportedly use more intramuscular TAG as an energy source during exercise, and depletion of muscle TAG stores has been linked to reciprocal changes in skeletal muscle LPL (lipoprotein lipase) activity. To test our hypothesis, we measured basal VLDL-TAG and VLDL-apoB-100 (apolipoprotein B-100), and plasma NEFA [non-esterified fatty acid ('free fatty acid')] kinetics, by using stable isotope-labelled tracer techniques, on the morning after a single session of evening exercise of moderate duration and intensity (1 h at 60% of VO(2 peak)) in eight sedentary pre-menopausal women (age, 28+/-3 years; body mass index, 27+/-2 kg/m(2); body fat, 34+/-3%; values are means+/-S.E.M.). Compared with an equivalent period of evening rest, exercise had no effect on post-absorptive NEFA concentrations and the rate of appearance in plasma, VLDL-TAG and VLDL-apoB-100 concentrations, hepatic VLDL-TAG and VLDL-apoB-100 secretion and plasma clearance rates (all P>0.05). We conclude that, in women, as in men, a single session of exercise of moderate intensity and duration is not sufficient to bring about the alterations in VLDL metabolism that have been linked to post-exercise hypotriacylglycerolaemia.

Postprandial lipemia test (PPLT) results are predictive of cardiovascular disease risk. However, their reproducibility must be established before they can be clinically useful. Therefore, we investigated PPLT reproducibility by testing 9 men and women (body mass index, 20-41 kg/m(2); age, 21-40 years) on 4 separate occasions (n = 36 PPLTs total) separated by 1 week. Furthermore, because PPLTs are time consuming, we assessed the validity of an abbreviated PPLT. During the PPLT, venous blood was obtained before and every hour for 8 hours after a high-fat meal, which consisted of ice cream and heavy cream (approximately 800 kcal, 71% fat calories). Total and triglyceride-rich lipoprotein (TRL) triglyceride concentrations were measured in plasma. Total area under the curve (AUC) for total triglycerides was highly reproducible (within-subject coefficient of variation, 8%; intraclass correlation coefficient, 0.82); however, reproducibility was low for total triglyceride incremental AUC and both total and incremental TRL triglyceride AUCs (within-subject coefficients of variation, 20%-31%; intraclass correlation coefficients, 0.28-0.54). Four-hour lipemic responses were highly predictive of 8-hour responses (R(2) = 0.89-0.96, P

Women have less muscle than men but lose it more slowly during aging. To discover potential underlying mechanism(s) for this we evaluated the muscle protein synthesis process in postabsorptive conditions and during feeding in twenty-nine 65-80 year old men (n = 13) and women (n = 16). We discovered that the basal concentration of phosphorylated eEF2(Thr56) was approximately 40% less (P<0.05) and the basal rate of MPS was approximately 30% greater (P = 0.02) in women than in men; the basal concentrations of muscle phosphorylated Akt(Thr308), p70s6k(Thr389), eIF4E(Ser209), and eIF4E-BP1(Thr37/46) were not different between the sexes. Feeding increased (P<0.05) Akt(Thr308) and p70s6k(Thr389) phosphorylation to the same extent in men and women but increased (P<0.05) the phosphorylation of eIF4E(Ser209) and eIF4E-BP1(Thr37/46) in men only. Accordingly, feeding increased MPS in men (P<0.01) but not in women. The postabsorptive muscle mRNA concentrations for myoD and myostatin were not different between sexes; feeding doubled myoD mRNA (P<0.05) and halved that of myostatin (P<0.05) in both sexes. Thus, there is sexual dimorphism in MPS and its control in older adults; a greater basal rate of MPS, operating over most of the day may partially explain the slower loss of muscle in older women.

Obesity is a risk factor for cardiovascular disease, including coronary artery disease and heart failure, but the mechanisms by which it may cause them are not completely clear. Currently, therapies aimed at obesity-related cardiovascular disease include weight loss strategies and reduction of the other risk factors that are associated with obesity and cardiovascular disease. Other pathways with for potential drug development for obesity-related CVD are also discussed.

A single bout of moderate-intensity exercise increases whole-body insulin sensitivity for 12-48 h post-exercise; however, the relationship between exercise energy expenditure and the improvement in insulin sensitivity is not known. We hypothesized that the exercise-induced increase in whole-body insulin sensitivity, assessed with HOMA(IR) (homoeostasis model assessment of insulin resistance), is directly related to the energy expended during exercise. We studied 30 recreationally active non-obese men (age, 27+/-5 years; body mass index, 24+/-2 kg/m(2)) in the post-absorptive state on two separate occasions: once after exercising at 60% of VO(22peak) (peak oxygen consumption) for 30-120 min on the preceding afternoon (expending a total of 1.28-5.76 MJ) and once after an equivalent period of rest. Blood samples were obtained the following morning. Exercise-induced changes in HOMA(IR) were curvilinearly related to exercise energy expenditure (r=-0.666, P=0.001) with a threshold of approx. 3.77 MJ (900 kcal) for improvements in HOMA(IR) to be manifested. In particular, HOMA(IR) was reduced by 32+/-24% (P=0.003) in subjects who expended more than 3.77 MJ during exercise, but did not change for those who expended fewer than 3.77 MJ (-2+/-21%; P=0.301). Furthermore, the magnitude of change in HOMA(IR) after exercise was directly associated with baseline (i.e. resting) HOMA(IR) (r=-0.508, P=0.004); this relationship persisted in multivariate analysis. We conclude that improved whole-body insulin resistance after a single bout of exercise is curvilinearly related to exercise energy expenditure, and requires unfeasible amounts of exercise for most sedentary individuals.

Smoking causes multiple organ dysfunction. The effect of smoking on skeletal muscle protein metabolism is unknown. We hypothesized that the rate of skeletal muscle protein synthesis is depressed in smokers compared with non-smokers. We studied eight smokers (> or =20 cigarettes/day for > or =20 years) and eight non-smokers matched for sex (4 men and 4 women per group), age (65 +/- 3 and 63 +/- 3 yr, respectively; means +/- SEM) and body mass index (25.9 +/- 0.9 and 25.1 +/- 1.2 kg/m(2), respectively). Each subject underwent an intravenous infusion of stable isotope-labeled leucine in conjunction with blood and muscle tissue sampling to measure the mixed muscle protein fractional synthesis rate (FSR) and whole body leucine rate of appearance (Ra) in plasma (an index of whole body proteolysis), the expression of genes involved in the regulation of muscle mass (myostatin, a muscle growth inhibitor, and MAFBx and MuRF-1, which encode E3 ubiquitin ligases in the proteasome proteolytic pathway) and that for the inflammatory cytokine TNF-alpha in muscle, and the concentration of inflammatory markers in plasma (C-reactive protein, TNF-alpha, interleukin-6) which are associated with muscle wasting in other conditions. There were no differences between nonsmokers and smokers in plasma leucine concentration, leucine rate of appearance, and plasma concentrations of inflammatory markers, or TNF-alpha mRNA in muscle, but muscle protein FSR was much less (0.037 +/- 0.005 vs. 0.059 +/- 0.005%/h, respectively, P = 0.004), and myostatin and MAFBx (but not MuRF-1) expression were much greater (by approximately 33 and 45%, respectivley, P < 0.05) in the muscle of smokers than of nonsmokers. We conclude that smoking impairs the muscle protein synthesis process and increases the expression of genes associated with impaired muscle maintenance; smoking therefore likely increases the risk of sarcopenia.

The goal of this study was to discover whether using different tracers affects the measured rate of muscle protein synthesis in human muscle. We therefore measured the mixed muscle protein fractional synthesis rate (FSR) in the quadriceps of older adults during basal, postabsorptive conditions and mixed meal feeding (70 mg protein x kg fat-free mass(-1) x h(-1) x 2.5 h) by simultaneous intravenous infusions of [5,5,5-(2)H(3)]leucine and either [ring-(13)C(6)]phenylalanine or [ring-(2)H(5)]phenylalanine and analysis of muscle tissue samples by gas chromatography-mass spectrometry. Both the basal FSR and the FSR during feeding were approximately 20% greater (P < 0.001) when calculated from the leucine labeling in muscle tissue fluid and proteins (fasted: 0.063 +/- 0.005%/h; fed: 0.080 +/- 0.007%/h) than when calculated from the phenylalanine enrichment data (0.051 +/- 0.004 and 0.066 +/- 0.005%/h, respectively). The feeding-induced increase in the FSR ( approximately 20%; P = 0.011) was not different with leucine and phenylalanine tracers (P = 0.69). Furthermore, the difference between the leucine- and phenylalanine-derived FSRs was independent of the phenylalanine isotopomer used (P = 0.92). We conclude that when using stable isotope-labeled tracers and the classic precursor product model to measure the rate of muscle protein synthesis, absolute rates of muscle protein FSR differ significantly depending on the tracer amino acid used; however, the anabolic response to feeding is independent of the tracer used. Thus different precursor amino acid tracers cannot be used interchangeably for the evaluation of muscle protein synthesis, and data from studies using different tracer amino acids can be compared qualitatively but not quantitatively.

HIV-infected patients with lipodystrophy (HIV lipodystrophy) are insulin resistant and have elevated plasma free fatty acid (FFA) concentrations. We aimed to explore the mechanisms underlying FFA-induced insulin resistance in patients with HIV lipodystrophy. Using a randomized, placebo-controlled, cross-over design, we studied the effects of an overnight acipimox-induced suppression of FFAs on glucose and FFA metabolism by using stable isotope-labeled tracer techniques during basal conditions and a two-stage euglycemic-hyperinsulinemic clamp (20 and 50 mU insulin/m(2) per min, respectively) in nine patients with nondiabetic HIV lipodystrophy. All patients received antiretroviral therapy. Biopsies from the vastus lateralis muscle were obtained during each stage of the clamp. Acipimox treatment reduced basal FFA rate of appearance by 68.9% (95% CI 52.6-79.5) and decreased plasma FFA concentration by 51.6% (42.0-58.9) (both, P < 0.0001). Endogenous glucose production was not influenced by acipimox. During the clamp, the increase in glucose uptake was significantly greater after acipimox treatment compared with placebo (acipimox: 26.85 micromol x kg(-1) x min(-1) [18.09-39.86] vs. placebo: 20.30 micromol x kg(-1) x min(-1) [13.67-30.13]; P < 0.01). Insulin increased phosphorylation of Akt Thr(308) and glycogen synthase kinase-3beta Ser(9), decreased phosphorylation of glycogen synthase (GS) site 3a + b, and increased GS activity (percent I-form) in skeletal muscle (P < 0.01). Acipimox decreased phosphorylation of GS (site 3a + b) (P < 0.02) and increased GS activity (P < 0.01) in muscle. The present study provides direct evidence that suppression of lipolysis in patients with HIV lipodystrophy improves insulin-stimulated peripheral glucose uptake. The increased glucose uptake may in part be explained by increased dephosphorylation of GS (site 3a + b), resulting in increased GS activity.

Our group (Magkos F, Wright DC, Patterson BW, Mohammed BS, Mittendorfer B, Am J Physiol Endocrinol Metab 290: E355-E362, 2006) has recently demonstrated that a single, prolonged bout of moderate-intensity cycling (2 h at 60% of peak oxygen consumption) in the evening increases basal whole-body free fatty acid (FFA) flux and fat oxidation, decreases hepatic VLDL-apolipoprotein B-100 (apoB-100) secretion, and enhances removal efficiency of VLDL-triglyceride (TG) from the circulation the following day in untrained, healthy, lean men. In the present study, we investigated the effect of a single, shorter-duration bout of the same exercise (1 h cycling at 60% of peak oxygen consumption) on basal FFA, VLDL-TG, and VLDL-apoB-100 kinetics in seven untrained, healthy, lean men by using stable isotope-labeled tracer techniques. Basal FFA rate of appearance in plasma and plasma FFA concentration were approximately 55% greater (P < 0.05) the morning after exercise than rest, whereas resting metabolic rate and whole-body substrate oxidation rates were not different after rest and exercise. Exercise had no effect on plasma VLDL-TG and VLDL-apoB-100 concentrations, hepatic VLDL-TG and VLDL-apoB-100 secretion rates, and VLDL-TG and VLDL-apoB-100 plasma clearance rates (all P > 0.05). We conclude that in untrained, healthy, lean men 1) the exercise-induced changes in basal whole-body fat oxidation, VLDL-TG, and VLDL-apoB-100 metabolism during the late phase of recovery from exercise are related to the duration of the exercise bout; 2) single sessions of typical recreational activities appear to have little effect on basal, fasting plasma TG homeostasis; and 3) there is a dissociation between systemic FFA availability and VLDL-TG and VLDL-apoB-100 secretion by the liver.

Context: Very low-density lipoproteins (VLDL) are a major risk factor for cardiovascular disease. The concentrations of VLDL particles and VLDL-triglyceride (TG) in plasma are lower in women than men, but the mechanisms responsible for these differences are unclear., Objective: The objective of the study was to investigate the effects of sex on VLDL-TG and VLDL-apolipoprotein B-100 (apoB-100) metabolism. EXPERIMENTAL DESIGN AND MAIN OUTCOME MEASURES: We measured basal VLDL-TG and VLDL-apoB-100 kinetics by using stable isotope labeled tracers., Setting/participants: Twenty-six healthy, lean subjects (13 men, aged 29+/-5 yr; 13 women, aged 28+/-6 yr) were studied in the General Clinical Research Center at Washington University School of Medicine., Results: VLDL-TG and VLDL-apoB-100 concentrations were less in women than men (P<0.05). The secretion rate of VLDL-TG was approximately 70% greater (P<0.05), whereas the secretion rate of VLDL-apoB-100 (i.e. VLDL particles) was approximately 20% less (P<0.05) in women than men. The molar ratio of VLDL-TG and VLDL-apoB-100 secretion rates was therefore more than double (P<0.05) in women than men. VLDL-TG plasma clearance rate was approximately 70% greater in women than men (P<0.05), whereas VLDL-apoB-100 plasma clearance rate was not different between sexes. However, VLDL-TG and VLDL-apoB-100 mean residence times in plasma were both shorter (by 45 and 25%, respectively; P<0.05) in women than men., Conclusions: Increased VLDL-TG plasma clearance is responsible for lower VLDL-TG concentration, whereas decreased VLDL-apoB-100 secretion rate, combined with shorter VLDL-apoB-100 residence time in plasma, is responsible for lower VLDL-apoB-100 concentration in women than men. The greater molar ratio of VLDL-TG and VLDL-apoB-100 secretion rates suggests that the liver in women secretes fewer but TG-richer VLDL particles than the liver in men.

The protease inhibitor (PI) ritonavir (RTV) has been associated with elevated resting lipolytic rate, hyperlipidemia, and insulin resistance/glucose intolerance. The purpose of this study was to examine relationships between lipolysis and fatty acid (FA) oxidation during rest, moderate exercise and recovery, and measures of insulin sensitivity/glucose tolerance and fat redistribution in HIV-positive subjects taking RTV (n=12), HAART but no PI (n=10), and HIV-seronegative controls (n=10). Stable isotope tracers [1-(13)C]palmitate and [1,1,2,3,3-(2)H5]glycerol were continuously infused with blood and breath collection during 1-h rest, 70-min submaximal exercise (50% VO2 peak), and 1-h recovery. Body composition was evaluated using DEXA, MRI, and MRS, and 2-h oral glucose tolerance tests with insulin monitoring were used to evaluate glucose tolerance and insulin resistance. Lipolytic and FA oxidation rates were similar during rest and recovery in all groups; however, they were lower during moderate exercise in both HIV-infected groups [glycerol Ra: HIV+RTV 5.1+/-1.2 vs. HIV+no PI 5.9+/-2.8 vs. Control 7.4+/-2.2 micromol.kg fat-free mass (FFM)-1.min-1; palmitate oxidation: HIV+RTV 1.6+/-0.8 vs. HIV+no PI 1.6+/-0.8 vs. Control 2.5+/-1.7 micromol.kg FFM.min, P<0.01]. Fasting and orally-challenged glucose and insulin values were similar among groups. Lipolytic and FA oxidation rates were blunted during moderate exercise in HIV-positive subjects taking HAART. Lower FA oxidation during exercise was primarily due to impaired plasma FA oxidation, with a minor contribution from lower nonplasma FA oxidation. Regional differences in adipose tissue lipolysis during rest and moderate exercise may be important in HIV and warrant further study.

Dyslipidemia, manifested by increased plasma triglyceride (TG), increased total and LDL-cholesterol concentrations and decreased HDL-cholesterol concentration, is an important risk factor for cardiovascular disease. Premenopausal women have a less atherogenic plasma lipid profile and a lower risk of cardiovascular disease than men, but this female advantage disappears after menopause. This suggests that female sex steroids affect lipoprotein metabolism. The impact of variations in the availability of ovarian hormones during the menstrual cycle on lipoprotein metabolism is not known. We therefore investigated whether very-low-density lipoprotein (VLDL)-TG and VLDL-apolipoprotein B-100 (apoB-100) kinetics are different during the follicular (FP) and luteal phases (LP) of the menstrual cycle. We studied seven healthy, premenopausal women (age 27 +/- 2 yr, BMI 25 +/- 2 kg/m(2)) once during FP and once during LP. We measured VLDL-TG, VLDL-apoB-100, and plasma free fatty acid (FFA) kinetics by using stable isotope-labeled tracers, VLDL subclass profile by nuclear magnetic resonance spectroscopy, whole body fat oxidation by indirect calorimetry, and the plasma concentrations of lipoprotein lipase (LPL) and hepatic lipase (HL) by ELISA. VLDL-TG and VLDL-apoB-100 concentrations in plasma, VLDL-TG and VLDL-apoB-100 secretion rates and mean residence times, VLDL subclass distribution, FFA concentration and rate of appearance in plasma, whole body substrate oxidation, and LPL and HL concentrations in plasma were not different during the FP and the LP. We conclude that VLDL-TG and VLDL-apoB-100 metabolism is not affected by menstrual cycle phase.

Inflammation is associated with insulin resistance, and both tumor necrosis factor (TNF)-alpha and interleukin (IL)-6 may affect glucose uptake. TNF induces insulin resistance, whereas the role of IL-6 is controversial. High plasma levels of IL-18 are associated with insulin resistance in epidemiological studies. We investigated the effects of TNF and IL-6 on IL-18 gene expression in skeletal muscle and adipose tissue. Nine human volunteers underwent three consecutive interventions, receiving an infusion of recombinant human (rh)IL-6, rhTNF, and saline. Insulin sensitivity was assessed by measurement of whole body glucose uptake with the stable isotope tracer method during a euglycemic hyperinsulinemic clamp (20 mU.min(-1).kg(-1)), which was initiated 1 h after the IL-6-TNF-saline infusion. Cytokine responses were measured in plasma, muscle, and fat biopsies. Plasma concentrations of TNF and IL-6 increased 10- and 38-fold, respectively, during the cytokine infusions. Whole body insulin-mediated glucose uptake was significantly reduced during TNF infusion but remained unchanged during IL-6 infusion. TNF induced IL-18 gene expression in muscle tissue, but not in adipose tissue, whereas IL-6 infusion had no effect on IL-18 gene expression in either tissue. We conclude that TNF-induced insulin resistance of whole body glucose uptake is associated with increased IL-18 gene expression in muscle tissue, indicating that TNF and IL-18 interact, and both may have important regulatory roles in the pathogenesis of insulin resistance.

Background & Aims: Most patients with extreme obesity have nonalcoholic fatty liver disease (NAFLD). Although gastric bypass (GBP) surgery is the most common bariatric operation performed in obese patients in the United States, the effect of GBP surgery-induced weight loss on the metabolic and hepatic abnormalities associated with NAFLD are not clear., Methods: Whole-body glucose, fatty acid and lipoprotein kinetics, liver histology, and hepatic cellular factors involved in inflammation and fibrogenesis were evaluated in 7 extremely obese subjects (body mass index, 58 +/- 4 kg/m(2)) before and 1 year after GBP surgery., Results: At 1 year after surgery, subjects lost 29% +/- 5% of initial body weight (P < .01); palmitate rate of appearance in plasma, an index of adipose tissue lipolysis, decreased by 47% +/- 4% (P < .01); endogenous glucose production rate decreased by 27% +/- 7% (P < .01); and very-low-density lipoprotein-triglyceride secretion rate decreased by 44% +/- 9% (P < .05). In addition, GBP surgery-induced weight loss decreased hepatic steatosis but did not change standard histologic assessments of inflammation and fibrosis. However, there was a marked decrease in hepatic factors involved in regulating fibrogenesis (collagen-alpha1(I), transforming growth factor-beta1, alpha-smooth muscle actin, and tissue inhibitor of metalloproteinase 1 expression and alpha-smooth muscle actin content) and inflammation (macrophage chemoattractant protein 1 and interleukin 8 expression) (P < .05, compared with values before weight loss)., Conclusions: These data demonstrate that weight loss induced by GBP surgery normalizes the metabolic abnormalities involved in the pathogenesis and pathophysiology of NAFLD and decreases the hepatic expression of factors involved in the progression of liver inflammation and fibrosis.

A reduced response of older skeletal muscle to anabolic stimuli may contribute to the development of sarcopenia. We hypothesized that muscle proteins are resistant to the anabolic action of insulin in the elderly. We examined the effects of hyperinsulinemia on muscle protein metabolism in young (25+/-2 year) and older (68+/-1 year) healthy subjects using stable isotope tracer techniques. Leg blood flow was higher in the young at baseline and increased during hyperinsulinemia, whereas it did not change in the elderly. Glucose concentrations and muscle uptake were not different between groups at baseline and during hyperinsulinemia. Leg phenylalanine net balance was not different at baseline and significantly increased in both groups with hyperinsulinemia (P<0.05) but to a greater extent in the young (P<0.05). Muscle protein synthesis increased only in the young during hyperinsulinemia. Muscle protein breakdown did not significantly change in either group, although it tended to decrease in the elderly. Changes in muscle protein synthesis were correlated with changes in leg amino acid delivery (R=0.89; P=0.0001) and blood flow (R=0.90; P<0.0001). In conclusion, skeletal muscle protein synthesis is resistant to the anabolic action of insulin in older subjects, which may be an important contributor to the development of sarcopenia.

To discover the alterations in lipid metabolism linked to postexercise hypotriglyceridemia, we measured lipid kinetics, lipoprotein subclass distribution and lipid transfer enzymes in seven healthy, lean, young men the day after 2 h of cycling and rest. Compared with rest, exercise increased fatty acid rate of appearance and whole body fatty acid oxidation by approximately 65 and 40%, respectively (P < 0.05); exercise had no effect on VLDL-triglyceride (TG) secretion rate, increased VLDL-TG plasma clearance rate by 40 +/- 8%, and reduced VLDL-TG mean residence time by approximately 40 min and VLDL-apolipoprotein B-100 (apoB-100) secretion rate by 24 +/- 8% (all P < 0.05). Exercise also reduced the number of VLDL but almost doubled the number of IDL particles in plasma (P < 0.05). Muscle lipoprotein lipase content was not different after exercise and rest, but plasma lipoprotein lipase concentration increased by approximately 20% after exercise (P < 0.05). Plasma hepatic lipase and lecithin:cholesterol acyltransferase concentrations were not affected by exercise, whereas cholesterol ester transfer protein concentration was approximately 10% lower after exercise than after rest (P = 0.052). We conclude that 1) greater fatty acid availability after exercise does not stimulate VLDL-TG secretion, probably because of the increase in fatty acid oxidation and possibly also fatty acid use for restoration of tissue TG stores; 2) reduced secretion of VLDL-apoB-100 lowers plasma VLDL particle concentration; and 3) increased VLDL-TG plasma clearance maintains low plasma TG concentration but is not accompanied by similar increases in subsequent steps of the delipidation cascade. Acutely, therefore, the cardioprotective lowering of plasma TG and VLDL concentrations by exercise is counteracted by a proatherogenic increase in IDL concentration.

Most lifestyle-related chronic diseases are characterized by low-grade systemic inflammation and insulin resistance. Excessive tumor necrosis factor-alpha (TNF-alpha) concentrations have been implicated in the development of insulin resistance, but direct evidence in humans is lacking. Here, we demonstrate that TNF-alpha infusion in healthy humans induces insulin resistance in skeletal muscle, without effect on endogenous glucose production, as estimated by a combined euglycemic insulin clamp and stable isotope tracer method. TNF-alpha directly impairs glucose uptake and metabolism by altering insulin signal transduction. TNF-alpha infusion increases phosphorylation of p70 S6 kinase, extracellular signal-regulated kinase-1/2, and c-Jun NH(2)-terminal kinase, concomitant with increased serine and reduced tyrosine phosphorylation of insulin receptor substrate-1. These signaling effects are associated with impaired phosphorylation of Akt substrate 160, the most proximal step identified in the canonical insulin signaling cascade regulating GLUT4 translocation and glucose uptake. Thus, excessive concentrations of TNF-alpha negatively regulate insulin signaling and whole-body glucose uptake in humans. Our results provide a molecular link between low-grade systemic inflammation and the metabolic syndrome.

Purpose of Review: This review summarizes recent advances in our understanding of the differences between the sexes in relation to insulin resistance. Alterations in the body's sensitivity to insulin cause a series of metabolic abnormalities representing essentially the metabolic syndrome (i.e. high fasting plasma triglyceride and glucose and low HDL-cholesterol concentrations, hypertension, abdominal obesity) and type 2 diabetes. Although our knowledge of the causes and consequences of impairments in the insulin signaling pathway at the metabolic, cellular and molecular level has progressed rapidly and continues to do so, serious attempts to discover whether and how sex affects the metabolic control by insulin has only recently started to evolve., Recent Findings: The most significant recent findings include data that suggest that females are intrinsically more insulin resistant than males, possibly because of specific sex-linked gene expression and the resulting differences in metabolic control elements (e.g. signaling pathway and substrate shuttling elements, receptors). Sex hormones, environmental and life-style factors augment or improve the female 'genetic' disadvantage, in ways that are possibly also genetically predetermined., Summary: Women are distinctly different to men with regard to the actions of insulin, the susceptibility to develop insulin resistance, and the response to stimuli that are known to enhance or impair sensitivity to the effects of insulin. Therefore, sex has to be considered when investigating insulin action, metabolic pathways known to be affected by the actions of insulin and diseases that result from abnormalities in insulin action and their treatment.

The existing work demonstrates that striking differences exist between men and women in lipid kinetics. These differences cannot be explained simply by the presence and action of sex hormones and are not always due to secondary, phenotypic traits that characterize men and women (e.g., body-composition, regional fat distribution). In fact, some of these secondary traits may even be the result of sexual dimorphism in metabolism, and being of female or male genotype also determines intermediary metabolism. This review provides an overview of the currently available information regarding sexual dimorphism in human lipid metabolism but does not provide an in-depth account of current knowledge (due to limited space); it will be a broad introduction to those interested in the field and will, hopefully, stimulate further efforts to unravel the secrets of male and female metabolism. What has been discovered so far regarding differences in lipid metabolism between men and women is likely only the tip of the iceberg; clearly, more work is necessary to fully understand human substrate metabolism and the implications the presence of sexual dimorphism in the control of substrate kinetics has on the prevention and treatment of disease.

This study investigated the frequency of persisting, idiopathic creatine-kinase (CK)-elevation, how often the cause of idiopathic CK-elevation could be clarified, and the most frequent causes of idiopathic CK-elevation. Among 28 patients with previously idiopathic CK-elevation, CK remained elevated in 32%. The cause of idiopathic CK-elevation could be determined in 46%. Causes were mitochondriopathy (n = 5), seizure (n = 2), stroke (n = 2), myositis (n = 1), intramuscular-injection (n = 1), alcohol myopathy (n = 1), and pravastátin myopathy (n = 1). In 10 of these patients CK was normal at follow-up. CK-elevation remained idiopathic in 54%. Idiopathic CK-elevation should be comprehensively re-evaluated, even if CK is only slightly elevated or normal at follow-up.

Background & Aim: A number of approaches have been employed in the past to measure very low-density lipoprotein (VLDL) triacylglycerol (TG) kinetics in humans in vivo, varying in the selection of tracer and mode of administration. All, however, make use of labeled TG precursors and more or less complicated mathematical models to derive the kinetic parameters of interest. The aim of the present study was to develop a conceptually straightforward method, based on the traditional tracer infusion technique, for quantifying VLDL-TG production rates in man using stable isotopes., Method: Our approach involves ingestion of [U-13C3]glycerol to endogenously label the glycerol in VLDL-TG, plasmapheresis, isolation of the newly 13C-labeled VLDL from plasma, and administration within the next 2-3 days via a primed constant autologous reinfusion. This procedure produces enough tracer for a priming dose plus 2-3 h of infusion. In the physiological conditions examined (basal and hyperglycemic states, fat- and carbohydrate-rich diets), with almost 3-fold ranging VLDL-TG pool sizes, a steady state in plasma VLDL-TG glycerol tracer-to-tracee ratio was readily achieved within 2 h. Consequently, calculations are made according to the isotope dilution principle, thus avoiding assumptions implicit in more complicated models., Conclusion: The stable isotope VLDL-TG tracer dilution method offers an alternative and reliable tool for the determination of endogenous VLDL-TG kinetics in man under a variety of metabolic states., (Copyright 2003 Elsevier Ltd.)

Syringe pumps are traditionally used to infuse tracers in metabolic research because they are perceived to be more accurate and precise than peristaltic pumps. This study evaluated the accuracy (actual v programmed infusion rate) and precision (reproducibility of infusion) of a peristaltic pump (Gemini PC 2; IMED, San Diego, CA) and a syringe pump (Model 22; Harvard Apparatus, Natick, MA) for metabolic research. In one protocol, saline delivery was measured in vitro in 5 trials at 4 flow rates: 3, 30, 150, and 300 mL/h. In the second protocol, basal glycerol rate of appearance (Ra) was determined in vivo in 5 women on 2 consecutive days. On day 1, [2-(13C)]glycerol was infused with 1 pump and [1,1,2,3,3-(2H5)]glycerol with the other. On day 2, the opposite pattern was used. The accuracy of the 2 pumps was the same (error approximately 2%). In addition, both the syringe and the peristaltic pumps were very precise, with coefficients of variation (CV) <1% at all flow rates. Glycerol Ra values were the same when tracer was infused with either a syringe or peristaltic pump on day 1 and day 2: 4.1 +/- 1.7 (syringe pump) and 4.2 +/- 1.9 (peristaltic pump) micromol. kg fat mass (FM)(-1). min(-1) on day 1; 4.2 +/- 1.2 (syringe pump) and 4.2 +/- 1.3 (peristaltic pump) micromol. kg FM(-1). min(-1) on day 2. These data demonstrate that both syringe and peristaltic pumps are very accurate and precise across a large range of flow rates. Moreover, the assessment of in vivo substrate kinetics in human subjects is the same when either pump is used to infuse isotope tracers.

The effect of relative body fat mass on exercise-induced stimulation of lipolysis and fatty acid oxidation was evaluated in 15 untrained men (5 lean, 5 overweight, and 5 obese with body mass indexes of 21 +/- 1, 27 +/- 1, and 34 +/- 1 kg/m2, respectively, and %body fat ranging from 12 to 32%). Palmitate and glycerol kinetics and substrate oxidation were assessed during 90 min of cycling at 50% peak aerobic capacity (VO2 peak) by use of stable isotope-labeled tracer infusion and indirect calorimetry. An inverse relationship was found between %body fat and exercise-induced increase in glycerol appearance rate relative to fat mass (r2 = 0.74; P < 0.01). The increase in total fatty acid uptake during exercise [(micromol/kg fat-free mass) x 90 min] was approximately 50% smaller in obese (181 +/- 70; P < 0.05) and approximately 35% smaller in overweight (230 +/- 71; P < 0.05) than in lean (354 +/- 34) men. The percentage of total fatty acid oxidation derived from systemic plasma fatty acids decreased with increasing body fat, from 49 +/- 3% in lean to 39 +/- 4% in obese men (P < 0.05); conversely, the percentage of nonsystemic fatty acids, presumably derived from intramuscular and possibly plasma triglycerides, increased with increasing body fat (P < 0.05). We conclude that the lipolytic response to exercise decreases with increasing adiposity. The blunted increase in lipolytic rate in overweight and obese men compared with lean men limits the availability of plasma fatty acids as a fuel during exercise. However, the rate of total fat oxidation was similar in all groups because of a compensatory increase in the oxidation of nonsystemic fatty acids.

Background: Nutritional supplementation may be used to treat muscle loss with aging (sarcopenia). However, if physical activity does not increase, the elderly tend to compensate for the increased energy delivered by the supplements with reduced food intake, which results in a calorie substitution rather than supplementation. Thus, an effective supplement should stimulate muscle anabolism more efficiently than food or common protein supplements. We have shown that balanced amino acids stimulate muscle protein anabolism in the elderly, but it is unknown whether all amino acids are necessary to achieve this effect., Objective: We assessed whether nonessential amino acids are required in a nutritional supplement to stimulate muscle protein anabolism in the elderly., Design: We compared the response of muscle protein metabolism to either 18 g essential amino acids (EAA group: n = 6, age 69 +/- 2 y; +/- SD) or 40 g balanced amino acids (18 g essential amino acids + 22 g nonessential amino acids, BAA group; n = 8, age 71 +/- 2 y) given orally in small boluses every 10 min for 3 h to healthy elderly volunteers. Muscle protein metabolism was measured in the basal state and during amino acid administration via L-[ring-(2)H(5)]phenylalanine infusion, femoral arterial and venous catheterization, and muscle biopsies., Results: Phenylalanine net balance (in nmol x min(-1). 100 mL leg volume(-1)) increased from the basal state (P < 0.01), with no differences between groups (BAA: from -16 +/- 5 to 16 +/- 4; EAA: from -18 +/- 5 to 14 +/- 13) because of an increase (P < 0.01) in muscle protein synthesis and no change in breakdown., Conclusion: Essential amino acids are primarily responsible for the amino acid-induced stimulation of muscle protein anabolism in the elderly.

We evaluated the validity of using a single fatty acid tracer to assess total plasma long-chain free fatty acid (FFA) kinetics and the relationship between the rate of appearance (R(a)) of fatty acids in plasma and the fatty acid composition of adipose tissue triglyceride (TG). A mixture of [(13)C]-labeled myristate, palmitate, stearate, oleate, and linoleate was infused in healthy men during basal conditions and during conditions that stimulate (epinephrine infusion) and inhibit (insulin infusion) lipolysis of adipose tissue TGs. Calculated total FFA, R(a) based on palmitate, oleate, or linoleate tracers, was within 15% of the measured sum of the individual fatty acid R(a) under all conditions, whereas stearate and myristate tracers consistently underestimated and overestimated total FFA R(a), respectively. The fatty acid R(a) profile closely matched the fatty acid profile of subcutaneous adipose tissue TGs during epinephrine infusion, but not during basal conditions and insulin infusion. Our data support the common practice of using labeled palmitate or oleate as fatty acid tracers for assessing total plasma FFA kinetics and suggest that a source of lipids other than adipose tissue TG release fatty acids into the systemic circulation.

We have previously shown that sex and obesity independently affect basal very low density lipoprotein (VLDL)-triglyceride (TG) kinetics. In the present study, we investigated the effect of hyperglycemia-hyperinsulinemia on VLDL-TG kinetics in lean and obese men and women (n = 6 in each group). VLDL-TG kinetics were measured during basal, postabsorptive conditions and during glucose infusion (5.5 mg x kg FFM(-1) x min(-1)) by using [(2)H(5)]glycerol bolus injection in conjunction with compartmental modeling analysis. Basal VLDL-TG secretion in plasma was greater in obese than in lean men (7.8 +/- 0.6 and 2.9 +/- 0.4 micromol x l plasma(-1) x min(-1); P < 0.001) but was not different in lean and obese women (5.0 +/- 1.1 and 5.9 +/- 1.1 micromol x l plasma(-1) x min(-1)). Glucose infusion decreased the VLDL-TG secretion rate by approximately 50% in lean and obese men and in lean women (to 1.5 +/- 0.4, 4.0 +/- 0.6, and 2.2 +/- 0.4 micromol x l plasma(-1) x min(-1), respectively; all P < 0.05) but had no effect on the VLDL-TG secretion rate in obese women (4.9 +/- 1.0 micromol x l plasma(-1) x min(-1)). These results demonstrate that both sex and adiposity affect the regulation of VLDL-TG metabolism. Glucose and insulin decrease VLDL-TG production in both lean men and lean women; obesity is associated with resistance to the glucose- and insulin-mediated suppression of VLDL-TG secretion in women, but not in men.

Background: Plasma fatty acid availability is a major regulator of VLDL-triacylglycerol production. Basal whole-body lipolysis is higher in women than in men and is higher in persons with abdominal obesity than in lean individuals., Objective: Our goal was to determine whether sex and abdominal obesity affect VLDL-triacylglycerol kinetics. We hypothesized that basal VLDL-triacylglycerol production would be greater in women than in men and greater in obese than in lean subjects., Design: VLDL-triacylglycerol kinetics were measured in 20 lean (10 men, 10 women; body mass index, in kg/m(2): 23 +/- 1) and 20 abdominally obese (10 men, 10 women; body mass index: 35 +/- 1) subjects by using a bolus injection of [(2)H(5)]glycerol and compartmental modeling analysis., Results: The rate of VLDL-triacylglycerol secretion was greater in the lean women than in the lean men (5.1 +/- 0.7 and 2.6 +/- 0.3 micro mol x L plasma(-1) x min(-1), respectively; P < 0.002). Obesity was associated with increased VLDL-triacylglycerol secretion in the men (P < 0.001) but not in the women, which resulted in greater rates of VLDL-triacylglycerol secretion in the obese men than in the obese women (6.8 +/- 0.5 and 5.0 +/- 0.5 micro mol x L plasma(-1) x min(-1), respectively; P < 0.05). The clearance of VLDL-triacylglycerol from plasma was greater (P < 0.05) in the lean women than in the lean men (42 +/- 7 and 27 +/- 4 mL plasma/min, respectively) or in the obese men and obese women (28 +/- 3 and 20 +/- 4 mL plasma/min, respectively). The plasma VLDL-triacylglycerol concentration was directly related to the rate of VLDL-triacylglycerol secretion in the men (R(2) = 0.79, P < 0.001) and inversely related to VLDL-triacylglycerol clearance in the women (R(2) = 0.84, P<0.001)., Conclusion: Sex and obesity have independent effects on basal VLDL-triacylglycerol kinetics.

The effects of obesity and weight loss on lipoprotein kinetics were evaluated in six lean women [body mass index (BMI): 21 +/- 1 kg/m(2)] and seven women with abdominal obesity (BMI: 36 +/- 1 kg/m(2)). Stable isotope tracer techniques, in conjunction with compartmental modeling, were used to determine VLDL-triglyceride (TG) and apolipoprotein B-100 (apoB-100) secretion rates in lean women and in obese women before and after 10% weight loss. VLDL-TG and VLDL-apoB-100 secretion rates were similar in lean and obese women. Weight loss decreased the rate of VLDL-TG secretion by approximately 40% (from 0.41 +/- 0.05 to 0.23 +/- 0.03 micromol x kg fat-free mass(-1) x min(-1); P < 0.05). The relative decline in VLDL-TG produced from nonsystemic fatty acids, derived from intraperitoneal and intrahepatic TG, was greater (61 +/- 7%) than the decline in VLDL-TG produced from systemic fatty acids, predominantly derived from subcutaneous TG (25 +/- 8%; P < 0.05). Weight loss did not affect VLDL-apoB-100 secretion rate. We conclude that weight loss decreases the rate of VLDL-TG secretion in women with abdominal obesity, primarily by decreasing the availability of nonsystemic fatty acids. There is a dissociation in the effect of weight loss on VLDL-TG and apoB-100 metabolic pathways that may affect VLDL particle size.

Several studies addressed the question whether needle-EMG causes elevation of muscle enzymes [aspartate-aminotransferase, alanine-aminotransferase, lactate-dehydrogenase, creatine-phosphokinase (CPK), isoenzyme-MB, aldolase] and lactate with conflicting results. However, these studies used sterilizable needle electrodes and different protocols and methods to record EMGs and determine muscle enzymes. This study examined if muscle enzymes are elevated immediately after or 24 h following EMGs with disposable, concentric needle-electrodes, and if they are dependent on age, sex, muscle, number of investigated sites and previous CPK-elevation. In 53 subjects, 24 woman, 29 men, aged 17-88 years, muscle enzymes were determined before, immediately after and 24 h following EMG with disposable, concentric needle-electrodes. Muscle enzymes were not different before, immediately after and 24 h following the EMG. Muscle enzymes were not different between patients 60 years of age. Apart from higher CPK in men than women, muscle enzymes were not different between the genders. Apart from CPK, muscle enzymes were not different between the brachial biceps and anterior tibial muscle. Muscle enzymes were not different if 20 sites were investigated and were independent on pre-EMG CPK-levels. In conclusion this study shows that muscle enzymes do not increase immediately or 24 h following EMG with disposable, concentric needle-electrodes, irrespective of age, gender, muscle, number of investigated sites and pre-EMG CK-levels.

We evaluated lipid metabolism during 90 min of moderate-intensity (50% VO(2) peak) cycle ergometer exercise in five men and five women who were matched on adiposity (24 +/- 2 and 25 +/- 1% body fat, respectively) and aerobic fitness (VO(2) peak: 49 +/- 2 and 47 +/- 1 ml x kg fat-free mass(-1) x min(-1), respectively). Substrate oxidation and lipid kinetics were measured by using indirect calorimetry and [(13)C]palmitate and [(2)H(5)]glycerol tracer infusion. The total increase in glycerol and free fatty acid (FFA) rate of appearance (R(a)) in plasma during exercise (area under the curve above baseline) was approximately 65% greater in women than in men (glycerol R(a): 317 +/- 40 and 195 +/- 33 micromol/kg, respectively; FFA R(a): 652 +/- 46 and 453 +/- 70 micromol/kg, respectively; both P < 0.05). Total fatty acid oxidation was similar in men and women, but the relative contribution of plasma FFA to total fatty acid oxidation was higher in women (76 +/- 5%) than in men (46 +/- 5%; P < 0.05). We conclude that lipolysis of adipose tissue triglycerides during moderate-intensity exercise is greater in women than in men, who are matched on adiposity and fitness. The increase in plasma fatty acid availability leads to a greater rate of plasma FFA tissue uptake and oxidation in women than in men. However, total fat oxidation is the same in both groups because of a reciprocal decrease in the oxidation rate of fatty acids derived from nonplasma sources, presumably intramuscular and possibly plasma triglycerides, in women.

Tracer methods for VLDL-TG kinetics vary in their ability to account for the effect of tracer recycling, which can influence the calculation of VLDL-TG fractional catabolic rates (FCRs). We evaluated a novel approach, involving stable isotopically labeled glycerol or palmitate tracers in conjunction with compartmental modeling, for measuring VLDL-TG kinetics in normolipidemic human subjects. When administered as a bolus simultaneously, both tracers provided identical VLDL-TG FCRs when the data were analyzed by a compartmental model that accounted for hepatic lipid tracer recycling, but not by non-compartmental analysis. The model-derived FCR was greater than that determined using a non-compartmental approach, and was 2- to 3-fold higher than that usually reported by using a bolus of radioactive [3H]glycerol. When palmitate tracer was given as a constant infusion, VLDL-TG turnover appeared 5-fold slower, because tracer recycling through hepatic lipid pools could not be resolved with the infusion protocol. We conclude that accounting for tracer recycling, particularly the contribution of hepatic glycerolipid pools, is essential to accurately measure VLDL-TG kinetics, and that bolus injection of stable isotopically labeled glycerol or palmitate tracers in conjunction with compartmental modeling analysis offers a reliable approach for measuring VLDL-TG kinetics.

Data obtained from studies conducted in animal models and humans suggest that gender affects the metabolic response to fasting. However, differences in body composition between males and females confound the interpretation of these studies, because increased adiposity itself alters the metabolic response to short-term fasting. We evaluated whole body lipid and glucose kinetics during basal (14-h fast) and short-term fasting (22-h fast) conditions in six women and six men who were matched for adiposity (24 +/- 2 and 23 +/- 2% body wt as fat, respectively). Substrate kinetics were measured by infusing stable isotope labeled tracers of glucose ([(2)H(2)]glucose) and glycerol ([(2)H(5)]glycerol). Basal glycerol rate of appearance (R(a)) in plasma, an indicator of whole body lipolytic rate, was greater in women than in men (2.1 +/- 0.2 vs. 1.5 +/- 0.1 micromol x kg body wt(-1) x min(-1); P < 0.05). However, the relative increase in glycerol R(a) with continued fasting was blunted in women compared with men (40 +/- 7 vs. 80 +/- 4% increase; P < 0.05), resulting in similar lipolytic rates in both genders at 22 h (2.8 +/- 0.2 and 2.6 +/- 0.1 micromol x kg body wt(-1) x min(-1) for women and men, respectively). In contrast, glucose R(a) was similar in men and women at 14 h (11 +/- 0.6 vs. 12 +/- 0.7 micromol x kg body wt(-1) x min(-1) and 22 h of fasting (9 +/- 0.6 vs 10 +/- 0.6 micromol x kg body wt(-1) x min(-1). These data demonstrate the presence of sexual dimorphism in lipid, but not glucose, metabolism during both basal and short-term fasting conditions.

Endurance exercise increases the use of endogenous fuels to provide energy for working muscles. Elderly subjects oxidize more glucose and less fat during moderate intensity exercise. This shift in substrate use is presumably caused by age-related changes in skeletal muscle, including decreased skeletal muscle respiratory capacity, because adipose tissue lipolysis and plasma fatty acid availability are not rate limiting. Endurance training in elderly subjects increases muscle respiratory capacity, decreases glucose production and oxidation, and increases fat oxidation thereby correcting or compensating for the alterations in substrate oxidation associated with aging.

Objective: Orlistat decreases the absorption of dietary triglycerides by inhibiting intestinal lipases. Orlistat therapy is associated with a greater decline in plasma low-density lipoprotein-cholesterol concentrations than that expected from weight loss alone. Therefore, we evaluated the effect of orlistat treatment on dietary cholesterol absorption as a possible mechanism for the independent effect of orlistat on plasma cholesterol concentration., Research Methods and Procedures: Cholesterol absorption from a standardized meal, containing 72 mg of cholesterol, was determined in 18 subjects with class II abdominal obesity (BMI, 35.0 to 39.9 kg/m(2)) by simultaneous administration of intravenous ([(2)H(6)] cholesterol) and oral ([(2)H(5)] cholesterol) cholesterol tracers. In protocol 1 (n = 9), cholesterol absorption was determined on two different occasions, 10 to 20 days apart, to assess the reproducibility of the tracer method. In protocol 2 (n = 9), cholesterol absorption was determined with and without orlistat therapy in a prospective, randomized, crossover design to assess the effect of orlistat on cholesterol absorption., Results: In protocol 1, cholesterol absorption from the test meal was the same on both occasions (53 +/- 5% and 51 +/- 5%). In protocol 2, orlistat treatment caused a 25% reduction in cholesterol absorption, from 59 +/- 6% to 44 +/- 5% (p < 0.01)., Discussion: These data demonstrate that orlistat inhibits dietary cholesterol absorption, which may have beneficial effects on lipoprotein metabolism in obese subjects that are independent of weight loss itself.

Delays in growth are commonly observed in children who have sustained a severe cutaneous burn. The reasons for this growth delay are not completely known, but in adults, plasma growth hormone (GH) levels have been shown to decrease after thermal injury. If this is also the case in severely burned children, the low GH levels may contribute to their chronic growth delay. We propose that treatment with rhGH may prevent this burn-induced growth delay. Height velocities were measured for up to 2 years after injury in 38 burned children (age 7+/-1 years) with a 64+/-2% total burn surface area (TBSA) burn and a 59+/-3% third-degree burn who received 0.2 mg/kg/day rhGH during hospitalization. These height velocities were compared to 41 burned children (age 8+/-1 years) with a 64+/-3% TBSA burn and a 60+/-3% TBSA third-degree burn who were treated similarly but did not receive rhGH. Height velocities and height percentiles were compared to standard height velocity and percentile nomograms of unburned children. To determine the effect of rhGH on energy requirements, resting energy expenditures (REE) were measured by indirect calorimetry and compared to values calculated from the Harris-Benedict equation. All data are presented as mean+/-S.E.M. No differences in average height percentile could be shown between those receiving GH and controls at admission and 6 months after burn. There was, however, a significant difference (P<0.05) in height velocity during the first 2 years after burn between GH (47th+/-6 percentile) and controls (32nd+/-5 percentile). For rhGH-treated children, the REE was elevated by 34+/-4% versus 35+/-5% for controls. Recombinant human GH, given during acute hospitalization, maintained growth in severely burned children who would otherwise experience a significant growth delay. Treatment with rhGH did not atttenuate their elevated REE.

Background: High-carbohydrate (HC) diets are recommended for lowering the risk of coronary heart disease because they decrease plasma LDL-cholesterol concentrations. However, an unfavorable effect of HC diets is an increase in plasma triacylglycerol concentrations. The underlying mechanisms of this effect are still unclear., Objective: We examined the effect of diet composition on VLDL-triacylglycerol metabolism using in vivo isotopically labeled VLDL-triacylglycerol tracers., Design: Six healthy subjects were studied on 2 occasions: after 2 wk of an HC diet (75% carbohydrates, 10% fat, and 15% protein) and after 2 wk of an isoenergetic high-fat (HF) diet (30% carbohydrates, 55% fat, and 15% protein)., Results: The plasma VLDL-triacylglycerol concentration was higher after the HC diet than after the HF diet (690 +/- 186 compared with 287 +/- 104 micromol/L; P < 0.05) because of higher rates of VLDL-triacylglycerol production (0.76 +/- 0.12 compared with 0.45 +/- 0.15 micromol x kg(-1) x min(-1); P < 0.05) rather than diminished VLDL-triacylglycerol clearance (1.5 +/- 0.5 compared with 1.7 +/- 0.5 mL x kg(-1) x min(-1) after the HC diet than after the HF diet, respectively). The increase in VLDL-triacylglycerol production was probably mediated by a decrease in hepatic fatty acid oxidation after the HC diet (0.13 +/- 0.02 compared with 0.69 +/- 0.24 micromol x kg(-1) x min(-1); P < 0.05), which presumably increased hepatic fatty acid availability for triacylglycerol synthesis., Conclusions: The increase in fasting plasma triacylglycerol concentrations in response to short-term HC diets is due to accelerated VLDL-triacylglycerol secretion. Increased hepatic fatty acid availability, resulting from reduced hepatic fatty acid oxidation, is most likely responsible for the observed increase in VLDL-triacylglycerol secretion.

Muscle mass declines with aging. Amino acids alone stimulate muscle protein synthesis in the elderly. However, mixed nutritional supplementation failed to improve muscle mass. We hypothesized that the failure of nutritional supplements is due to altered responsiveness of muscle protein anabolism to increased amino acid availability associated with endogenous hyperinsulinemia. We measured muscle protein synthesis and breakdown, and amino acid transport in healthy young (30 +/- 3 yr) and elderly (72 +/- 1 yr) volunteers in the basal postabsorptive state and during the administration of an amino acid-glucose mixture, using L-[ring-(2)H(5)]phenylalanine infusion, femoral artery and vein catheterization, and muscle biopsies. Basal muscle amino acid turnover was similar in young and elderly subjects. The mixture increased phenylalanine leg delivery and transport into the muscle in both groups. Phenylalanine net balance increased in both groups (young, -27 +/- 8 to 64 +/- 17; elderly, -16 +/- 4 to 29 +/- 7 nmol/(min.100 mL); P: < 0.0001, basal vs. mixture), but the increase was significantly blunted in the elderly (P: = 0.030 vs. young). Muscle protein synthesis increased in the young, but remained unchanged in the elderly [young, 61 +/- 17 to 133 +/- 30 (P: = 0. 005); elderly, 62 +/- 9 to 70 +/- 14 nmol/(min.100 mL) (P: = NS)]. In both groups, protein breakdown decreased (P: = 0.012) and leg glucose uptake increased (P: = 0.0258) with the mixture. We conclude that the response of muscle protein anabolism to hyperaminoacidemia with endogenous hyperinsulinemia is impaired in healthy elderly due to the unresponsiveness of protein synthesis.

We evaluated palmitate rate of appearance (R(a)) in plasma during basal conditions and during a four-stage epinephrine infusion plus pancreatic hormonal clamp in nine white and nine black women with abdominal obesity, who were matched on fat-free mass, total and percent body fat, and waist-to-hip circumference ratio. On the basis of single-slice magnetic resonance imaging analysis, black women had the same amount of subcutaneous abdominal fat but less intra-abdominal fat than white women (68 +/- 9 vs. 170 +/- 14 cm(2), P < 0.05). Basal palmitate R(a) was lower in black than in white women (1.95 +/- 0.26 vs. 2.88 +/- 0.23 micromol. kg fat-free mass(-1). min(-1), P < 0.005), even though plasma insulin and catecholamine concentrations were the same in both groups. Palmitate R(a) across a physiological range of plasma epinephrine concentrations remained lower in black women, because the increase in palmitate R(a) during epinephrine infusion was the same in both groups. We conclude that basal and epinephrine-stimulated palmitate R(a) is lower in black than in white women with abdominal obesity. The differences in basal palmitate kinetics are not caused by alterations in plasma insulin or catecholamine concentrations or lipolytic sensitivity to epinephrine. The lower rate of whole body fatty acid flux and smaller intra-abdominal fat mass may have clinical benefits because of the relationship between excessive fatty acid availability and metabolic diseases.