The influence of plasma triglycerides on human growth hormone response to arginine and insulin: a study in hyperlipemics and normal subjects.

Human growth hormone (HGH) response to arginine (25 gm IV in 30 min) and to insulin (0.1 U/kg B.W.) was studied in 12 male patients (mean age 36 +/- 2 years), with normal glucose tolerance and normal body weight, affected with Fredrickson's Type IV primary hyperlipemia. The patients were examined both when plasma triglycerides (TG) were elevated and following clofibrate (2 gm/die for 30-60 days) induced TG reduction. No variations in glucose or FFA behaviour or in body weight were observed after clofibrate. HGH response to arginine was absent, while that to insulin was only inhibited, when plasma TG were elevated. A significant increase in HGH peaks after arginine (from 1.99 +/- 0.59 to 9.34 +/- 1.58 ng/ml) and a slight increment in HGH peaks after insulin (from 23.09 +/- 7.19 to 31.46 +/- 7.95 ng/ml) were observed following reduction in plasma TG. Arginine test was carried out in 7 normal subjects during saline infusion and at the 3rd hour of lipid infusion (Intralipid 20%). HGH response to arginine was absent in all of the subjects during lipid infusion. The HGH response to insulin test, carried out in 9 other normal subjects during saline infusion and at the 3rd hour of lipid infusion (Lipiphysan 15%) was significantly inhibited during lipid infusion. Since lipid infusion provoked an increment, not only in plasma TG but also in FFA, the inhibition of HGH release could be correlated with the elevated plasma levels of both TG and FFA. The results obtained in both spontaneous and experimental hyperlipemia not only confirm the role played by FFA in the regulation of HGH secretion, but also support the hypothesis that elevated TG levels could inhibit HGH response to some stimuli.     

Chronobiological pattern of growth hormone secretion in normal subjects and in retinopathic diabetics. Lack of suppression by a plurichronocorticoid drug.

Nyctohemeral variations in plasma concentrations of HGH, glucose, and FFA were studied in 22 normal subjects and 48 diabetic patients affected with retinopathy. In the normal subjects, (fourteen males and eight females, mean age 40+/-3 years; body weight less than 110% of I.B.W.) the determinations were made on blood samples drawn every hour. Seven of these normal subjects were examined before and after 10 days of administration of a new plurichronocorticoid drug (administered at 08(00) and 15(00), with a total amount of 14 mg of prednisolone and 15 mg of cortisone). In patients with diabetic retinopathy (32 male and sixteen female patients, mean age 46+/-2 years, body weight less than 110% of I.B.W.) the determinations were made on blood samples drawn every 3 hrs. All the diabetic patients were insulin treated and were under good or discrete metabolic control, and presented advanced retinopathy. Both in the normal subjects and in retinopathic diabetics, the mean HGH curve showed a characteristic elevation during the early nighttime hours (between 21(00) and 02(00). Despite higher values in plasma glucose and FFA, in diabetics the nocturnal elevation of HGH was only slightly lower than in the normals. The comparison between daytime and nighttime determinations, both in the normal subjects and in the diabetics, reveals statistically significant differences. These results suggest that in subjects with diabetic retinopathy, in the phase of good or discrete metabolic control, spontaneous HGH secretion is not increased, and that nocturnal elevation of HGH is not substantially influenced by higher plasma levels of glucose and FFA. Ten days of plurichronocorticoid treatment with a new drug which exhausts its activity before the evening, did not modify the circadian rhythm of HGH.     

Early effects of short-term endurance training on hormonal responses to graded exercise.

Twelve male, sedentary volunteers (22.0 +/-) were submitted to three weeks of a bicycle ergometer training, consisting of 45 min exercise (at 70% VO2max), 4 times in the first week and 3 times in the next 2 weeks. They performed four incremental exercise tests with the power output increased by 50 W every 3 min until volitional exhaustion: two before training (C1 and C2), and after one (T1) and three (T3) weeks of training. Before and after each load the plasma noradrenaline (NA), adrenaline (A) and blood lactate (LA) concentrations were determined in venous blood samples as well as plasma growth hormone (HGH) and cortisol concentrations before and at the end of exercise. A decrease in NA concentration was found already after 1 week of training at power output of 100 W (p<0.01) and 200 W (p<0.05). Similar decline was maintained after 3 weeks of training. No significant training-induced differences in plasma A concentration were found, however, the thresholds for both catecholamines were significantly shifted towards higher values after 3 weeks of training. One week of training caused a decrease in the pre-exercise (p<0.01), as well as post-exercise (p<0.05) plasma cortisol and HGH concentrations. It was concluded that endurance training induced a decrease in HGH, cortisol and NA concentration already after one week of training. A decline of pre-exercise plasma HGH and cortisol levels with time of experiment may, in part, indicate familiarization to exercise protocol.     

Effects of high fat provision on muscle PDH activation and malonyl-CoA content in moderate exercise.

This study examined the effects of elevated free fatty acid (FFA) provision on the regulation of pyruvate dehydrogenase (PDH) activity and malonyl-CoA (M-CoA) content in human skeletal muscle during moderate-intensity exercise. Seven men rested for 30 min and cycled for 10 min at 40% and 10 min at 65% of maximal O(2) uptake while being infused with either Intralipid and heparin (Int) or saline (control). Muscle biopsies were taken at 0, 1 (rest-to-exercise transition), 10, and 20 min. Exercise plasma FFA were elevated (0.99 +/- 0.11 vs. 0.33 +/- 0.03 mM), and the respiratory exchange ratio was reduced during Int (0.87 +/- 0.02) vs. control (0.91 +/- 0.01). PDH activation was lower during Int at 1 min (1.33 +/- 0.19 vs. 2.07 +/- 0.14 mmol. min(-1). kg(-1) wet muscle) and throughout exercise. Muscle pyruvate was reduced during Int at rest [0.17 +/- 0.03 vs. 0.25 +/- 0.03 mmol/kg dry muscle (dm)] but increased above control during exercise. NADH was higher during Int vs. control at rest and 1 min of exercise (0.122 +/- 0.016 vs. 0.102 +/- 0.005 and 0.182 +/- 0.016 vs. 0.150 +/- 0.016 mmol/kg dm), but not at 10 and 20 min. M-CoA was lower during Int vs. control at rest and 20 min of exercise (1.12 +/- 0.22 vs. 1.43 +/- 0.17 and 1.33 +/- 0.16 vs. 1.84 +/- 0.17 micromol/kg dm). The reduced PDH activation with elevated FFA during the rest-to-exercise transition was related to higher mitochondrial NADH at rest and 1 min of exercise and lower muscle pyruvate at rest. The decreased M-CoA may have increased fat oxidation during exercise with elevated FFA by reducing carnitine palmitoyltransferase I inhibition and increasing mitochondrial FFA transport.     

Effects of beta-adrenergic receptor stimulation and blockade on substrate metabolism during submaximal exercise

We used beta-adrenergic receptor stimulation and blockade as a tool to study substrate metabolism during exercise. Eight moderately trained subjects cycled for 60 min at 45% of VO(2 peak) 1) during a control trial (CON); 2) while epinephrine was intravenously infused at 0.015 microg. kg(-1) x min(-1) (beta-STIM); 3) after ingesting 80 mg of propranolol (beta-BLOCK); and 4) combining beta-BLOCK with intravenous infusion of Intralipid-heparin to restore plasma fatty acid (FFA) levels (beta-BLOCK+LIPID). beta-BLOCK suppressed lipolysis (i.e., glycerol rate of appearance) and fat oxidation while elevating carbohydrate oxidation above CON (135 +/- 11 vs. 113 +/- 10 micromol x kg(-1) x min(-1); P < 0.05) primarily by increasing rate of disappearance (R(d)) of glucose (36 +/- 2 vs. 22 +/- 2 micromol x kg(-1) x min(-1); P < 0.05). Plasma FFA restoration (beta-BLOCK+LIPID) attenuated the increase in R(d) glucose by more than one-half (28 +/- 3 micromol x kg(-1) x min(-1); P < 0.05), suggesting that part of the compensatory increase in muscle glucose uptake is due to reduced energy from fatty acids. On the other hand, beta-STIM markedly increased glycogen oxidation and reduced glucose clearance and fat oxidation despite elevating plasma FFA. Therefore, reduced plasma FFA availability with beta-BLOCK increased R(d) glucose, whereas beta-STIM increased glycogen oxidation, which reduced fat oxidation and glucose clearance. In summary, compared with control exercise at 45% VO(2 peak) (CON), both beta-BLOCK and beta-STIM reduced fat and increased carbohydrate oxidation, albeit through different mechanisms.     

Serum glucose and free fatty acids modulate growth hormone and luteinizing hormone secretion in the pig

Two experiments were conducted to determine the effect of free fatty acids (FFA) and glucose treatment on growth hormone (GH) and luteinizing hormone secretion in the pig. In Experiment (Exp) 1, 15 prepuberal gilts received an intravenous infusion of FFA (n = 5; 3 ml of 10% Liposyn II/kg), glucose (n = 5; 1 g/kg), or saline (n = 5; 3 ml of 0.9%/kg). Jugular blood samples were collected every 15 min for 2 hr before and 3 hr after intravenous infusion of saline, FFA, and glucose. Synthetic [Ala15]-h growth hormone-releasing factor-(1-29)NH2 (1 microgram/kg) and gonadotropin-releasing hormone (0.2 micrograms/kg) were administered 30 min after infusion (Time 0 = infusion). In Exp 2, eight prepuberal gilts received either FFA (n = 4) or saline (n = 4) as described in Exp 1, except that treatments were given every hour ove a 10-hr period. Blood samples were collected every 15 min from 1 hr before to 10 hr after the start of FFA or saline infusion. In Exp 1, the peak GH response to growth hormone-releasing factor was delayed by 45 min (P less than 0.01) by glucose treatment and suppressed (P less than 0.01) by FFA treatment. The luteinizing hormone response to gonadotroph-releasing hormone was suppressed (P less than 0.03) by glucose and enhanced (P less than 0.03) by FFA. In Exp 2, the number of GH pulses was increased (P less than 0.05) by FFA infusion and GH concentrations were positively correlated (r = 0.58, P less than 0.0003) with FFA concentrations, while luteinizing hormone pulse amplitude was greater (P less than 0.01) in FFA gilts than in saline gilts. These results indicate that FFA are more effective modulators of GH secretion than acute hyperglycemia, while metabolic status can alter pituitary responsiveness to gonadotropin-releasing hormone.     

Decrease in human growth hormone (HGH) levels during transsphenoidal surgery for acromegaly as a guide for prognosis

To evaluate the clinical significance of human growth hormone (HGH) dynamics during transsphenoidal microsurgery for acromegaly, serial HGH levels during the surgery were compared with the post-operative basal HGH levels in 15 acromegalic patients, retrospectively. In all patients, in whom the HGH level immediately after tumor resection was reduced below 5 ng/ml or the decreasing rate which stood for the magnitude of decrease of HGH during resection procedure was above 80%, postoperative permanent HGH levels fell to below 5 ng/ml, namely, within the normal range. The rapid radioimmunoassay (RIA) of HGH was developed by the use of high affinity antibody in order to inform the surgeons of plasma HGH levels quickly during the surgery. It is now possible to know HGH levels about 1 hour after submitting the samples. It was verified that HGH levels measured in the rapid RIA correlated well with those obtained in the conventional way. The rapid RIA method was applied to 6 patients and the correlation between HGH levels during the surgery and post operative levels was also studied prospectively. The results were essentially identical to those in a retrospective study. It was suggested that the HGH level immediately after tumor resection and the extent of the decrease in HGH during the resection procedure were good indicators of the prognosis of surgical results in acromegaly and the rapid RIA method was useful in order to judge HGH levels quickly during the surgery.     

Enhancement of beta-cell sensitivity to glucose by oral fat load.

Recent studies have demonstrated that 6 h infusions of lipid emulsion enhance insulin release, whereas 24 h infusions inhibit insulin secretion. How insulin release is modulated after oral fat loading has not yet been elucidated. 17 healthy fasting volunteers were subjected to 3 experiments in random order: test 1 was a frequently sampled i. v. glucose tolerance test (FSIVGTT, 0.3 g/kg glucose), test 2 began with the ingestion of 50 % sunflower oil (1.5 g/kg) followed by FSIVGTT 4 h later. Test 3 was identical to test 2 with i. v. addition of 100 U/kg heparin prior to FSIVGTT. Glucose and insulin data were analyzed by minimal model assumptions - glucose sensitivity of the beta-cells (Theta1), acute insulin response (AIR) (10 min), 3 h insulin release (Theta2), glucose threshold of insulin secretion (h), insulin degradation rate (n), peripheral insulin sensitivity (S(I)), and glucose-dependent glucose disposal (S(G)). After drinking the fat emulsion, FFAs increased to 0.8 +/- 0.3 mmol/l (test 2) and to 3.0 +/- 0.3 mmol/l (test 3). Moderately increased FFA concentrations were associated with elevation of Theta1 (test 1, control 335 +/- 157 vs. test 2: 859 +/- 612 pM x min x mM(-1), p = 0.030). At high plasma FFA levels and in the presence of heparin (test 3), Theta1 was reduced compared to test 2 and unchanged compared to test 1. Theta2 and h were elevated in both tests 2 and 3 compared to test 1. No changes of n, S(I) and S(G) were found. In conclusion, the ingestion of sunflower oil triglyceride emulsion resulted in a 60 % increase in plasma free fatty acids and enhanced the capacity of beta-cells to secrete insulin. Heparin-induced high levels of FFA further augmented the total insulin release and inhibited parameters of glucose responsiveness.     

FFA cause hepatic insulin resistance by inhibiting insulin suppression of glycogenolysis

Free fatty acids (FFA) have been shown to inhibit insulin suppression of endogenous glucose production (EGP). To determine whether this is the result of stimulation by FFA of gluconeogenesis (GNG) or glycogenolysis (GL) or a combination of both, we have determined rates of GNG and GL (with (2)H(2)O) and EGP in 16 healthy nondiabetic volunteers (11 males, 5 females) during euglycemic-hyperinsulinemic (~450 pM) clamping performed either with or without simultaneous intravenous infusion of lipid plus heparin. During insulin infusion, FFA decreased from 571 to 30 micromol/l (P < 0.001), EGP from 15.7 to 2.0 micromol x kg(-1) x min(-1) (P < 0.01), GNG from 8.2 to 3.7 micromol x kg(-1). min(-1) (P < 0.05), and GL from 7.4 to -1.7 micromol x kg(-1). min(-1) (P < 0.02). During insulin plus lipid/heparin infusion, FFA increased from 499 to 1,247 micromol/l (P < 0.001). EGP decreased 64% less than during insulin alone (-5.1 +/- 0.7 vs. -13.7 +/- 3.4 micromol x kg(-1). min(-1)). The decrease in GNG was not significantly different from the decrease of GNG during insulin alone (-2.6 vs. -4.5 micromol x kg(-1). min(-1), not significant). In contrast, GL decreased 66% less than during insulin alone (-3.1 vs. -9.2 micromol x kg(-1). min(-1), P < 0.05). We conclude that insulin suppressed EGP by inhibiting GL more than GNG and that elevated plasma FFA levels attenuated the suppression of EGP by interfering with insulin suppression of GL.     

Kinetics of intramuscular triglyceride fatty acids in exercising humans.

A pulse ([(14)C]palmitate)-chase ([(3)H]palmitate) approach was used to study intramuscular triglyceride (imTG) fatty acid and plasma free fatty acid (FFA) kinetics during exercise at approximately 45% peak O(2) consumption in 12 adults. Vastus lateralis muscle was biopsied before and after 90 min of bicycle exercise; (3)H(2)O production, breath (14)CO(2) excretion and lipid oxidation (indirect calorimetry) rates were measured during exercise. Results: during exercise, 8.2+/-1.2 and 8.4+/-0.7 micromol x kg(-1) x min(-1) of imTG fatty acids and plasma FFA, respectively, were oxidized according to isotopic measurements. The sum of these two values was not different (P = 0.6) from lipid oxidation by indirect calorimetry (15.4 +/-1.6 micromol x kg(-1) x min(-1)); the isotopic and indirect calorimetry values were correlated (r = 0.79, P<0.005). During exercise, imTG turnover rate was 0.32+/-0.07%/min (6.0+/-2.0 micromol of imTG x kg wet muscle(-1) x min(-1)) and plasma FFA were incorporated into imTG at a rate of 0.7+/-0.1 micromol x kg wet muscle(-1) x min(-1). The imTG pool size did not change during exercise. This pulse-chase, dual tracer appears to be a reasonable approach to measure oxidation and synthesis kinetics of imTG.     

Influence of carnitine supplementation on muscle substrate and carnitine metabolism during exercise

We examined 1) the effect of L-carnitine supplementation on free fatty acid (FFA) utilization during exercise and 2) exercise-induced alterations in plasma levels and skeletal muscle exchange of carnitine. Seven moderately trained human male subjects serving as their own controls participated in two bicycle exercise sessions (120 min, 50% of VO2max). The second exercise was preceded by 5 days of oral carnitine supplementation (CS; 5 g daily). Despite a doubling of plasma carnitine levels, with CS, there were no effects on exercise-induced changes in arterial levels and turnover of FFA, the relation between leg FFA inflow and FFA uptake, or the leg exchange of other substrates. Heart rate during exercise after CS decreased 7-8%, but O2 uptake was unchanged. Exercise before CS induced a fall from 33.4 +/- 1.6 to 30.8 +/- 1.0 (SE) mumol/l in free plasma carnitine despite a release (2.5 +/- 0.9 mumol/min) from the leg. Simultaneously, acylated plasma carnitine rose from 5.0 +/- 1.0 to 14.2 +/- 1.4 mumol/l, with no evidence of leg release. Consequently, total plasma carnitine increased. We concluded that in healthy subjects CS does not influence muscle substrate utilization either at rest or during prolonged exercise and that free carnitine released from muscle during exercise is presumably acylated in the liver and released to plasma.     

Sulfonylurea therapy fails to diminish insulin resistance in type I-diabetic subjects

To assess whether extrapancreatic effects of sulfonylureas in vivo are detectable in the absence of endogenous insulin secretion, insulin sensitivity was determined in six insulin-deficient type 1-diabetic subjects. Peripheral uptake and hepatic production of glucose and lipolysis were measured during hyperinsulinemia using the euglycemic clamp technique and 3-3H-glucose infusions twice, once during a period with glibornuride treatment (50 mg b.i.d.), and once without. Hepatic glucose production decreased in diabetic subjects during hyperinsulinemia (insulin infusion of 20 mU/m2 X min; plasma free insulin levels of 40 +/- 4 mU/l) from 2.9 +/- 0.6 mg/kg min to 0.2 +/- 0.1 mg/kg X min after 120 min, and plasma free fatty acid (FFA) concentrations decreased from 1.33 +/- 0.29 to 0.38 +/- 0.08 mmol/l. Hepatic production, peripheral uptake of glucose and plasma FFA concentrations before and during hyperinsulinemia were not influenced by pretreatment with glibornuride. Compared to 8 non-diabetic subjects, type 1-diabetics demonstrated a diminished effect of hyperinsulinemia on peripheral glucose clearance (2.4 +/- 0.04 vs 4.2 +/- 0.5 ml/kg X min, P less than 0.01), whereas hepatic glucose production and plasma FFA levels were similarly suppressed by insulin. The data indicate that sulfonylurea treatment did not improve the diminished insulin sensitivity of peripheral glucose clearance in type 1-diabetic subjects; insulin action on hepatic glucose production and lipolysis was unimpaired in diabetics and remained uninfluenced by glibornuride. Thus, extrapancreatic effects of sulfonylureas in vivo are dependent on the presence of functioning beta-cells.     

The relation between free fatty acid levels and tolerance for glucose in a triple glucose tolerance test

The improved glucose tolerance observed in a multiple glucose tolerance test (Staub-Traugott effect) has been observed in dogs with concomitant measurement of immunoreactive insulin (IRI) and plasma free fatty acid (FFA). It was possible to reduce and in one experiment eliminate the improved glucose tolerance observed in the Staub-Traugott procedure. This was done in successive experiments in which the glucose challenge dose was 1 × BW^{0 period; 7} grams: (1) by injecting octanoate (0.1 mmoles/kg each hour) at the same time as the glucose; (2) by supplementing the injections with the infusion of octanoate (0.1 mmoles/kg/15 mins) during the second and third hours; (3) by repeating this last procedure after a seven day fast. Similar experiments were carried out with a larger glucose challenge dose (1 g/kg).Glucose tolerance appeared to depend as strongly on FFA levels as it did on IRI levels, and improvement in glucose tolerance occurred only when there was an associated reduction in FFA for a given glucose challenge. A measure of the Staub-Traugott effect was defined in terms of the different glucose utilizations during a multiple glucose tolerance test. An increase in the mean FFA levels achieved before or during a multiple glucose tolerance test lessened or eliminated the Staub-Traugott effect.     

Effects of reduced free fatty acid availability on hormone-sensitive lipase activity in human skeletal muscle during aerobic exercise.

Hormone-sensitive lipase (HSL) catalyzes the hydrolysis of intramuscular triacylglycerol (IMTG); however, its regulation in skeletal muscle is poorly understood. To examine the effects of reduced free fatty acid (FFA) availability on HSL activity in skeletal muscle during aerobic exercise, 11 trained men exercised at 55% maximal O2 uptake for 40 min after the ingestion of nicotinic acid (NA) or nothing (control). Muscle biopsies were taken at rest and 5, 20, and 40 min of exercise. Plasma FFA were suppressed (P < 0.05) in NA during exercise ( approximately 0.40 +/- 0.04 vs. approximately 0.07 +/- 0.01 mM). The respiratory exchange ratio (RER) was increased throughout exercise (0.020 + 0.008) after NA ingestion. However, the provision of energy from fat oxidation only decreased from 33% of the total in the control trial to 26% in the NA trial, suggesting increased IMTG oxidation in the NA trial. Mean HSL activity was 2.25 + 0.15 mmol x kg dry mass(-1) x min(-1) at rest and increased (P < 0.05) to 2.94 +/- 0.20 mmol x kg dry mass(-1) x min(-1) at 5 min in control. Contrary to the hypothesis, mean HSL was not activated to a greater extent in the NA trial during exercise (2.20 + 0.28 at rest to 2.88 + 0.21 mmol x kg dry mass(-1) x min(-1) at 5 min). No further HSL increases were observed at 20 or 40 min in both trials. There was variability in the response to NA ingestion, as some subjects experienced a large increase in RER and decrease in fat oxidation, whereas other subjects experienced no shift in RER and maintained fat oxidation despite the reduced FFA availability in the NA trial. However, even in these subjects, HSL activity was not further increased during the NA trial. In conclusion, reduced plasma FFA availability accompanied by increased epinephrine concentration did not further activate HSL beyond exercise alone.     

Changes in free fatty acids and diglycerides in mouse brain at birth and during anoxia

Abstract: Within the first few hours of life in the mouse, marked changes were seen in brain endogenous free fatty acids (FFA). A 21% decrease in the total FFA pool occurred during the 1st h of life, and a constant value was maintained thereafter to 10 h. Polyunsaturated fatty acids displayed a different pattern of change. There was 27% less free ararhidonic acid at birth (0 h) than 1 h later. Similar values were obtained for docosahexaenoic acid at birth and at 10 h, although palmitoleic and oleic acids decreased markedly after 1 h. The polyunsaturated fatty acyl chains of diglycerides (DG) showed a statistically significant increase as a function of time after birth, despite an unchanged total DG pool size. The brains of pups subjected to 40 min of N₂-anoxia immediately after delivery exhibited a decrease in FFA, especially the monoenoic components, but 60 min of anoxia yielded higher FFA levels. Anoxia induced at 10 h increased FFA and arachidonic acid was higher than when anoxia was induced at 0 h. FFA accumulation was further stimulated by raising the environmental temperature during anoxia. When anoxia was induced, DG exhibited a net increase in palmitate, oleate, and palmitoleate at 0 and 10 h. No arachidonoyl-DG accumulated at 0 h, even after 60 min of anoxia, and stearate was unchanged at 0 and 10 h. The lipid changes observed in the brain during the first hours of life suggest that the enzymatic reactions that promote accumulation of free arachidonic and docosahexaenoic acids and arachidonoyl-DG in the mature brain are present at low levels at the time of delivery. The sluggish modifications found in our study may be related to the longer resistance of newborns to oxygen deficiency.     

Muscle triglyceride utilization during exercise: effect of training

The respiratory exchange ratio (RER) is lower during exercise of the same intensity in the trained compared with the untrained state, even though plasma free fatty acids (FFA) and glycerol levels are lower, suggesting reduced availability of plasma FFA. In this context, we evaluated the possibility that lipolysis of muscle triglycerides might be higher in the trained state. Nine adult male subjects performed a prolonged bout of exercise of the same absolute intensity before and after adapting to a strenuous 12-wk program of endurance exercise. The exercise test required 64% of maximum O2 uptake before training. Plasma FFA and glycerol concentrations and RER during the exercise test were lower in the trained than in the untrained state. The proportion of the caloric expenditure derived from fat, calculated from the RER, during the exercise test increased from 35% before training to 57% after training. Muscle glycogen utilization was 41% lower, whereas the decrease in quadriceps muscle triglyceride concentration was roughly twice as great (12.7 +/- 5.5 vs. 26.1 +/- 9.3 mmol/kg dry wt, P less than 0.001) in the trained state. These results suggest that the greater utilization of FFA in the trained state is fueled by increased lipolysis of muscle triglyceride.     

Effect of elevated FFA on carbohydrate and lipid oxidation during prolonged exercise in humans

Increased availability of circulating free fatty acids (FFA) inhibits the rate of glycolysis in heart and resting skeletal muscle (Randle effect). Whether elevated FFA may play a role in decreasing carbohydrate oxidation during prolonged exercise in humans is more controversial. Using respiratory exchange measurements, we measured substrate utilization during 2.5 h of exercise at approximately 44 +/- 1% maximal O2 uptake (VO2 max) in the presence or absence of elevated FFA levels. After 30 min of base-line determinations, 1,000 U heparin was given intravenously and a 3-h constant infusion of Intralipid 10% (150 g/h) and heparin (500 U/h) was started. After an additional 30 min of rest, subjects exercised for 2.5 h (study 1, n = 6). In another five subjects (study 2) 100 g glucose was ingested after 30 min of exercise. The same protocols (studies 1 and 2) were also performed during a 0.9%-saline infusion. During exercise, without glucose ingestion, higher FFA concentrations prevailed during the Intralipid infusion (1,122 +/- 40 vs. 782 +/- 65 mumol/l), but the relative contributions of carbohydrate (49 +/- 4 vs. 50 +/- 4%) or lipid (49 +/- 4 vs. 47 +/- 6%) oxidation to the total energy expenditure were different only during the first 30 min of exercise. Similarly, higher FFA levels (1,032 +/- 62 vs. 568 +/- 46 mumol/l) did not alter the relative contributions of carbohydrate (62 +/- 4 vs. 69 +/- 2%) or lipid (36 +/- 4 vs. 29 +/- 2%) oxidation to the total energy expenditure after glucose feeding.(ABSTRACT TRUNCATED AT 250 WORDS)     

Preventive effect of naringin on lipids, lipoproteins and lipid metabolic enzymes in isoproterenol-induced myocardial infarction in Wistar rats

This study was designed to evaluate the preventive effect of naringin in isoproterenol (ISO)-induced myocardial infarction (MI) in rats. Rats were pretreated with naringin (10, 20, and 40 mg/kg body weight) orally for a period of 56 days. After the treatment period, ISO (85 mg/kg body weight) was administered subcutaneously to rats at an interval of 24 h for 2 days. There was a significant increase in the levels of total, ester, and free cholesterol, triglycerides (TG), and free fatty acids (FFA) in serum and heart and decrease in heart phospholipids (PL) in ISO-induced rats. Altered levels of lipoproteins and activities of 3-hydroxy-3-methylglutaryl-Coenzyme reductase A in liver and heart, lecithin cholesterol acyl transferase and lipoprotein lipase in plasma were also observed in ISO-induced rats. Pretreatment with naringin (10, 20, and 40 mg/kg) for a period of 56 days significantly decreased the levels of total, ester, and free cholesterol, TG, FFA in serum and heart and increased PL in heart. It also minimized the alterations in serum lipoproteins and lipid metabolic enzymes in ISO-induced rats. Thus, naringin has a lipid-lowering effect in ISO-induced MI rats.     

Exercise training and the differential prolactin response in male and female rats

Adult male and female Sprague-Dawley rats were trained on a horizontal treadmill for 0, 1, 3, 5, or 7 days/wk for 10 wk. Speed and duration were progressively increased over 5 wk to a maximum of 20 m/min for 1 h. Between weeks 9 and 10 of training, animals were placed on the nonmoving treadmill, and blood (500 microliters) was sampled via chronic venous cannulas 30 min before, 0, 10, 20, 30, 45, and 60 min during exercise, and 15, 30, 60, 90, and 120 min after exercise. In another study, resting animals in the various groups were injected with thyrotropin-releasing hormone (TRH; 2 micrograms/kg for males and 0.4 microgram/kg for females) to determine pituitary prolactin responsiveness. In males, exercise induced a significant increase in plasma prolactin levels, with the greatest increase observed in the least trained and the smallest increase in the most highly trained animals. Female rats displayed the opposite trend with the greatest increase in prolactin secretion observed in the highest trained and the smallest increase observed in the least trained animals. TRH induced similar increases in plasma prolactin in all male groups, whereas TRH-induced prolactin release was greatest in the highest trained and smallest in the least trained females. The reduced prolactin response in highly trained males may reflect their acclimation to repetitive exercise stress, whereas the enhanced response in the highly trained female rats appears to result from increased pituitary sensitivity to prolactin-releasing factors.     

Suppressing lipolysis increases interleukin-6 at rest and during prolonged moderate-intensity exercise in humans.

IL-6 induces lipolysis when administered to humans. Consequently, it has been hypothesized that IL-6 is released from skeletal muscle during exercise to act in a "hormonelike" manner and increase lipolysis from adipose tissue to supply the muscle with substrate. In the present study, we hypothesized that suppressing lipolysis, and subsequent free fatty acid (FFA) availability, would result in a compensatory elevation in IL-6 at rest and during exercise. First, we had five healthy men ingest nicotinic acid (NA) at 30-min intervals for 120 min at rest [10 mg/kg body mass (initial dose), 5 mg/kg body mass (subsequent doses)]. Plasma was collected and analyzed for FFA and IL-6. After 120 min, plasma FFA concentration was attenuated (0 min: 0.26 +/- 0.05 mmol/l; 120 min: 0.09 +/- 0.02 mmol/l; P < 0.01), whereas plasma IL-6 was concomitantly increased approximately eightfold (0 min: 0.75 +/- 0.18 pg/ml; 120 min: 6.05 +/- 0.89 pg/ml; P < 0.001). To assess the effect of lipolytic suppression on the exercise-induced IL-6 response, seven active, but not specifically trained, men performed two experimental exercise trials with (NA) or without [control (Con)] NA ingestion 60 min before (10 mg/kg body mass) and throughout (5 mg/kg body mass every 30 min) exercise. Blood samples were obtained before ingestion, 60 min after ingestion, and throughout 180 min of cycling exercise at 62 +/- 5% of maximal oxygen consumption. IL-6 gene expression, in muscle and adipose tissue sampled at 0, 90, and 180 min, was determined by using semiquantitative real-time PCR. IL-6 mRNA increased in Con (rest vs. 180 min; P < 0.01) approximately 13-fold in muscle and approximately 42-fold in fat with exercise. NA increased (rest vs. 180 min; P < 0.01) IL-6 mRNA 34-fold in muscle, but the treatment effect was not statistically significant (Con vs. NA, P = 0.1), and 235-fold in fat (Con vs. NA, P < 0.01). Consistent with the study at rest, NA completely suppressed plasma FFA (180 min: Con, 1.42 +/- 0.07 mmol/l; NA, 0.10 +/- 0.01 mmol/l; P < 0.001) and increased plasma IL-6 (180 min: Con, 9.81 +/- 0.98 pg/ml; NA, 19.23 +/- 2.50 pg/ml; P < 0.05) during exercise. In conclusion, these data demonstrate that circulating IL-6 is markedly elevated at rest and during prolonged moderate-intensity exercise when lipolysis is suppressed.