Increased Plasma Free Fatty Acid Research Articles

Epinephrine stimulates human muscle lipoprotein lipase activity in vivo

Lipoprotein lipase (LPL) is involved in lipoprotein metabolism and nutrient partitioning in both adipose tissue and skeletal muscle, and LPL activity is regulated by various hormones and the nutritional state. However, the action of catecholamines has not been thoroughly investigated in humans. Therefore, the effects of exogenous epinephrine on skeletal muscle LPL (SM-LPL) activity and whole-body lipid oxidation were studied. Muscle biopsies were obtained from eight healthy subjects before, during, and after epinephrine infusion. Somatostatin was infused to suppress endogenous insulin production and insulin was infused at a constant rate to maintain basal insulin levels throughout the study. After an equilibrium period (120 minutes), epinephrine (0.05 μg/kg/min) was infused for another 120 minutes. Epinephrine stimulated SM-LPL activity by 21.8% ± 6.8% above basal levels from 1.44 ± 0.25 to 1.69 ± 0.28 μmol free fatty acid (FFA)/h/g muscle ( P < .02), increased plasma FFA 270% from 0.147 to 0.544 mmol/L ( P < .05), and increased lipid oxidation 45% from 4.37 to 6.36 mg/kg/min ( P < .05). The increase in SM-LPL activity was positively correlated with the increase in whole-body lipid oxidation ( R = .75, P < .05). Finally, lipid oxidation and SM-LPL activity were negatively correlated with whole-body glucose oxidation. Overall, the results demonstrate that epinephrine is able to stimulate SM-LPL activity in humans, and thus may have opposite effects on adipose tissue and SM-LPL activity.

Rapid leptin decrease in immediate post-exercise recovery.

Leptin concentrations in humans are known to decrease in response to fasting. The aim of this work was to investigate whether leptin levels might also be modified by exercise-induced negative energy balance. Eight male runners reported in the morning from 0800 to 1200 h for (i) one resting session (sitting) and (ii) one exercise-and-rest session (2 h run and 2 h rest). Plasma leptin, free fatty acids (FFA), glycerol, cortisol and salivary cortisol were assayed in both sessions at 1200 h. After exercise-and-rest the leptin concentrations were lower than after rest (1.7 +/- 0.1 vs 2.5 +/- 0.2 micrograms/l, P < 0.05), i.e. a mean decrease of 30.3 +/- 4.5% (range 9.5-45.8). Plasma FFA, glycerol and cortisol concentrations increased: FFA 0.78 +/- 0.08 vs 0.18 +/- 0.04 mmol/l, glycerol 0.13 +/- 0.01 vs 0.04 +/- 0.01 mmol/l, and cortisol 428 +/- 36 vs 279 +/- 27 nmol/l. A negative correlation was found between plasma FFA and leptin levels (r = -0.5, P < 0.05) and between plasma glycerol and leptin levels (r = -0.05, P < 0.05). No correlation was found between leptin and cortisol levels. In normal subjects with low body fat, a strenuous exercise-and-rest lowers leptin levels by a mean of 30%. A role of lipolysis possibly via increased plasma free fatty acids and glycerol levels is suggested. Cortisol does not seem to be involved.

Effects of thiamine and clenbuterol on body composition, plasma metabolites and hepatic oxygen consumption in broiler chicks

1. We examined the effects of thiamine-hydrochloride (10 mg/kg body weight) and a beta-agonist, clenbuterol (50 mug/kg body weight), on plasma metabolites and hepatic oxygen consumption in female broiler chicks. 2. Clenbuterol, thiamine or both, dissolved in saline, were injected into thigh muscle on 2, 4 and 6 d of age. At 7 d of age blood samples in each treatment group were obtained and breast muscle and liver were weighed; liver slices were used for measurement of oxygen consumption. 3. Body weight gain was reduced by clenbuterol. Thiamine increased breast muscle weight as a proportion of body weight regardless of clenbuterol dose. Clenbuterol increased relative liver weight markedly , especially when chicks received thiamine also. 4. Clenbuterol increased plasma free fatty acid concentration in chicks treated with thiamine. Thiamine decreased plasma triglyceride regardless of clenbuterol dose. Plasma glucose concentration was decreased by both thiamine and clenbuterol. 5. The absolute rate of oxygen consumption in liver slices was greater in the thiamine-treated chicks; clenbuterol did not affect hepatic oxygen consumption. 6. These findings suggest that thiamine-induced energy expenditure results not only from thermogenesis in the liver, but also from increasing energy utilisation for muscle hypertrophy and this vitamin supplementation facilitates the lipolytic effects of the beta-agonist.

Effects of fatty acids and ketone bodies on basal insulin secretion in type 2 diabetes.

The objective of this study was to assess the role of free fatty acids (FFAs) as insulin secretagogues in patients with type 2 diabetes. To this end, basal insulin secretion rates (ISR) in response to acute increases in plasma FFAs were evaluated in patients with type 2 diabetes and in age- and weight-matched nondiabetic control subjects during 1) intravenous infusion of lipid plus heparin (L/H), which stimulated intravascular lipolysis, and 2) the FFA rebound, which followed lowering of plasma FFAs with nicotinic acid (NA) and was a consequence of increased lipolysis from the subject's own adipose tissue. At comparable euglycemia, diabetic patients had similar ISR but higher plasma beta-hydroxybutyrate (beta-OHB) levels during L/H infusion and higher plasma FFA and beta-OHB levels during the FFA rebound than nondiabetic control subjects. Correlating ISR with plasma FFA plus beta-OHB levels showed that in response to the same changes in FFA plus beta-OHB levels, diabetic patients secreted approximately 30% less insulin than nondiabetic control subjects. In addition, twice as much insulin was secreted during L/H infusion as during the FFA rebound in response to the same FFA/beta-OHB stimulation by both diabetic patients and control subjects. Glycerol, which was present in the infused lipid (272 mmol/l) did not affect ISR. We concluded that 1) assessment of FFA effects on ISR requires consideration of effects on ISR by ketone bodies; 2) ISR responses to FFA/beta-OHB were defective in patients with type 2 diabetes (partial beta-cell lipid blindness), but this defect was compensated by elevated plasma levels of FFAs and ketone bodies; and 3) approximately two times more insulin was released per unit change in plasma FFA plus beta-OHB during L/H infusion than during the FFA rebound after NA. The reason for this remains to be explored.

Rat adipose tissue rapidly accumulates and slowly releases an orally-administered high vitamin D dose.

We investigated the effect of oral high-dose cholecalciferol on plasma and adipose tissue cholecalciferol and its subsequent release, and on plasma 25-hydroxyvitamin D (25(OH)D). Female Wistar rats (n 126) received 37.5 micrograms cholecalciferol/d for 14 d and were subsequently studied for a further 88 d. Two subgroups of eighteen rats each were fasted for 3 d immediately after treatment (days 14-17) and at the end of the study (days 98-101). During treatment, plasma cholecalciferol increased rapidly to reach a steady-state. Plasma 25(OH)D and adipose tissue cholecalciferol increased linearly for 1-2 d after treatment. Serum Ca and inorganic phosphate also increased. Subsequently half-lives of plasma cholecalciferol and 25(OH)D, and perirenal and subcutaneous adipose tissue were: 1.4, 22.5, 97.5 and 80.9 d respectively. Fasting, as compared with ad libitum feeding, caused increased plasma free fatty acids, weight loss up to 14% and increased adipose tissue cholecalciferol (nmol/g wet weight). It did not affect plasma cholecalciferol immediately after cholecalciferol treatment, but raised plasma 25(OH)D. Fasting at the end of the study decreased plasma cholecalciferol and increased plasma 25(OH)D. We conclude that orally-administered cholecalciferol rapidly accumulates in adipose tissue and that it is very slowly released while there is energy balance. Fasting causes preferential loss of triacylglycerols from adipose tissue, as opposed to cholecalciferol, but nevertheless augments plasma 25(OH)D. Adipose tissue may act as a 'buffer to functional vitamin D status' by preventing, to a certain extent, unregulated production of 25(OH)D from dietary vitamin D, and by slowly releasing vitamin D under fasting conditions.

4.P.106 Increased plasma free fatty acids and adipose tissue lipopolysis in an animal model of metabolic syndrome X

4.P.106 Increased plasma free fatty acids and adipose tissue lipopolysis in an animal model of metabolic syndrome X

Relationships of Plasma Leptin Levels to Changes in Plasma Free Fatty Acids in Women Who Are Lean and Women Who Are Abdominally Obese

Regulation of leptin production by the hormonal and metabolic milieu is poorly understood. Because abdominal obesity is commonly associated with elevated plasma free fatty acid (FFA) flux, we examined the effects of augmenting FFA on plasma leptin levels in women who were lean and of suppressing FFA in women with abdominal obesity. In study 1, nine subjects who were lean, after a 12-hour overnight fast, received either intravenous saline or Intralipid plus heparin to increase the plasma FFA concentration to approximately 1000 mumol/ L. After 3 hours of additional fasting, subjects underwent 3-hour hyperglycemic clamps. In study 2, seven subjects with abdominal obesity were evaluated by a similar protocol, but lipolysis and plasma FFA flux were instead maximally suppressed by acipimox. In the individuals who were lean, leptin levels were unchanged during clamping. Increasing plasma FFA reduced plasma leptin from 7.66 +/- 0.66 to 7.05 +/- 0.66 (p = 0.03), but 3 hours of hyperglycemia plus hyperinsulinemia had no additional effect on leptin levels (7.15 +/- 0.71). Basal leptin levels, 4-fold higher in the subjects with obesity, were reduced from 34.6 +/- 2.4 micrograms/L to 32.3 +/- 1.1 micrograms/L (p = 0.004) during the clamp period. When plasma FFA flux was suppressed, however, plasma leptin levels after clamped hyperglycemia/hyperinsulinemia were increased to 38.9 +/- 1.2 micrograms/L (p = 0.014 vs. time 0 and 0.001 vs. saline protocol). Changes in leptin concentrations are not correlated with changes in FFA. These results suggest that plasma FFA concentration does not regulate plasma leptin levels in basal, extended fasting, or hyperglycemic/hyperinsulinemic states.

Effects of adrenaline infusion on plasma lipids and noradrenaline levels in rabbits with adriamycin-induced cardiomyopathy.

1. We investigated the acute effects of adrenaline infusion on plasma lipid levels in vehicle- and adriamycin-treated rabbits. Lipids were measured before and 30 and 60 min after the commencement of continuous intravenous administration of adrenaline (0.06 microgram/kg per min) or saline in pentobarbital-anaesthetized rabbits. 2. Adrenaline infusion significantly increased plasma free fatty acid (P < 0.05) and noradrenaline (NA) levels (P < 0.05) in vehicle-treated control rabbits, but not in adriamycin-treated rabbits. However, adrenaline had no effect on plasma total cholesterol, free cholesterol, high-density lipoprotein-cholesterol, triglyceride or phospholipid levels. 3. Pretreatment with propranolol almost completely inhibited increased plasma free fatty acid and NA levels associated with adrenaline infusion, suggesting that adrenaline increases plasma free fatty acid and NA levels via the stimulation of beta-adrenoceptors in vehicle-treated rabbits. 4. It is suggested that both the production of plasma free fatty acids and the release of NA via the activation of beta-adrenoceptors is reduced in rabbits with adriamycin-induced cardiomyopathy. This may be related to the down-regulation of beta-adrenoceptors caused by elevated plasma NA levels induced by cardiac failure.

Responses of plasma glutamine, free tryptophan and branched-chain amino acids to prolonged exercise after a regime designed to reduce muscle glycogen.

Prolonged exercise can elicit a reduction in the plasma glutamine concentration and an increase in the plasma concentration ratio of free tryptophan (FTrp) to branched-chain amino acids (BCAA). The purpose of this investigation was to study the effects of a 60-min bout of vigorous treadmill running with dietary manipulation on plasma concentrations of glutamine, FTrp and BCAA after an exercise and diet regime designed to reduce muscle glycogen. Seven male distance runners [mean (SD) age: 29.3 (2.1) years; VO2max: 62.7 (3.3) ml.kg-1.min-1] acted as subjects. Each undertook a regime designed to reduce muscle glycogen, then performed a 60-min treadmill run (75% VO2max) under two dietary conditions: after a 14-h fast (fasted) and after ingestion of a high carbohydrate meal (30 kJ.kg-1: 80% carbohydrate, 10% protein, 10% fat) 3 h before running (fed). Plasma concentrations of glutamine, FTrp, BCAA, free fatty acids (FFA), glycerol and glucose were measured 5 min before and 5 min after the run, under each dietary condition. Plasma glutamine did not change in response to exercise when fasted (P > 0.05), but increased when fed (P = 0.007). Plasma FTrp increased under both dietary conditions (P < 0.001), but the magnitude of this increase was greater when fasted than when fed (P < 0.001). Plasma BCAA did not change under either dietary condition (P < 0.05). Increases in the plasma FTrp/BCAA ratio reflected increases in plasma FFA and glycerol concentrations (P < 0.001; both dietary conditions) and these changes were all greater under fasted conditions when a fall in blood glucose concentration was observed (P = 0.007). These data emphasise the importance of dietary carbohydrate intake between repeated bouts of prolonged exercise on responses of plasma glutamine, FTrp and BCAA during subsequent exercise.

Effect of endurance training on fatty acid metabolism: local adaptations

Older studies of humans seem to suggest a correlation between free fatty acid (FFA) turnover and oxidation on the one hand and plasma FFA concentration on the other hand during submaximal exercise. However, recent studies, in which higher concentrations of plasma FFA have been reached during prolonged submaximal exercise, have revealed a levelling off in net uptake in spite of increasing plasma FFA concentrations. Furthermore, this relationship between FFA concentration and FFA uptake and oxidation is altered by endurance training. These recent findings in humans support the notion from other cell types that transmembrane fatty acid transport is not only by simple diffusion, but predominantly carrier-mediated. During prolonged submaximal knee-extension exercise it has been demonstrated that the total oxidation of fatty acids was approximately 60% higher in trained subjects than in nontrained subjects. The training-induced adaptations responsible for this increased utilization of plasma fatty acids by the muscle could be located at several steps from the mobilization of fatty acids to skeletal muscle metabolism in the mitochondria. In this paper regulation at the transport steps and also at various metabolic steps is discussed.

13C and 31P NMR Studies on the Effects of Increased Plasma Free Fatty Acids on Intramuscular Glucose Metabolism in the Awake Rat

The effects of increased plasma free fatty acids (FFA) on insulin-dependent whole body glucose disposal, skeletal muscle glycolysis, glycogen synthesis, pyruvate versus FFA/ketone oxidation, and glucose 6-phosphate (Glu-6-P) were investigated in the awake rat. A control group (glycerol-infused) and high plasma FFA group (Liposyn-infused) were clamped at euglycemia (approximately 6 mM)-hyperinsulinemia (10 milliunits/kg/min) throughout the experiment (180-240 min). In the initial experiment, 13C NMR was used to observe [1-13C]glucose incorporation into [1-13C]glycogen in the rat hindlimb for glycogen synthesis calculations and into [3-13C]lactate and [3-13C]alanine for glycolytic flux calculations. These experiments were followed by 31P NMR measurements of Glu-6-P changes under identical conditions of the initial experiment. Plasma FFA concentrations were 2.25 +/- 0.36 and 0.20 +/- 0.03 mM in the high plasma FFA and control groups respectively (p < 0.0005). Glucose infusion rates (Ginf) decreased significantly in the Liposyn-infused rats (29.5 +/- 0.7 and 27.2 +/- 1.2 mg/kg/min for control and high plasma FFA group, respectively, at 15 min to 30.7 +/- 2.3 and 17.7 +/- 1.3 mg/kg/min, respectively, at the end of the experiment, p < 0.002). Glycogen synthesis rates were 163 +/- 32 and 104 +/- 17 nmol/g/min, and glycolytic rates were 57.9 +/- 8.0 and 19. 5 +/- 3.6 nmol/g/min (p < 0.002) in the control and high plasma FFA groups, respectively. The relative flux of pyruvate versus free fatty acids and ketones entering the tricarboxylic acid cycle was greater in the control (57 +/- 9%) versus high plasma FFA group (25 +/- 4%) (p < 0.005) as assessed by [4-13C]glutamate/[3-13C]lactate steady state isotopic enrichment measurements. Finally, Glu-6-P concentrations increased by 29.8 +/- 7.0 and 52.8 +/- 12.3% (p < 0. 05) in the control and high plasma FFA groups, respectively, above their basal concentrations by 180 min. In conclusion, we have demonstrated the ability to use in vivo NMR to elucidate the metabolic fate of glucose within skeletal muscle of an awake rat during a euglycemic-hyperinsulinemic clamp and increased levels of plasma FFA. These data suggest that increased concentrations of plasma FFA inhibit insulin-stimulated muscle glucose metabolism in the rat through inhibition of glycolysis.

Effect of in vivo injection of cholera and pertussis toxin on glucose transport in rat skeletal muscle.

Cholera toxin (CTX) and pertussis toxin (PTX) were examined for their ability to inhibit glucose transport in perfused skeletal muscle. Twenty-five hours after an intravenous injection of CTX, basal transport was decreased approximately 30%, and insulin- and contraction-stimulated transport was reduced at least 86 and 49%, respectively, in both the soleus and red and white gastrocnemius muscles. In contrast, PTX treatment was much less efficient. Impairment of glucose transport appeared to develop 10-15 h after CTX administration, which coincided with development of hyperglycemia despite hyperinsulinimia, increased plasma free fatty acid levels, increased adenosine 3',5'-cyclic monophosphate (cAMP) concentrations in muscle, but no difference in plasma catecholamines. Twenty-five hours after CTX treatment, GLUT-4 protein in both soleus and red gastrocnemius muscles was decreased, whereas no change in GLUT-1 protein content was found. In contrast, GLUT-4 mRNA was unchanged, but transcripts for GLUT-1 were increased > or = 150% in all three muscles from CTX-treated rats. The findings suggest that CTX via increased cAMP impairs basal as well as insulin- and contraction-stimulated muscle glucose transport, at least in part from a decrease in intramuscular GLUT-4 protein.

Hyperinsulinemia, hyperproinsulinemia and insulin resistance in the metabolic syndrome.

For better comprehension of the metabolic syndrome, it is necessary to differentiate the effect of insulin on glucose metabolism on the one hand, and on other metabolic activities on the other hand. Whereas glucose utilization is affected by insulin resistance, the effect of insulin on lipid metabolism, ion and aminoacid transport does not seem to be diminished. Lipid metabolism, however, seems to play a crucial role in the induction of the vicious cycle. Increased energy and fat ingestion may be due to an increased number of galanin secreting cells in the hypothalamus. The excessive fat intake results in an increased rate of release of insulin and increased influx of triglycerides into the blood. From these triglycerides an excess of free fatty acids is released by the action of lipoprotein lipase. The increased plasma free fatty acid level then results in insulin resistance affecting glucose metabolism. Also, these free fatty acids may impair the secretion of insulin. Induction of insulin resistance results in higher glucose levels, which may cause hyperinsulinemia. Hyperinsulinemia maintains the elevation of triglycerides. When diabetes becomes overt and elevated glucose levels prevail, the hyperinsulinism acts on the metabolic pathways which are still sensitive to insulin, namely lipid metabolism, aminoacid transport and ion transport.

Responses of heat stressed chickens to exogenous reverse triiodothyronine (rT3).

Heat stress is accompanied by a decrease in basal metabolic rate and plasma thyroid hormones. Unlike 3,5,3'-triiodothyronine (T3) and thyroxine (T4), 3,3',5'-triiodothyronine (rT3) displays hypometabolic properties and antagonizes the hypermetabolic effect of T3. This study analyses the role of rT3 in heat (38-39 degrees C) stressed immature chickens. Two experiments which differed in frequency of rT3 injections (one or two times a day), duration of heat stress (72 or 48 h) and blood sampling were performed. The dose was 14 micrograms rT3/100 gb.wt./injection (s.c.). It has been shown that rT3 treatment aggravates heat stress symptoms (enhances circulating corticosterone, catecholamines and free fatty acids) and increases mortality. The critical survival time of the rT3 treated and heated birds was at first 24 h of stress. No more chickens died during the next days of the experiment despite the continuation of rT3 injection, suggesting that rT3 might disturb the adaptation to heat. Reverse T3 in heat stressed chickens led to the highest reduction in food consumption (69.9%) and body weight gain (14.0% compared to initial weight). The opposite effect in water consumption (216.9%) was observed. In a neutral environment, rT3 significantly suppressed body temperature 6 h after injection (40.4; control; 41.1 degrees C), confirming its hypometabolic properties. However, at the same time rT3 significantly enhanced body temperature in heat stress (43.03 versus heated control 42.56 degrees C). In addition, in rT3 treated birds decreased plasma triglycerides (TG; 24.3%) and increased plasma free fatty acids (FFA; neutral temperature; 26.4% heat stress: 57%) were demonstrated. A correlation between corticosterone and FFA (r = 0.52) shows that some of the FFA may originate from lipolysis since hormones of the pituitary-adrenocortical axis accelerate lipolysis. The remaining part of the increased FFA appears to be due to suppressed utilization of FFA as a consequence of hypometabolic properties of rT3. Low and negative relation between TG and FFA (r = -0.26; P < 0.05) may support such an assumption. The two times higher peak of corticosterone in the rT3 and the overheated group, as compared to the heated control, occurred at 6 h of heat stress and indicates that rT3 increases the unfavourable effect of high temperature. This was also confirmed by elevated plasma adrenaline and noradrenaline in rT3-injected and heated chickens (55.5 and 120%, respectively). However, a single and two times higher peak of adrenaline at 24 h of heat stress was observed in saline treated birds, but not in rT3 supplemented animals, suggesting that this difference might explain one of the factors responsible for high mortality. In conclusion, the results obtained demonstrate that physiological doses of rT3, a hypometabolic hormone, enhance the unfavourable effect of heat stress in chickens.

The effect of plasma free fatty acids and long-chain triglycerides on glucose metabolism in uncomplicated falciparum malaria

To investigate the therapeutic potential of increased plasma free fatty acid (FFA) and triglyceride concentrations in hypoglycaemic patients receiving quinine, 32 untreated Thai adults with uncomplicated falciparum malaria were allocated at random to one of 4 regimens: 2 mg/kg/min dextrose infused over 60 min either alone (group A) or with a prior injection of 5000 units of heparin and simultaneous Intralipid ® infusion (group C), or 4 min/kg/min dextrose alone (group B) or with heparin and Intralipid ® (group D). Quinine (10 mg/kg) was also infused over 60 min in all cases. In patients of groups A and C, mean changes in plasma glucose concentrations from the beginning to the end of the infusion were 0·1 ( sd 0·8) and 1·0 ( sd0·7) mmol/L respectively ( P = 0·015). In groups B and D, plasma glucose increased by 1·8 ( sd 1·2) and 2·2 ( sd 0·4) mmol/L respectively ( P < 0·5). Plasma FFA levels fell by approximately 50% during the infusion in groups A and B but increased by a similar percentage in groups C and D. Despite significant mean increases in plasma insulin during the infusion (from 12·2 milliunits (mu)/L in group A to 38·8 mu/L in group D), no rebound hypoglycaemia was observed in any patient during the ensuing 7 h. These data suggest that the glycaemic response to dextrose given at high rates, which match average glucose utilization in a severely ill patient with malaria, is not augmented by increased plasma FFA and long-chain triglycerides. However, this strategy increases the glycaemic efficacy of lower dextrose infusion rates and the combination could, therefore, reduce the volumes of hypertonic dextrose required to prevent hypoglycaemia in severely ill patients in whom optimal fluid balance is crucial.

Interactive effect of food deprivation and agonistic behavior on blood parameters and muscle glycogen in pigs

Agonistic behavior, neuroendocrine and plasma metabolite changes, and muscle glycogen content were studied in 16 fed and 16 24 h-fasted domestic Large White pigs (100 ± 5 kg) submitted to dyadic encounters (30 min) in a novel environment. Comparisons were made with corresponding control pigs (eight fed and eight 24 h-fasted animals) kept under resting conditions. At rest, fasting resulted in a significant decrease in plasma insulin, increase in plasma-free fatty acids, and decrease in glycogen content in the predominantly red Semispinalis muscle. Fasted pigs displayed significantly more submissive acts than fed ones. In response to dyadic encounters, fed and fasted pigs showed similar rise in plasma levels of cortisol, catecholamines, and lactate, but stress-induced hyperglycemia was suppressed in food-deprived animals. Fasting enhanced stress-induced glycogen depletion in the predominantly white Longissimus muscle but this effect was significant only in fast-twitch glycolytic fibres (αW). In the Semispinalis of fasted pigs, however, dyadic encounters did not induce further glycogen depletion. The present findings suggest that in response to dyadic encounters, fasting-induced changes in glucose metabolism lead to a higher dependence on endogenous energy reserves, i.e., glycogen, in working muscles.

Thermogenic effect of amrinone in healthy men

The thermogenic effect of amrinone is unknown and its utilization in patients with severe cardiac failure could potentially increase oxygen requirements and therefore aggravate oxygen debt. Consequently, the present study was undertaken to assess the thermogenic response to amrinone at three different plasma concentrations under controlled conditions and to analyze amrinone's effects on various biochemical variables. A prospective, unblinded, controlled study. The initial control period was followed by three sequential, experimental treatments. Ten young, healthy, male volunteers with normal body weight. Three experimental periods. Amrinone was administered intravenously in progressive doses: a) 0.5 mg/kg followed by 5 micrograms/kg/min; b) 0.5 mg/kg followed by 10 micrograms/kg/min; and c) 1.0 mg/kg followed by 10 micrograms/kg/min. Oxygen consumption (VO2) and CO2 production were continuously measured by means of a computerized indirect calorimeter. At the highest dose, amrinone produced a slight and significant (p < .01) increase in VO2 and in resting metabolic rate (+4.5% and +3.7%, respectively), while no change in CO2 production or in respiratory quotient occurred throughout the study. At the medium and high doses, amrinone increased plasma free fatty acid concentrations by 38% and 53%, respectively (p < .05). No variation in plasma glucose, lactate, insulin, norepinephrine, or epinephrine concentrations was observed during the study. Amrinone administered intravenously at therapeutic doses has minimal thermogenic and metabolic effects in humans without cardiac failure.

Effects of estrogen on free fatty acid metabolism in humans

To determine whether estrogen directly affects effective adipose lipolysis, palmitate rate of appearances ([14C]palmitate) was measured in 15 postmenopausal women. Each volunteer was studied after > or = 2 mo of estrogen treatment and again after > or = 2 mo of estrogen deficiency. Plasma hormone concentrations were controlled and identical on the 2 study days with use of the pancreatic clamp technique, and the lipolytic response to epinephrine and epinephrine + phentolamine was assessed. Results showed that overall palmitate flux was greater (10-20%, P < 0.05) during the estrogen-deficient than during the estrogen-replete study. Adrenergic stimulation of lipolysis was not specifically influenced by estrogen treatment, and control of plasma hormone concentrations did not eliminate the difference in palmitate flux between the estrogen-deficient and estrogen-replete study days. We conclude that estrogen deficiency is associated with increased plasma free fatty acid availability and that estrogen likely has direct, albeit small, effects on adipose tissue lipolysis.

Hepatic vagotomy effects on metabolic challenges during parenteral nutrition in rats.

During parenteral nutrition (PN) glucoprivic-induced feeding appeared to be neutralized by the oxidation of infused fatty acids. With the use of a latin-square design, the feeding response to 2-deoxy-D-glucose (2-DG) and/or 2-mercaptoacetate (MA) was evaluated in male Sprague-Dawley rats with hepatic branch vagotomy (HV) or sham operations (SO). Rats received continuous infusions of 0.9% saline or PN providing 100% of daily caloric needs (PN-100) for four consecutive days. During PN-100, food intake was stimulated by 2-DG in HV rats and when fatty acid oxidation was simultaneously inhibited by MA. 2-DG-induced hyperglycemia was apparent under all conditions. Lipoprivic-induced feeding and increased plasma free fatty acid concentrations were absent in HV rats, whether MA was administered alone or with 2-DG. The feeding response to glucoprivic challenges is influenced by the relative availability of alternate energy sources. The lack of feeding response to 2-DG during PN-100 is mediated by vagal input of hepatic fatty acid oxidation status.

In vivo effect of free fatty acids on the specific binding of glucocorticosteroids to corticosteroid binding globulin and liver receptors in immature rats

Stimulating lipase activity with heparin (200 IU/kg b.w.) increased the plasma free fatty acid (FFA) concentration of immature rats (15 days). The effect of this elevated FFA concentration on glucocorticoid binding to corticosteroid binding globulin (CBG), and liver cytosol glucocorticoid receptor (GR), was analyzed. The plasma FFA concentration increased 2-fold, 10 minutes ( P < 0.001), 20 minutes ( P < 0.01), and 60 minutes ( P < 0.01) post-heparin. The corticosterone (B) and progesterone concentrations were unchanged 60 minutes post-injection. The binding activity of immature rat CBG for B dropped 50% ( P < 0.001) 60 minutes post-heparin injection, decreased B binding and increased plasma FFA were correlated ( r = −0.8 ). The decreased B binding resulted from a 2-fold decrease in the apparent number of CBG binding sites; the affinity constant (K a) remained unchanged. The liver cytosol endogenous FFA content of immature rats was also increased 2-fold, 60 minutes after heparin-induced lipolysis. The increased cytosol FFA, with no significant change in glucocorticoid, was accompanied by a significant decrease in dexamethasone binding to liver cytosol glucocorticoid receptor. The decrease resulted from a significantly lower apparent K a for dexamethasone and fewer receptor binding sites (n). There was a good inverse correlation between K a ( r = −0.93 ) and n ( r = −0.90 ) and the increased liver cytosol FFA content. Thus the higher plasma FFA induced in vivo by lipase activation or a standard FFA mixture probably causes conformational changes in CBG and GR, reducing glucocorticoid binding to immature rat CBG and liver GR.