Free Fatty Acid Availability Research Articles

Regional postprandial fatty acid metabolism in different obesity phenotypes.

To examine if postprandial splanchnic/hepatic free fatty acid (FFA) delivery is increased in upper-body (UB) obesity, and to determine the adipose tissue depots responsible for the greater postprandial FFA availability, we measured systemic and regional uptake and release of FFAs ([1-(14)C]palmitate) before and during a 5-h frequent-feeding mixed meal in eight UB and eight lower-body (LB) obese women. Postabsorptive FFA flux and splanchnic FFA delivery were not different in UB and LB obese women; however, postprandial FFA concentrations (257 +/- 45 vs. 81 +/- 12 micromol/l, P < 0.0001), FFA flux (8.5 +/- 1.2 vs. 3.9 +/- 0.8 micromol x kg(-1) fat-free mass x min(-1), P < 0.0001), splanchnic FFA delivery (275 +/- 45 vs. 88 +/- 24 micromol/min, respectively, P < 0.005), and estimated hepatic FFA delivery were greater in UB than LB obese women. Nonsplanchnic UB adipose tissue FFA release was greater in UB than in LB obese women (276 +/- 71 vs. 97 +/- 37 micromol/min, respectively, P < 0.05) and accounted for the greater postprandial FFA availability in UB obesity. Postprandial leg glucose uptake was less in UB than in LB obese women (8.4 +/- 5.1 vs. 22.9 +/- 2.6 micromol x kg(-1) leg fat-free mass x min(-1), P < 0.05). We conclude that the elevated postprandial FFA release observed in UB obese women originates from the nonsplanchnic UB fat, not visceral fat. These results suggest that visceral fat may be a marker for, but not the source of, excess postprandial FFAs in obesity.

Regulation of fatty acid oxidation in skeletal muscle.

Researchers using animals are beginning to elucidate the control of fatty acid metabolism in muscle at the molecular and enzymatic level. This review examines the physiological data that has been collected from human subjects in the context of the proposed control mechanisms. A number of factors, including the availability of free fatty acids and the abundance of fatty acid transporters, may influence the rate of muscle fatty acid oxidation. However, the predominant point of control appears to be the rate at which fatty acyl-coenzyme A is transported into the mitochondria by the carnitine palmitoyl transferase system. In turn, evidence suggests that the intracellular concentration of malonyl-coenzyme A in muscle is an important regulator of carnitine palmitoyl transferase-I activity. Malonyl-coenzyme A is increased by glucose, which is likely the mechanism whereby glucose intake suppresses the transfer of fatty acids into the mitochondria for subsequent oxidation. In contrast, malonyl-coenzyme A levels decrease during exercise, which enables increased fatty acid oxidation. However, for any given carnitine palmitoyl transferase-I activity, there may be an effect of free fatty acid availability on fatty acid oxidation, particularly at low levels of free fatty acids. Nonetheless, the rate of glucose or glycogen metabolism is probably the primary regulator of the balance between glucose and fatty acid oxidation in muscle.

The effects of timing and amount of forage and grain on exercise response in thoroughbred horses.

There is considerable debate among horsemen about how to feed horses before exercise. Should horses be fed or fasted before work and when should hay be fed relative to grain and/or exercise? Three experiments were conducted to evaluate if feeding hay with and without grain affects glycaemic and haematological responses in Thoroughbred (TB) horses at rest and during a simulated competition exercise test (CET) on a high-speed treadmill. In Experiment 1, 6 TB horses were fed hay at 3 different times relative to a grain meal. Time of feeding hay affected glycaemic response, plasma protein and water intake post grain feeding. During Experiment 2, 4 TB horses were used in a 4 x 4 Latin square design to determine whether feeding grain with or without hay prior to a CET would affect substrate utilisation and exercise. Feeding grain reduced free fatty acid (FFA) availability and increased blood glucose disappearance during exercise (P < 0.05). Feeding hay either along with grain or ad libitum the night before exercise resulted in reduced plasma volume (P < 0.05) and higher lactate production (P < 0.05) and heart rates (P < 0.05) during exercise. During Experiment 3, 4 TB horses were used in a 4 x 4 Latin square design experiment to determine whether feeding forage but no grain prior to CET would affect substrate utilisation and performance. Feeding only forage before exercise did not adversely affect performance. It was concluded that grain should be withheld from horses before exercise, but that small quantities of hay should be fed to ensure proper gastrointestinal tract function.

Impaired free fatty acid uptake in skeletal muscle but not in myocardium in patients with impaired glucose tolerance: studies with PET and 14(R,S)-[18F]fluoro-6-thia-heptadecanoic acid.

Free fatty acids (FFAs) are an important substrate for myocardial and skeletal muscle metabolism, and increased availability and oxidation of FFA are suggested to be associated with insulin resistance. This study was undertaken to assess whether myocardial or muscle uptake of FFA is altered in patients with impaired glucose tolerance (IGT). Eight healthy men (control group; age 48+/-1 years, BMI 25+/-1 kg/m2, mean +/- SE) and eight men with IGT (glucose-intolerant group; age 49+/-1 years, BMI 29+/-1 kg/m2) were studied in the fasting state. Myocardial oxygen consumption and blood flow and myocardial and femoral muscle FFA uptake rates were measured with positron emission tomography (PET) and [15O]O2, [15O]H2O, [15O]CO, and 14(R, S)-[18F]fluoro-6-thia-heptadecanoic acid ([18F]FTHA), a fatty acid tracer trapped into the cell after undergoing initial steps of beta-oxidation. Serum glucose and insulin concentrations were higher in the glucose-intolerant group during the PET study, but FFA concentrations were comparable between the groups. No differences between the groups were observed in the myocardial blood flow, oxygen consumption, fractional FTHA uptake rates, or FFA uptake indices (5.6+/-0.4 vs. 5.2+/-0.4 pmol x 100 g(-1) x min(-1), glucose-intolerant versus control, NS). In the femoral muscle, fractional FTHA uptake (0.0062+/-0.0003 vs. 0.0072+/-0.0003 min(-1), P = 0.044) and FFA uptake indices (0.30+/-0.02 vs. 0.43+/-0.04 min(-1), P = 0.020) were significantly lower in the glucose-intolerant group than in the control group. In conclusion, when studied at the fasting state and normal serum FFA concentrations, subjects with IGT have similar myocardial but lowered femoral muscle FFA uptake. This finding argues against the hypothesis that an increased oxidation of serum FFA, via the competition of glucose and FFA as fuel sources, is the primary cause for impaired peripheral glucose utilization and insulin resistance commonly observed in IGT.

This Month in the Journal

This Month in the Journal

Effects of FFA on insulin-stimulated glucose fluxes and muscle glycogen synthase activity in rats.

To examine effects of free fatty acids (FFA) on insulin-stimulated glucose fluxes, euglycemic hyperinsulinemic (86 pmol . kg-1 . min-1) clamps were performed for 5 h in conscious rats with (n = 8) or without (n = 8) lipid-heparin infusion. Glucose infusion rate required to maintain euglycemia was not different between the two groups during the first 2 h of clamps but became significantly lower with lipid-heparin infusion in the 3rd h and thereafter. To investigate changes in intracellular glucose metabolism during lipid-heparin infusion, additional clamps (n = 8 each) were performed for 1, 2, 3, or 5 h with an infusion of [3-3H]glucose. Insulin-stimulated whole body glucose utilization (Rd), glycolysis, and glycogen synthesis were estimated on the basis of tracer concentrations in plasma during the final 40 min of each clamp. Similar to changes in glucose infusion rate, Rd was not different between the two groups in the 1st and 2nd h but was significantly lower with lipid-heparin infusion in the 3rd h and thereafter. Whole body glycolysis was significantly lower with lipid-heparin infusion in all time periods, i.e., 1st, 2nd, 3rd, and 5th h of clamps. In contrast, whole body glycogen synthesis was higher with lipid-heparin infusion in the 1st and 2nd h but lower in the 5th h. Similarly, accumulation of [3H]glycogen radioactivity in muscle glycogen was significantly higher with lipid-heparin during the 1st and 2nd h but lower during the 3rd and 5th h. Glucose 6-phosphate (G-6-P) concentrations in gastrocnemius muscles were significantly higher with lipid-heparin infusion throughout the clamps. Muscle glycogen synthase (GS) activity was not altered with lipid-heparin infusion at 1, 2, and 3 h but was significantly lower at 5 h. Thus increased availability of FFA significantly reduced whole body glycolysis, but compensatory increase in skeletal muscle glycogen synthesis in association with accumulation of G-6-P masked this effect, and Rd was not affected in the early phase (within 2 h) of lipid-heparin infusion. Rd was reduced in the later phase (>2 h) of lipid-heparin infusion, when glycogen synthesis was reduced in association with reduced skeletal muscle GS activity.

Gender differences in fat oxidation and sympathetic nervous system activity at rest and during submaximal exercise in older individuals

1. Gender differences in fat oxidation at rest and during exercise may contribute to higher body fat in women. We examined gender differences in fat oxidation at rest and during submaximal exercise and their relationship to sympathetic nervous system activity, free fatty acid availability, body composition and aerobic capacity in older volunteers. 2. We measured free fatty acid kinetics using [14C]palmitate, absolute (micromol/min) and relative (respiratory quotient) rates of fat oxidation by indirect calorimetry and sympathetic nervous system activity from noradrenaline kinetics using [3H]noradrenaline in 12 older men (70+/-4 years) and 12 older women (66+/-4 years) at rest and during 30 min of submaximal exercise (45% of peak oxygen consumption). 3. At rest, men oxidized more fat than women on both an absolute (88+/-19 versus 51+/-15 micromol/min; P<0.01) and relative (respiratory quotient: 0.80+/-0. 04 versus 0.85+/-0.04; P<0.01) basis. These differences were not related to noradrenaline appearance rate, free fatty acid concentration, body composition or aerobic capacity. During exercise, fat oxidation was higher (P<0.05 to P<0.01) in men on an absolute level, but respiratory quotient did not differ. Higher absolute fat oxidation in men during exercise was explained by their higher absolute workload. Plasma free fatty acids and free fatty acid rate of appearance did not differ between men and women during exercise despite higher (P<0.05 to P<0.01) plasma noradrenaline concentrations in men. 4. We conclude that: (i) resting fat oxidation is higher in older men compared with older women independent of differences in noradrenaline appearance rate, free fatty acid availability, body composition or aerobic capacity, and (ii) despite higher plasma noradrenaline concentrations during submaximal exercise, no gender differences in free fatty acid appearance rate or fat oxidation were found. These results suggest a sex dimorphism in post-absorptive fat metabolism in the elderly.

Training-induced alterations in fat and carbohydrate metabolism during exercise in elderly subjects.

Compared with young adults, fat oxidation is lower in elderly persons during endurance exercise performed at either the same absolute or relative intensity. We evaluated the effect of 16 wk of endurance training on fat and glucose metabolism during 60 min of moderate intensity exercise [50% of pretraining peak oxygen consumption (VO2peak)] in six elderly men and women (74 +/- 2 yr). Training caused a 21% increase in mean VO2peak. The average rate of fat oxidation during exercise was greater after (221 +/- 28 mumol/min) than before (166 +/- 17 mumol/min) training (P = 0.002), and the average rate of carbohydrate oxidation during exercise was lower after (3,180 +/- 461 mumol/min) than before (3,937 +/- 483 mumol/min) training (P = 0.003). Training did not cause a significant change in glycerol rate of appearance (Ra), free fatty acid (FFA) Ra, and FFA rate of disappearance during exercise. However, glucose Ra during exercise was lower after (1,027 +/- 95 mumol/min) than before (1,157 +/- 69 mumol/min) training (P = 0.01). These results demonstrate that a 16-wk period of endurance training increases fat oxidation without a significant change in lipolysis (glycerol Ra) or FFA availability (FFA Ra) during exercise in elderly subjects. Therefore, the training-induced increase in fat oxidation during exercise is likely related to alterations in skeletal muscle fatty acid metabolism.

Increased VLDL in nephrotic patients results from a decreased catabolism while increased LDL results from increased synthesis

Increased VLDL in nephrotic patients results from a decreased catabolism while increased LDL results from increased synthesis

Regulation of fat/carbohydrate interaction in human skeletal muscle during exercise.

There has been continued interest in the regulation of fat and carbohydrate utilization in muscle tissue, as they are the main substrates for energy production during exercise in well fed humans. Many investigations have demonstrated that increasing fat availability increases fat oxidation and decreases carbohydrate use in the whole body and skeletal muscle. However, little work has been performed in skeletal muscle to identify the mechanisms, and specific biochemical signals which mediate these shifts in fuel selection. The classic work in this area, using contracting heart and resting diaphragm muscle, led to a theory that could explain reciprocal changes in fat and carbohydrate use from a biochemical perspective (glucose-fatty acid cycle). Using this information, we embarked on a number of studies demonstrating that the biochemical regulation of fat/carbohydrate interaction in human skeletal muscle during exercise is different than exists in the continually active heart and diaphragm muscles. By increasing the availability of free fatty acids to the working muscles, it was demonstrated that carbohydrate downregulation during moderate and intense aerobic exercise occurred mainly at glycogen phosphorylase, the enzyme that regulates the degradation of muscle glycogen. There was also coordinate downregulation of pyruvate dehydrogenase activity at low and moderate exercise intensities. We have also investigated the roles that carnitine palmitoyl-transferase I and its regulator malonyl-CoA play in governing the transport of long-chain fatty acids into the mitochondria for oxidation, and therefore the impact on carbohydrate use in human skeletal muscle. The regulation of Carnitine Palmitoyltransferase I (CPTI) activity appears to involve more than changes in the concentration of malonyl-CoA. Several additional mechanisms may exist that interact with or override the effects of malonyl-CoA during exercise, although this work is just beginning. The present work has identified several regulatory sites in the pathways of carbohydrate and fat metabolism that help explain the regulation of fat/carbohydrate interaction in human skeletal muscle during exercise.

Enhanced hepatic fatty acid oxidation and upregulated carnitine palmitoyltransferase II gene expression by methyl 3-thiaoctadeca-6,9,12,15-tetraenoate in rats

This study reports the effects of a novel polyunsaturated 3-thia fatty acid, methyl 3-thiaoctadeca-6,9,12,15-tetraenoate on serum lipids and key enzymes in hepatic fatty acid metabolism compared to a saturated 3-thia fatty acid, tetradecylthioacetic acid. Palmitic acid treated rats served as controls. Fatty acids were administered by gavage in daily doses of 150 mg/kg body weight for 10 days. The aim of the present study was: (a) To investigate the effect of a polyunsaturated 3-thia fatty acid ester, methyl 3-thiaoctadeca-6,9,12,15-tetraenoate on plasma lipids in normolipidemic rats; (b) to verify whether the lipid-lowering effect could be consistent with enhanced fatty acid oxidation; and (c) to study whether decreased activity of esterifying enzymes and diversion to phospholipid synthesis is a concerted mechanism in limiting the availability of free fatty acid as a substrate for hepatic triglyceride formation. Repeated administration of the polyunsaturated 3-thia fatty acid ester for 10 days resulted in a reduction of plasma triglycerides (40%), cholesterol (33%) and phospholipids (20%) compared to controls. Administration of polyunsaturated and saturated 3-thia fatty acids (daily doses of 150 mg/kg body weight) reduced levels of lipids to a similar extent and followed about the same time-course. Both mitochondrial and peroxisomal fatty acid oxidation increased (1.4-fold- and 4.2-fold, respectively) and significantly increased activities of carnitine palmitoyltransferase (CPT) (1.6-fold), 2,4-dienoyl-CoA reductase (1.2-fold) and fatty acyl-CoA oxidase (3.0-fold) were observed in polyunsaturated 3-thia fatty acid treated animals. This was accompanied by increased CPT-II mRNA (1.7-fold), 2,4-dienoyl-CoA reductase mRNA (2.9-fold) and fatty acyl-CoA oxidase mRNA (1.7-fold). Compared to controls, the hepatic triglyceride biosynthesis was retarded as indicated by a decrease in liver triglyceride content (40%). The activities of glycerophosphate acyltransferase, acyl-CoA: 1,2-diacylglycerol acyltransferase and CTP:phosphocholine cytidylyltransferase were increased. The cholesterol lowering effect was accompanied by a reduction in HMG-CoA reductase activity (80%) and acyl-CoA:cholesterol acyltransferase activity (33%). In hepatocytes treated with methyl 3-thiaoctadeca-6,9,12,15-tetraenoate, fatty acid oxidation was increased 1.8-fold compared to controls. The results suggest that treatment with methyl 3-thiaoctadeca-6,9,12,15-tetraenoate reduces plasma triglycerides by a decrease in the availability of fatty acid substrate for triglyceride biosynthesis via enhanced fatty acid oxidation, most likely attributed to the mitochondrial fatty acid oxidation. It is hypothesized that decreased phosphatidate phosphohydrolase activity may be an additive mechanism which contribute whereby 3-thia fatty acids reduce triglyceride formation in the liver. The cholesterol-lowering effect of the polyunsaturated 3-thia fatty acid ester may be due to changes in cholesterol/cholesterol ester synthesis as 60% of this acid was observed in the hepatic cholesterol ester fraction.

Exercise in transgenic mice overexpressing GLUT4 glucose transporters: Effects on substrate metabolism and glycogen regulation

We assessed the effects of GLUT4 glucose transporter expression on substrate metabolism and glycogen regulation during exercise. Transgenic mice overexpressing human (h)GLUT4 in muscle and fat (TG) and their wild-type littermates (WT) were studied by indirect calorimetry at rest and during acute treadmill exercise (30 minutes) and recovery (30 minutes). The rate of carbon dioxide production (V co 2) increased to a greater degree in TG during exercise, whereas resting V co 2, resting oxygen production (V o 2), and exercise-induced increments in V o 2 were similar in TG and WT. As a result, the respiratory quotient (RQ) was increased by .03 to .05 in TG during exercise, due to greater consumption of carbohydrate (up to ∼64% more) and less consumption of lipid (up to ∼40% less) compared with WT, without differences in overall energy expenditure. These differences in substrate metabolism were observed despite relative hypoglycemia and elevated free fatty acids (FFAs) in TG that persisted throughout resting, exercise, and recovery periods. To further assess substrate availability, glycogen content and glycogen synthase activity were measured in skeletal muscle and liver. At rest, muscle glycogen content was 50% higher and glycogen synthase I was 40% lower in TG compared with WT. During exercise and recovery, muscle glycogen was more profoundly depleted in TG than in WT, and glycogen synthase I increased to levels observed in WT, with no change in total glycogen synthase. In the liver, glycogen content and total glycogen synthase were similar in TG and WT under resting conditions, while glycogen synthase I was reduced by 48%. Exercise and recovery induced a more profound depletion of liver glycogen (76% v 30%) and greater increments in both I-form and total glycogen synthase in TG. In conclusion, (1) TG overexpressing GLUT4 exhibit greater muscle glycogen content at rest than WT; (2) during exercise, TG metabolize more carbohydrate, made possible by increased glycogenolysis in muscle and liver, and this predominates as a fuel source despite hypoglycemia and increased availability of FFA; (3) increased carbohydrate metabolism is linked to a decrease in lipid metabolism such that there is no change in overall energy expenditure; and (4) glycogen synthase I activity is inversely proportional to tissue glycogen content despite differences in circulating glucose, insulin, and FFA concentrations, indicating that glycogen content has an overriding regulatory influence on glycogen synthase.

Regulation of plasma fatty acid oxidation during low- and high-intensity exercise.

In the present study we examined the hypothesis that fatty acid oxidation is less during high-intensity exercise than during moderate-intensity exercise because of inhibition of long-chain fatty acid entry into the mitochondria. Six volunteers exercised at 40% peak oxygen consumption (VO2peak) for 60 min and at 80% VO2peak for 30 min on two different occasions. [1-13C]oleate, a long-chain fatty acid, and [1-14C]octanoate, a medium-chain fatty acid, were infused for the duration of the studies. Lipids and heparin were infused during exercise at 80% VO2peak to prevent the expected decrease in plasma free fatty acid (FFA) concentration. Plasma oleate and total FFA availability were similar in the two experiments. Oleate oxidation decreased from 2.8 +/- 0.6 (40% VO2peak) to 1.8 +/- 0.2 mumol.kg-1.min-1 (80% VO2peak, P < 0.05), whereas octanoate oxidation increased from 1.0e-05 +/- 1.0e-06 (40% VO2peak) to 1.3e-05 +/- 5.1e-06 mumol.kg-1.min-1 (80% VO2peak, P < 0.05). Furthermore, the percentage of oleate uptake oxidized decreased from 67.7 +/- 2.8% (40% VO2peak) to 51.8 +/- 4.6% (80% VO2peak, P < 0.05), whereas the percentage of octanoate oxidized was similar during exercise at 40 and 80% VO2peak (84.8 +/- 2.7 vs. 89.3 +/- 2.7%, respectively). Our data suggest that, in addition to suboptimal FFA availability, fatty acid oxidation is likely limited during high-intensity exercise because of direct inhibition of long-chain fatty acid entry into mitochondria.

The effect of substrate utilization, manipulated by nicotinic acid, on excess postexercise oxygen consumption.

Increased fat oxidation during the recovery period from exercise is thought to be a contributing factor for excess postexercise oxygen consumption (EPOC). In an attempt to study the effect of serum free fatty acid (FFA) availability during exercise and recovery on the EPOC, nicotinic acid, a potent inhibitor of FFA mobilization from adipose tissue, was administered to five trained male cyclists prior to, during, and after a bout of cycling at 65% VO2max. In the nicotinic acid trial, a 500 mg dose of nicotinic acid was ingested prior to exercise, and 100 mg doses were ingested at 15, 30, and 45 min exercise, and 30 min recovery. The cyclists also completed a trial under control conditions. Serum FFA, serum glycerol, RER and VO2 were monitored during rest, exercise, and recovery, each of which was 1-h in duration. Nicotinic acid ingestion prevented the increase in serum FFA that occurred during exercise in the control trial. FFA levels during the nicotinic acid trial were significantly lower than control values during both exercise and recovery. Serum glycerol levels were also significantly lower during exercise in the nicotinic acid trial, indicative of a reduction in lipolysis. RER was not significantly different at rest or during exercise; however, RER values were significantly lower during recovery in the control trial, indicative of greater fat oxidation. For both treatments, postexercise VO2 remained elevated above resting levels at the completion of the 1-h recovery period. However, the magnitude of EPOC was significantly reduced after FFA blockade with nicotinic acid (3.4 +/- 0.61 vs 5.5 +/- 0.71). These results support the hypothesis that increased FFA metabolism during exercise and recovery is an important contributing factor to the magnitude of EPOC.

Effect of Chemical Stimulation of the Dorsomedial Hypothalamic Nucleus on Blood Plasma Glucose, Triglycerides and Free Fatty Acids in Rats

The effects of chemical stimulation of the dorsomedial hypothalamic nucleus (DMH) on blood plasma concentration of glucose, triglycerides, insulin, and free fatty acids (FFA) were investigated in anesthetized adult Wistar rats. Microinjection of 12.5 nmol of norepinephrine into the DMH increased blood plasma concentration of glucose and FFA, decreased triglycerides, and did not change plasma insulin within 5 min; after 20 min, blood glucose and FFA reached control values. Microinjection of epinephrine (12.5 nmol) into the DMH also increased blood plasma glucose concentration and decreased triglycerides after 5 min. These effects are probably mediated by beta-adrenergic mechanisms, because they were prevented by beta-adrenergic antagonist propranolol, but not by alpha-adrenergic antagonist prazosin. Microinjection into the DMH of glutamate, dopamine, or acetylcholine failed to cause any change in those metabolic parameters, corroborating the hypothesis that the DMH is part of a beta-adrenergic pathway involved in short-term modulation of the availability of glucose and FFA.

Nutritional strategies for promoting fat utilization and delaying the onset of fatigue during prolonged exercise

Carbohydrate ingestion before and during endurance exercise delays the onset of fatigue (reduced power output). Therefore, endurance athletes are recommended to ingest diets high in carbohydrate (70% of total energy) during competition and training. However, increasing the availability of plasma free fatty acids has been shown to slow the rate of muscle and liver glycogen depletion by promoting the utilization of fat. Ingested fat, in the form of long-chain (C 16-22 ) triacylglycerols, is largely unavailable during acute exercise, but medium-chain (C 8-10 ) triacylglycerols are rapidly absorbed and oxidized. We have shown that the ingestion of medium-chain triacylglycerols in combination with carbohydrate spares muscle carbohydrate stores during 2 h of submaximal (< 70% VO 2 peak) cycling exercise, and improves 40 km time-trial performance. These data suggest that by combining carbohydrate and medium-chain triacylglycerols as a pre-exercise supplement and as a nutritional supplement during exercise, fat oxidation will be enhanced, and endogenous carbohydrate will be spared. We have also examined the chronic metabolic adaptations and effects on substrate utilization and endurance performance when athletes ingest a diet that is high in fat (> 70% by energy). Dietary fat adaptation for a period of at least 2-4 weeks has resulted in a nearly two-fold increase in resistance to fatigue during prolonged, low- to moderate-intensity cycling (< 70% VO 2 peak). Moreover, preliminary studies suggest that mean cycling 20 km time-trial performance following prolonged submaximal exercise is enhanced by 80 s after dietary fat adaptation and 3 days of carbohydrate loading. Thus the relative contribution of fuel substrate to prolonged endurance activity may be modified by training, pre-exercise feeding, habitual diet, or by artificially altering the hormonal milieu or the availability of circulating fuels. The time course and dose-response of these effects on maximizing the oxidative contribution of fat for exercise metabolism and in exercise performance have not been systematically studied during moderate- to high-intensity exercise in humans.

Health consequences of fat distribution.

Body fat distribution is now recognized as an important predictor of the adverse health consequences of obesity. Upper body obesity, especially with increasing visceral fat, is associated with hypertension, insulin resistance, dyslipidemia, type II diabetes mellitus and premature coronary death. Several lines of evidence suggest that abnormal adipose tissue lipolysis, resulting in elevated free fatty acid (FFA) availability, may contribute to some of the metabolic consequences of upper body obesity. The vast majority of the elevated systemic FFA release appears to come from upper body, non-splanchnic adipose tissue. Thus, dysregulation of upper body, non-splanchnic adipose tissue lipolysis may play an important role in contributing to health consequences of fat distribution.

Fat and carbohydrate metabolism during exercise in elderly and young subjects.

We evaluated the effect of aging on fat and carbohydrate metabolism during moderate intensity exercise. Glycerol, free fatty acid (FFA), and glucose rate of appearance (Ra) in plasma and substrate oxidation were determined during 60 min of cycle ergometer exercise in six elderly (73 +/- 2 yr) and six young adults (26 +/- 2 yr) matched by gender and lean body mass. The elderly group was studied during exercise performed at 56 +/- 3% of maximum oxygen uptake, whereas the young adults were studied during exercise performed at the same absolute and at a similar relative intensity as the elderly subjects. Mean fat oxidation during exercise was 25-35% lower in the elderly subjects than in the young adults exercising at either the same absolute or similar relative intensities (P < 0.05). Mean carbohydrate oxidation in the elderly group was 35% higher than the young adults exercising at the same absolute intensity (P < 0.001) but 40% lower than the young adults exercising at the same relative intensity (P < 0.001). Average FFA Ra in the elderly subjects was 85% higher than in the young adults exercising at the same absolute intensity (P < 0.05) but 35% lower than the young adults exercising at a similar relative intensity (P < 0.05). We conclude that fat oxidation is decreased while carbohydrate oxidation is increased during moderate intensity exercise in elderly men and women. The shift in substrate oxidation was caused by age-related changes in skeletal muscle respiratory capacity because lipolytic rates and FFA availability were not rate limiting in the older subjects.

Effect of decreasing plasma free fatty acids by acipimox on hepatic glucose metabolism in normal rats

Increased availability of free fatty acids (FFA) may play a role in the pathogenesis of insulin resistance in the liver. We examined the effects of an antilipolytic nicotinic acid analog (acipimox) on hepatic glucose metabolism in basal and hyperinsulinemic states in normal rats. Acipimox decreased plasma FFA levels profoundly and enhanced the ability of insulin to suppress hepatic glucosa production (HGP) and to stimulate peripheral glucose utilization. In the basal state, acipimox inhibited hepatic gluconeogenesis. However, this inhibition was not associated with the change in overall HGP due to the compensatory increase in hepatic glycogenolysis that might occur as a consequence of decreased hepatic glucose-6-phosphate (G-6-P) and/or plasma insulin levels with acipimox. These results support the contention that FFA are an important determinant of insulin action in the liver, and suggest the existence of intrahepatic autoregulatory and/or hormonal regulatory processes for constant HGP in the basal state.

Choosing the right lipid-regulating agent. A guide to selection.

If dietary therapy and other lifestyle changes do not adequately normalise blood lipid levels, lipid-regulating drugs, as single-drug or combination-drug therapy, may be prescribed to supplement lifestyle changes. Evaluation of the individual patient's health and risk status, determination of the dyslipidaemia, definition of treatment goals and a clear understanding of the mechanisms and effects of lipid-regulating agents are necessary for optimisation of treatment. Although all the available lipid-regulating agents lower low density lipoprotein (LDL) cholesterol, the agents with the greatest LDL cholesterol-lowering effect are the bile acid sequestrants, which up-regulate the LDL receptor by the decrease in intrahepatic cholesterol caused by the interruption of enterohepatic circulation of cholesterol-rich bile acids, and the HMG-CoA reductase inhibitors, which partially inhibit HMG-CoA reductase. The agents with the greatest triglyceride-lowering effect are nicotinic acid, which decreases the production of very low density lipoprotein (VLDL) cholesterol and reduces the availability of free fatty acids in the circulation, and the fibric acid derivatives, which increase lipoprotein lipase activity and may also decrease the release of free fatty acids. Although the safety profile of the available lipid-regulating drugs has been established, patients should be monitored for potential adverse effects and interactions with concomitantly administered agents. When used correctly, lipid-regulating drug therapy is highly effective in the treatment of a variety of dyslipidaemias.