We have investigated the role of triglyceride-fatty acid cycling in amplifying control of the net flux of fatty acids in response to exercise and in recovery from exercise. Five normal volunteers were infused with [1-13C]palmitate and D-5-glycerol throughout rest, 4 h of treadmill exercise at 40% maximum O2 consumption, and 2 h of recovery. Total fat oxidation was quantified by indirect calorimetry. Lipolysis (rate of appearance of glycerol) increased from 2.1 +/- 0.3 to 6.0 +/- 1.2 mumol.kg-1.min-1 after 30 min of exercise and progressively increased thereafter to a value of 10.5 +/- 0.8 mumol.kg-1.min-1 after 4 h. Lipolysis decreased rapidly during the first 20 min of recovery, but it was still significantly elevated after 2 h of recovery. The rate of appearance of free fatty acids followed the same pattern of response. Seventy percent of released fatty acids were reesterified at rest, and this value decreased to 25% within the first 30 min of exercise. Reesterification remained less than 35% of lipolysis until the start of recovery, at which time the value rose to 90%. In exercise, more than one-half the increase in fat oxidation could be attributed to the reduction in the percent reesterification. Most of the change in percent reesterification during exercise and recovery was caused by changes in extracellular cycling of fatty acids released into plasma. We conclude that triglyceride-fatty acid cycling plays an important role in enabling a rapid response of fatty acid metabolism to major changes in energy metabolism.

The relative roles of circulatory glucose, muscle glycogen, and lipids in shivering thermogenesis are unclear. Using a combination of indirect calorimetry and stable isotope methodology ([U-13C]glucose ingestion), we have quantified the oxidation rates of these substrates in men acutely exposed to cold for 2 h (liquid conditioned suit perfused with 10 degrees C water). Cold exposure stimulated heat production by 2.6-fold and increased the oxidation of plasma glucose from 39.4 +/- 2.4 to 93.9 +/- 5.5 mg/min (+138%), of muscle glycogen from 126.6 +/- 7.8 to 264.2 +/- 36.9 mg glucosyl units/min (+109%), and of lipids from 46.9 +/- 3.2 to 176.5 +/- 17.3 mg/min (+376%). Despite the observed increase in plasma glucose oxidation, this fuel only supplied 10% of the energy for heat generation. The major source of carbohydrate was muscle glycogen (75% of all glucose oxidized), and lipids produced as much heat as all other fuels combined. During prolonged, low-intensity shivering, we conclude that total heat production is unequally shared among lipids (50%), muscle glycogen (30%), plasma glucose (10%), and proteins (10%). Therefore, future research should focus on lipids and muscle glycogen that provide most of the energy for heat production.

. This large increase in total cycling was caused by an 85% rise in primary cycling (reesterification without transit in the circulation) and accounted for 14% of the difference in metabolic rate between the controls and the leptin-treated animals. This study shows that leptin causes a strong activation of TAG/FA cycling, lipolysis, and FA oxidation, shifting fuel preference from carbohydrates to lipids. Therefore, the acceleration of substrate cycling is a new mechanism triggered by leptin to increase metabolic rate, besides the known induction of uncoupling proteins. futile cycling; energy expenditure; lipid reserve homeostasis; body weight regulation; obesity LEPTIN IS THOUGHT TO MAINTAIN normal body mass by modulating rates of energy intake and expenditure (9, 18), and it plays a fundamental role in the regulation of fat reserves [adipose triacylglycerol (TAG)] (21). This lipostatic hormone adjusts the size of lipid stores through multiple mechanisms acting on metabolic rate (7,14,15,23,37), fuel selection (17), and food consumption (4, 15, 28). The hydrolysis of lipid stores, or lipolysis, releases fatty acids (FA) that can be either oxidized or reesterified (TAG resynthesis). Simultaneous lipolysis and reesterification form the TAG/FA cycle (40, 41), a substrate cycle known to dissipate energy for thermogenesis or weight reduction (26, 38). Concurrent flux through these opposing reactions catalyzed by different enzymes uses energy without net conversion of substrate to product.Most of the information available on leptin-induced changes in lipid metabolism has been obtained in vitro (29), and it is unclear how TAG/FA cycling might be influenced by this hormone in vivo. For example, leptin could reduce fat mass by decreasing reesterification to channel more FA toward oxidation, a strategy supported by some findings on isolated cells (25, 31, 33) but not by others (39). Alternatively, it could stimulate reesterification to promote TAG/FA cycling as another means to increase energy expenditure besides the wellrecognized pathway involving uncoupling proteins (32,43). Leptin is thought to increase energy expenditure primarily by driving the hypothalamic-pituitary-thyroid axis to produce more triiodothyronine (T 3 ) (20), a key regulator of standard metabolic rate (16). One of the ways T 3 can stimulate energy expenditure is by inducing uncoupling proteins (UCPs) to increase the proton leakiness of mitochondria and reduce the efficiency of ATP production from metabolic fuels (30). A lot of attention has been focused on the role of UCPs, because leptin increases the expression of their mRNA, and a clear link between UCP-1 and the thermogenic capacity of brown adipose tissue has been established (31,32,43). Because hormones often elicit the same physiological response through redundant pathways, we have investigated the possible stimulation of substrate cycling, a UCP-independent mechanism to increase energy expenditure. The TAG/FA cycle is one such potential target that plays a known thermogenic role (26,38,40), i...

The aim of this study was to examine some metabolic properties and changes that occur in skeletal muscle and blood of greyhounds after an 800-m sprint. Three prime moving fast-twitch muscles were selected: biceps femoris (BF), gastrocnemius (G), and vastus lateralis (VL). The amount of glycogen utilized during the event was 42.57, 43.86, and 42.73 mumol glucosyl units/g wet wt, respectively. Expressed as a function of race time (48.3 +/- 0.7 s, n = 3), the mean rate of glycogen breakdown was 53.48 +/- 0.5 mumol.g wet wt-1.min-1 during the sprint. This is equivalent to an ATP turnover of 160 mumol.g wet wt-1.min-1, assuming 100% anaerobic conversion to lactate. This represents a conservative estimate, since greyhound muscle is heterogeneous and comprised of a large percentage of fast-twitch oxidative fibers (Armstrong et al., Am. J. Anat. 163: 87-98, 1982). The large decrease in muscle glycogen was accompanied by a 6- to 7-fold increase in muscle lactate from 3.48 +/- 0.13 to 25.42 +/- 3.54 (BF), 2.54 +/- 1.05 to 18.96 +/- 2.60 (G), and 4.57 +/- 0.44 to 30.09 +/- 1.94 mumol.g wet wt (VL), and a fall in muscle pH from 6.88 +/- 0.03 to 6.40 +/- 0.02 (BF), 6.92 +/- 0.02 to 6.56 +/- 0.02 (G), and 6.93 +/- 0.02 to 6.47 +/- 0.01 (VL). Cytosolic phosphorylation potential in BF decreased 10-fold from 11,360 +/- 680 to 1,184 +/- 347, and redox potential decreased 5-fold, indicating a marked reduction in the cytosol at this time.(ABSTRACT TRUNCATED AT 250 WORDS)

We examined the chest CT scans of 1,453 WTC responders using the International Classification of High-resolution CT for Occupational and Environmental Respiratory Diseases. Univariate and bivariate analyses of potential work-related pleural abnormalities were performed with pre-WTC and WTC-related occupational exposure data, spirometry, demographics and quantitative CT measurements. Logistic regression was used to evaluate occupational predictors of those abnormalities. Chest CT scans were performed first at a median of 6.8 years after 9/11/2001. Pleural abnormalities were the most frequent (21.1%) across all occupational groups In multivariable analyses, significant pre-WTC occupational asbestos exposure, and work as laborer/cleaner were predictive of pleural abnormalities, with prevalence being highest for the Polish subgroup (n = 237) of our population. Continued occupational lung disease surveillance is warranted in this cohort.

Plasma fatty acid (FA) and albumin concentrations, cardiac output, and hematocrit of dogs and goats [dog-to-goat ratio of maximal oxygen consumption (VO2max) = 2.2] were measured to determine rates of circulatory FA delivery during exercise. Our goals were 1) to characterize the mechanism(s) used by the endurance-adapted species (dog) to support higher rates of FA delivery to working muscles than the sedentary species (goat) and 2) to determine whether circulatory transport is scaled with VO2max. Lipid oxidation was 2.5 times higher in dogs than in goats. Dogs had higher cardiac outputs than goats, but this positive effect on their FA delivery was canceled by higher hematocrit. Dogs always had higher plasma FA concentrations than goats. In contrast, albumin was steady and identical in both species, showing that dogs transport FA at higher rates than goats only because they load more FA on their albumin. Average dog-to-goat ratios for FA delivery (1.5-2.0) were lower than would be expected if this rate were scaled with VO2max. In vitro experiments showed that dog albumin is designed for high rates of FA transport because it can bind 50% more FA than goat albumin. All endurance-adapted species may possess such "aerobic albumins" to supply more circulating FA to their working muscles than sedentary species.

Oxygen levels and temperature can fluctuate rapidly in aquatic environments. Even though the effects of environmental stresses on fish metabolism have been studied extensively, information on fuel kinetics is extremely limited because it relies almost exclusively on changes in substrate concentrations. The turnover rate of nonesterified fatty acids (NEFA) has never been measured in fish. Therefore, our goal was to quantify glucose and NEFA fluxes in rainbow trout acutely exposed to severe hypoxia (25% O2 saturation) or low temperature (6°C for fish acclimated to 15°C) by performing continuous infusions of 6-[3H]glucose and 1-[14C]palmitate in vivo. Results show that hypoxia causes a 53% decrease in NEFA turnover rate, together with a transient increase in hepatic glucose production, whereas a rapid drop in temperature induces equivalent declines in glucose, NEFA, and oxygen fluxes [temperature coefficient ≅ 2]. More importantly, kinetic changes in glucose and NEFA fluxes are not accompanied by interpretable changes in the plasma concentrations of these metabolites. Thus using concentration changes to draw conclusions about fluxes must be avoided.

Lactate and glucose turnover rates were measured by bolus injection of [U-14C]lactate and [6-3H]glucose in cannulated lightly anesthetized skipjack tuna, Katsuwonus pelamis. Our goals were to find out whether the high rates of lactate clearance reported during recovery from burst swimming in tuna could be accounted for by high blood lactate fluxes; to extend the observed correlation between lactate turnover and lactate concentration in mammals to a nonmammalian system, and to assess the importance of lactate and glucose as metabolic fuels in tuna and to compare their flux rates with values reported for mammals. Measured lactate turnover rates ranged from 112 to 431 mumol X min-1 X kg-1 and were correlated with blood lactate concentration. Glucose turnover rate averaged 15.3 mumol X min-1 X kg-1. When correcting for body mass and temperature, skipjack tuna has at least as high or even higher lactate turnover rates than those recorded for mammals. Tuna glucose turnover rate is similar to that of mammals but much higher than levels found in other teleosts. Even the highest lactate turnover rate measured in tuna cannot fully account for the rate of blood lactate clearance observed during recovery, suggesting that some of the lactate produced in skeletal muscle must be metabolized in situ. After injection of [U-14C]lactate, less than 5% of the total blood activity was recovered in glucose, suggesting that the Cori cycle is not an important pathway of lactate metabolism in tuna.