Free Fatty Acid Turnover Research Articles

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.

Effect of endurance training on fatty acid metabolism during whole body exercise.

Endurance exercise training increases fat oxidation during large muscle mass exercise. Although the source of this fat has been thought to be plasma free fatty acids (FFA) released from adipose tissue, the training-induced decrease in lipolytic hormonal responses to exercise is not consistent with this concept. The purpose of this communication is to review findings, from our laboratory indicating that, in young healthy subjects, endurance exercise training reduces plasma FFA turnover and oxidation during moderate intensity prolonged 2-leg cycling while simultaneously enhancing depletion of triglycerides from the active musculature. Evidence is presented that metabolism of intramuscular triglycerides can explain the increase in total fat oxidation observed in the trained state during large muscle mass exercise. However, these results may not be applicable to exercise involving small muscle groups, a distinction that is likely to be important in explaining the apparent conflict between our findings and those from other laboratories where experimental conditions were different. In summary, for large muscle mass exercise up to 2 h in duration, plasma FFA are a less important fuel source in the trained state, and intramuscular triglycerides supply the major portion of the increase in oxidized fatty acids.

Metabolic effects of liver transplantation in cirrhotic patients.

To assess whether liver transplantation (LTx) can correct the metabolic alterations of chronic liver disease, 14 patients (LTx-5) were studied 5+/-1 mo after LTx, 9 patients (LTx-13) 13+/-1 mo after LTx, and 10 patients (LTx-26) 26+/-2 months after LTx. Subjects with chronic uveitis (CU) and healthy volunteers (CON) were also studied. Basal plasma leucine and branched-chain amino acids were reduced in LTx-5, LTx-13, and LTx-26 when compared with CU and CON (P < 0.01). The basal free fatty acids (FFA) were reduced in LTx-26 with respect to CON (P < 0.01). To assess protein metabolism, LTx-5, LTx-13, and LTx-26 were studied with the [1-14C]leucine turnover combined with a 40-mU/m2 per min insulin clamp. To relate changes in FFA metabolism to glucose metabolism, eight LTx-26 were studied with the [1-14C]palmitate and [3-3H]glucose turnovers combined with a two-step (8 and 40 mU/m2 per min) euglycemic insulin clamp. In the postabsorptive state, LTx-5 had lower endogenous leucine flux (ELF) (P < 0.005), lower leucine oxidation (LO) (P < 0.004), and lower non-oxidative leucine disposal (NOLD) (P < 0.03) with respect to CON (primary pool model). At 2 yr (LTx-26) both ELF (P < 0.001 vs. LTx-5) and NOLD (P < 0.01 vs. LTx-5) were normalized, but not LO (P < 0.001 vs. CON) (primary and reciprocal pool models). Suppression of ELF by insulin (delta-reduction) was impaired in LTx-5 and LTx-13 when compared with CU and CON (P < 0.01), but normalized in LTx-26 (P < 0.004 vs. LTx-5 and P = 0.3 vs. CON). The basal FFA turnover rate was decreased in LTx-26 (P < 0.01) and CU (P < 0.02) vs. CON. LTx-26 showed a lower FFA oxidation rate than CON (P < 0.02). Tissue glucose disposal was impaired in LTx-5 (P < 0.005) and LTx-13 (P < 0.03), but not in LTx-26 when compared to CON. LTx-26 had normal basal and insulin-modulated endogenous glucose production. In conclusion, LTx have impaired insulin-stimulated glucose, FFA, and protein metabolism 5 mo after surgery. Follow-up at 26 mo results in (a) normalization of insulin-dependent glucose metabolism, most likely related to the reduction of prednisone dose, and, (b) maintenance of some alterations in leucine and FFA metabolism, probably related to the functional denervation of the graft and to the immunosuppressive treatment.

Chylomicron metabolism in rats: lipolysis, recirculation of triglyceride-derived fatty acids in plasma FFA, and fate of core lipids as analyzed by compartmental modelling

Chylomicrons labeled in vivo with [14C]oleic acid (primarily in triglycerides (TG), providing a tracer for lipolysis) and [3H]retinol (primarily in ester form, providing a tracer for the corelipids) were injected into rats. Disappearance of the two labels from plasma and appearance of label in plasma free fatty acids (FFA) were analyzed by compartmental modelling. Both core and TG label distributed into an apparent volume 10-15% larger than the blood volume. Part of this probably represents margination to endothelial-binding-lipolysis sites. An open two-compartmental model for plasma FFA was derived from experiments where unesterified oleic acid complexed to albumin was injected. Applying this model revealed that most of the oleic acid from chylomicron triglycerides mixes with the FFA. The disappearance of chylomicron core label required a model in which the label transfers into a second compartment before it leaves the blood. The rate constant for the transformation was high and predicted that, on average, chylomicron spent less than 2 min in the first compartment. The rate out from the second compartment predicted that about 60% of the core label left blood while, on average, chylomicron retained more than half of its triglyceride molecules, i.e., after rather limited lipolysis. The mechanism by which the core label leaves blood is not clear. Modelling showed that under the assumption that the process is shared by chylomicron triglycerides, about half of them go out by this pathway. Comparing fed and fasted rats, the main differences were in the turnover of FFA and in the extent to which chylomicron TG label reappeared in the FFA. This study indicates that a large fraction of the triglycerides in chylomicrons leave plasma together with the core lipids and that most of the fatty acids from chylomicron triglycerides mix into the same metabolic compartments as do plasma free fatty acids.

Effect of pancreas transplantation on free fatty acid metabolism in uremic IDDM patients.

To assess the effect of pancreas transplantation on free fatty acid (FFA) and glucose metabolism, we studied seven uremic IDDM patients (HbA1c 9.1%), nine IDDM patients after combined kidney-pancreas transplantation (HbA1c 5.8%), seven patients with chronic uveitis (HbA1c 5.6%), and nine normal control subjects (HbA1c 5.5%) by means of the [3(- 3)H]glucose and [1(-14)C]palmitate infusion techniques combined with indirect calorimetry and euglycemic insulin clamp. In the postabsorptive state, pancreas-transplant patients had similar plasma glucose and FFA concentrations and non-statistically different rates of hepatic glucose production (HGP) and FFA turnover, while demonstrating a reduced rate of FFA oxidation (42 +/- 5 vs. 73 +/- 10 micromol x m-2 x min-1; P < 0.05) compared with control subjects. After 180 min of tracer equilibration, all subjects underwent a low-dose (100 min, 8 mU x m-2 x min-1) followed by a high-dose (100 min, 40 mU x m-2 x min-1) euglycemic insulin infusion. During insulin infusion, pancreas-transplant patients showed a greater inhibition of FFA concentration (609 +/- 76 to 58 +/- 15 micromol/l) compared with healthy subjects (681 +/- 90 to 187 +/- 25 micromol/l; P < 0.01 vs. pancreas-transplant patients). FFA turnover and oxidation rates during both low-dose and high-dose insulin infusions were lower in pancreas-transplant patients compared with healthy subjects (P < 0.03 and P < 0.01, for turnover and oxidation, respectively). Uremic IDDM patients demonstration altered basal and insulin-mediated glucose metabolism. Pancreas transplantation normalized only insulin-mediated glucose oxidation, leaving the stimulation of non-oxidative glucose disposal still markedly defective. In conclusion, patients after pancreas transplantation have normal basal FFA turnover and reduced basal FFA oxidation rates. During hyperinsulinemia, pancreas-transplant patients show a normal inhibition of FFA turnover and FFA oxidation. Insulin-mediated glucose metabolism remained abnormal after pancreas transplantation. Our findings may be related to the effect of chronic immunosuppressive therapy on glucose and FFA metabolism.

A Comparison of Fat Utilization during Exercise: Walking and Swimming

Women, considering swimming as a form of exercise to lose weight, have been discouraged from doing so, since researchers suggest that swimming does not burn fat as efficiently as land exercise. The purpose of this study was to compare carbohydrate and fat utilization by women engaging in two different forms of exercise, walking and swimming, at the same intensity and duration. Subjects were 20 moderately trained female subjects, walkers (W) = 10 and swimmers (S) = 10; ages 18-40 years. Measurements of blood free fatty acids (FFA), glycerol, lactate, glucose, free fatty acid turnover (FFAT), respiratory quotient (RQ), and fat oxidation were made during 60 minutes of walking or swimming at the same exercise intensity. Multivariate analysis of variance determined no significant differences between groups in net energy expenditure (NEE), RQ, fat oxidation, blood FFA, glycerol, glucose, and FFAT(p &gt; .05). There was a significant difference between groups in blood lactic acid levels (p &lt; .01). Since it was found that swimming and walking at the same duration and intensity bum similar amounts of fat and carbohydrate as energy sources during exercise, women may find swimming to be a viable form of exercise for weight control.

Decreasing triglyceride by gemfibrozil therapy does not affect the glucoregulatory or antilipolytic effect of insulin in nondiabetic subjects with mild hypertriglyceridemia

We studied the effects of gemfibrozil on glucose and fatty acid metabolism in subjects with mild endogenous hypertriglyceridemia. Twenty subjects (serum triglycerides, 3.2 ± 1.4 mmol/L; age, 52 ± 7 years; body mass index, 27.8 ± 1.8 kg/m 2) were randomly allocated to receive either placebo or gemfibrozil 1,200 mg daily for 12 weeks in a double-blind study. Gemfibrozil decreased serum total and very—low-density lipoprotein (VLDL) triglycerides by 53% and 57%, respectively, and serum apolipoprotein (apo) B concentration by 21%. Gemfibrozil had no effect on the diurnal concentration of free fatty acids (FFA). Neither did gemfibrozil change diurnal blood glucose or serum insulin concentrations. The endogenous glucose production rate remained unchanged in both groups during the treatment period, and was similarly suppressed by hyperinsulinemia. The rate of insulin-induced whole-body glucose disposal increased similarly both before (basal 10.8 ± 1.8, low-dose insulin 10.5 ± 2.1, and high-dose insulin 20.9 ± 11.9 μmol · kg −1 · min −1) and after (11.1 ± 1.7, 10.7 ± 1.2, and 18.6 ± 7.9, respectively) gemfibrozil treatment. Rates of oxidative and nonoxidative glucose metabolism remained unchanged during gemfibrozil treatment. Basal pretreatment and posttreatment FFA turnover rates were similar in both study groups, as were the rates of substrate oxidation. In summary, gemfibrozil proved to be an effective serum triglyceride-lowering agent in patients with mild hypertriglyceridemia, but had no effect on the insulin sensitivity of glucose metabolism or of antilipolysis. These data support the idea that triglycerides per se do not cause insulin resistance, and that the triglyceride-lowering effect of gemfibrozil is not mediated via antilipolytic action.

Effects of dexfenfluramine on free fatty acid turnover and oxidation in obese patients with type 2 diabetes mellitus

To test the potential effects of dexfenfluramine (dF) on enhancing free fatty acid (FFA) turnover and oxidation rates, 11 obese female non—insulin-dependent diabetes mellitus (NIDDM) outpatients (age, 52.5 ± 1.5 years; weight, 81.3 ± 3.2 kg; height, 158 ± 3.04 cm; body mass index, 32.4 ± 0.7 kg/m 2) received a primed-constant infusion of 1- 14C-palmitate. The waist to hip ratio (WHR) was 0.91 ± 0.04. Fat body mass and lean body mass, assessed by dual-energy x-ray densitometry, were 32.0 ± 1.5 and 49.30 ± 2.67 kg, respectively. All patients had an average hemoglobin A 1 of 6.3% ± 0.3% in the month preceding the study and had not received oral hypoglycemic agents. Gas exchange was measured both basally and during a ventilated-hood system, indirect-calorimetry session. The protocol was a randomized, placebo-controlled, single-blind design. Subjects received dF 30 mg acutely (n = 6) or a placebo (n = 5). A dose of dF 15 mg twice daily or placebo was then administered over 15 days (chronic). To obtain serum peak level of the drug, dF was administered 2 hours before starting palmitate infusion. A free diet was allowed throughout the study, and the group treated with dF lost approximately 0.5 kg body weight. Acute and chronic dF administration resulted in a significant increase in FFA oxidation, expressed as a percentage of the dose of radiocarbon (respectively, 11.47% ± 0.46% v 9.50% ± 0.46% [ P < .01] and 12.06% ± 0.71% v 9.88% ± 0.62% [ P < .01]). FFA turnover rate was higher after both acute and chronic dF administration (respectively, 10.71 ± 2.18 v 7.79 ± 1.48 μmol/kg/min [ P < .05] and 11.92 ± 2.74 v 8.43 ± 1.86 μmol/kg/min [ P < .05]). Serum FFA concentration during both acute and chronic dF administration increased, but not significantly. Mean serum glucose level decreased after acute dF from 114.3 ± 8.6 to 86.5 ± 5.1 mg/dL ( P < .001] and after chronic dF from 120.3 ± 7.3 to 89.8 ± 5.8 mg/dL ( P < .001). Serum insulin was not affected by dF administration. In conclusion, oral acute and chronic dF administration increase FFA turnover and oxidation rates in NIDDM obese patients. This may play an important role in weight reduction. In addition, dF shows a weight-independent effect on glucose metabolism, reducing serum glucose levels without acting on insulin secretion.

Free fatty acid metabolism in aerobically fit individuals

The impact of aerobic fitness level on the production and disposal of serum free fatty acids was investigated in 26 normal young volunteers. The fitness level was ascertained by history and confirmed by determination of maximal aerobic capacity. Energy expenditure and substrate oxidation at rest were measured with indirect calorimetry. Free fatty acid turnover was measured with an infusion of [14C]palmitic acid. All tests were done > or = 48 h after the last bout of exercise. The sedentary (SED) volunteers had higher rates of systemic delivery of fatty acids than aerobically fit (FIT) individuals (532 +/- 53.4 vs. 353 +/- 62.3 mumol/min; P = 0.05). This difference was accentuated when the values were normalized to fat-free mass (9.2 +/- 0.8 and 5.9 +/- 0.98 mumol.kg-1.min-1 for SED and FIT, respectively). Fatty acid oxidation was similar between FIT and SED volunteers in absolute numbers (209 +/- 25 vs. 202 +/- 21 mumol/min, respectively; NS) as well as when normalized to fat-free mass (3.8 +/- 0.9 vs. 3.6 +/- 1.4 mumol.kg-1.min-1, respectively; NS). In contrast, the nonoxidative disposal of serum fatty acids was higher in SED (330 +/- 46.1 mumol/min) than in FIT individuals (144 +/- 52 mumol/min; P = 0.026). Thus, the ratio of nonoxidative to oxidative disposal rates of fatty acids was higher in SED than in FIT individuals (1.65 +/- 0.29 vs. 0.75 +/- 0.17; P = 0.021). The data support the hypothesis that high aerobic fitness level is associated with a low rate of systemic delivery of fatty acids at rest. Nevertheless, subjects with high aerobic fitness levels have fat oxidation at the same rate as unfit individuals.

Fast gas chromatographic—mass spectrometric method for the evaluation of plasma fatty acid turnover using [1- 13C]palmitate

Turnover of plasma free fatty acids (FFAs) can be determined from the palmitate enrichment of plasma after administration of analogues labeled with stable isotopes. We studied the conditions to measure both the concentration and the 13C enrichment of plasma palmitate by gas chromatography—mass spectrometry (GC—MS) using crude extracts. The method used plasma extraction after addition of heptadecanoic acid as internal standard and methylation with diazomethane. Subsequently the samples were analyzed by GC—MS. Plasma palmitate levels determined with this simplified method did not differ statistically from those obtained by a more “classical” procedure using FFA separation from other plasma lipids. Palmitic acid turnover rates ( R a) were evaluated in the steady-state period, in two normal subjects after 90 min infusion with [1- 13C]palmitate bound to human albumin. The rate of appearance ( R a) was found to be 0.92 and 1.08 mmol kg −1 min −1, which is in good agreement with the turnover rate previously reported for normal subjects. Sample preparation and GC—MS analysis by the proposed procedure are simple and rapid and thus the method appears to be particularly useful in clinical studies where numerous samples have to be analyzed.

Fat metabolism in human obesity

Excessive fat turnover and oxidation might cause the insulin resistance of carbohydrate metabolism in obese humans. We studied the response of free fatty acid (FFA) metabolism in lean and obese volunteers to sequential insulin infusions of 4, 8, 25, and 400 mU.m-2.min-1. The insulin dose-response curves for suppression of FFA concentration, FFA turnover ([1-14C]palmitate), and lipolysis ([2H5]glycerol) were shifted to the right in the obese subjects (insulin concentrations that produced a half-maximal response, lean vs. obese: 103 +/- 21 vs. 273 +/- 41, 96 +/- 11 vs. 264 +/- 44, and 101 +/- 23 vs. 266 +/- 44 pM, all P < 0.05), consistent with insulin resistance of FFA metabolism in obesity. After the overnight fast, FFA turnover per fat mass was decreased in obese subjects (37 +/- 4 vs. 20 +/- 3 mumol.kg fat mass-1.min-1, P < 0.01) as the result of suppression of lipolysis by the hyperinsulinemia of obesity and an increased fractional reesterification of FFA before leaving the adipocyte (primary FFA reesterification; 0.14 +/- 0.03 vs. 0.35 +/- 0.06, P < 0.05). Nevertheless, FFA turnover per fat-free mass (FFM) was also greater in the obese volunteers (8.5 +/- 0.7 vs. 11.0 +/- 1.0 mumol.kg FFM-1.min-1, P < 0.05) but only as the result of increased reesterification of intravascular FFA (secondary reesterification; 1.8 +/- 0.5 vs. 4.8 +/- 1.1 mumol.kg FFM-1.min-1, P < 0.01), since FFA oxidation was the same in the two groups throughout the insulin dose-response curve.(ABSTRACT TRUNCATED AT 250 WORDS)

Free fatty acid and glucose metabolism in human aging: evidence for operation of the Randle cycle.

We assessed insulin effects on plasma free fatty acid (FFA) and glucose metabolism in seven elderly (71 +/- 2 yr) and in seven younger (21 +/- 1 yr) subjects matched for body weight and body mass index but not for percent body fat (32.4 +/- 3.8% in elderly vs. 20.4 +/- 3.5% in young, P < 0.05), by performing sequential euglycemic clamps at five insulin doses (0.6, 1.5, 3, 6, and 15 pmol.min-1.kg-1) in combination with indirect calorimetry and [1-14C]palmitate plus [3-3H]glucose infusion. At baseline, plasma FFA concentration, turnover infusion. At baseline, plasma FFA concentration, turnover and oxidation, and total lipid oxidation were all increased in the elderly (897 +/- 107 vs. 412 +/- 50 mumol/l and 11.2 +/- 1.4 vs. 5.14 +/- 0.86, 3.45 +/- 0.65 vs. 1.37 +/- 0.25, and 4.63 +/- 0.72 vs. 3.01 +/- 0.33 mumol.min-1.kg-1 lean body mass, P < 0.05 for all comparisons), whereas glucose turnover was similar as a result of decreased glucose oxidation (8.2 +/- 1.4 vs. 13 +/- 1.9 mumol.min-1.kg-1 lean body mass, P < 0.05) and increased glucose storage (6.6 +/- 1.4 vs. 1.7 +/- 1.3 mmol.min-1.kg-1 lean body mass, P < 0.05). At all insulin infusions, plasma FFA concentration, turnover and oxidation, and total lipid oxidation were higher in the elderly than in the younger group (P < 0.05). However, if normalized per fat mass, all FFA and lipid metabolic fluxes, both in the postabsorptive state and during hyperinsulinemia, were comparable in the two groups.(ABSTRACT TRUNCATED AT 250 WORDS)

24-Hour energy expenditure and substrate oxidation rates are unaffected by body fat distribution in obese women

Twenty-four-hour energy expenditure (EE) and nonprotein respiratory quotient (RQ np) were measured by indirect calorimetry in 19 upper-body-obese (UBO) and 15 lower-body-obese (LBO) women with similar body mass index (BMI) and body fat percent. The measurements were performed in a respiration chamber on a predetermined physical activity program and a controlled diet. No differences between the UBO and LBO groups were found in 24-hour, daytime, and sleeping EE after adjustment for differences in fat-free mass (FFM). Furthermore, no group effect was observed in RQ np, but a positive correlation was found between RQ np and age. Despite the fact that an increased free fatty acid (FFA) turnover has been found in UBO subjects, the present study does not support the contention that upper-body obesity is accompanied by an increased lipid oxidation.

Effect of endurance training on plasma free fatty acid turnover and oxidation during exercise.

Plasma free fatty acid (FFA) levels tend to be lower and the plasma lipolytic hormone response to prolonged exercise of the same intensity is blunted after endurance exercise training. To determine whether training elicits a corresponding decrease in plasma FFA turnover and metabolism during prolonged exercise, we measured plasma [1-13C]palmitate kinetics and oxidation and respiratory gas exchange in 13 subjects during the latter portion of a 90- to 120-min bout of cycle ergometer work performed before and after 12 wk of alternate-day cycling and running. Training increased total fat oxidation during prolonged exercise by 41% (P < 0.005). However, for the final 30-60 min of the cycle ergometer protocol, the rate of 13CO2 production from [1-13C]palmitate oxidation was 27% lower (P < 0.05), the rate of palmitate turnover was 33% less (P < 0.05), and plasma FFA and glycerol concentrations were 32 and 20% lower (P < 0.05), respectively, than in the untrained state. Thus endurance exercise training results in decreased plasma FFA turnover and oxidation during a 90- to 120-min bout of submaximal exercise because of a slower rate of FFA release from adipose tissue.

Visceral Obesity: A “Civilization Syndrome”

The controversial question of the relationship between obesity and disease has been considerably clearer after the demonstration in several prospective, epidemiological studies that the subgroup of central, visceral obesity is particularly prone to develop cardiovascular disease, stroke, and non-insulin dependent diabetes mellitus. Visceral obesity is associated with multiple central endocrine aberrations. The hypothalamo-adrenal axis is apparently sensitive to stimuli, sex steroid hormone secretion blunted, and hyperandrogenicity is found in women. In addition, there seem to be signs of central dysfunctions in the regulation of hemodynamic factors after stress, and growth hormone secretion appears to be particularly blunted. Several of these endocrine abnormalities are associated with insulin resistance, particularly glycogen synthesis in muscle. Fiber composition with low type I/type II ratio might be secondary to the prevailing hyperinsulinemia, but low capillary density in muscle may well be of importance. In combination with elevated turn-over of free fatty acids (FFA) this will probably provide powerful mechanisms whereby insulin resistance is created. Portal FFA, from the highly lipolytic visceral depots may, in addition, affect hepatic metabolism to induce increased gluconeogenesis, production of very low density lipoproteins as well as to perhaps inhibit clearance of insulin. By these mechanisms a Metabolic Syndrome Visceral adipocytes seem to have a high density of several steroid hormone receptors, directing steroid hormone effects particularly to these depots. The net effect of cortisol is apparently a stimulation of lipid storage, with opposing effects of sex steroid hormones which also facilitate lipid mobilization, regulations most often found at the gene transcription level. Growth hormone inhibits cortisol effects on lipid accumulation, and amplifies the lipid mobilizing effects of steroid hormones. The combined perturbations of hormonal secretions will therefore probably direct triglycerides toward visceral depots. Circulatory and nervous regulatory mechanisms require, however, more attention. The multiple central endocrine and nervous aberrations of visceral obesity suggest neuroendocrine dysregulations, and have features characteristic of the hypothalamic arousal seen after certain types of stress, alcohol intake, and smoking. Such factors can be traced to subjects with visceral fat accumulation. Standardized stress, eliciting a "defeat reaction" in primates is followed by an apparently identical syndrome. This integrated picture of the multiple symptoms of visceral obesity is based on epidemiological, clinical, experimental, cellular, and molecular evidence. The ingredients of positive energy balance, including physical inactivity, stress, smoking, and alcohol consumption are frequent features of modern, urbanized society. Visceral obesity may therefore be an expression of a "Civilization Syndrome."

Effect of insulin on oxidative and nonoxidative pathways of free fatty acid metabolism in human obesity.

The dose-response relationship between the plasma insulin concentration and oxidative and nonoxidative pathways of free fatty acid (FFA) metabolism was examined in 11 obese and 7 lean subjects using a stepwise insulin clamp technique in combination with indirect calorimetry and infusion of [1-14C]palmitate. The fasting plasma FFA concentration was elevated in obese subjects (793 +/- 43 vs. 642 +/- 39 mumol/l; P less than 0.01) and was associated with an increased basal rate of plasma FFA turnover, FFA oxidation, and nonoxidative FFA disposal, i.e., reesterification (all P less than 0.01). Suppression of plasma FFA turnover by physiological increments in plasma insulin was impaired in obese compared with lean subjects. However, plasma FFA turnover expressed per kilogram fat mass was normally suppressed by insulin in obese subjects. Although insulin suppressed plasma FFA oxidation to the same extent in lean and obese subjects, inhibition of total lipid oxidation by insulin was impaired in the obese group. Obese subjects had an enhanced basal rate of nonoxidative FFA disposal, which was suppressed less by physiological increments in plasma insulin compared with lean controls. Therefore, we conclude that 1) lipolysis in uncomplicated obesity is normally sensitive to insulin; the enhanced FFA flux is simply a consequence of the increased fat mass. 2) Nonoxidative FFA disposal expressed per lean body mass is enhanced in obese subjects and correlates with the increase in plasma FFA concentration and fat mass. 3) Enhanced oxidation of intracellular lipids contributes to the enhanced rate of total lipid oxidation in obese subjects.

Palmitic acid kinetics in fasting, traumatized patients.

The contribution of free fatty acid oxidation to the elevation in energy expenditure after trauma has not been well characterized. Six control subjects and six traumatized patients were fasted for 48 hours and given a primed continuous infusion of (1-14C)palmitate to measure plasma palmitate and total free fatty acid kinetics. Traumatized patients had greater urinary nitrogen losses (20.8 vs. 9.3 g N per day) and a significantly greater ratio of measured to predicted resting energy expenditure (+36% vs. -6%) compared with controls. Individual and total plasma free fatty acid concentrations were similar for the two groups. The turnover and oxidation of plasma palmitate and total free fatty acids were not changed by multiple trauma. These results demonstrated that plasma free fatty acids and palmitate do not contribute to increased energy expenditure following trauma.

Glucose regulation of lipid metabolism in humans

The role of plasma glucose in the regulation of lipid metabolism in humans, independent of associated changes in hormone concentrations, is controversial. Therefore we examined the role of glucose in the regulation of lipolysis and free fatty acid (FFA) reesterification in six healthy lean male volunteers. Blood glucose concentration was clamped at either 5 or 10 mM during 2-h pancreatic-pituitary clamps. Glycerol and palmitate turnover were measured by isotope dilution ([1-14C]palmitate and [2H5]-glycerol). All hormone concentrations were the same during the euglycemic and hyperglycemic studies. FFA turnover, which represents the difference between lipolysis and FFA reesterification, was reduced 30% by hyperglycemia (29 +/- 2 vs. 20 +/- 3 mumol.kg fat mass-1.min-1, P less than 0.05). Glycerol turnover, which represents lipolysis only, was reduced to a similar extent (9.4 +/- 0.9 vs. 6.2 +/- 0.7 mumol.kg fat mass-1.min-1, P less than 0.05). We conclude that glucose regulates lipid metabolism, independently of changes in hormone concentrations. The equivalent suppression of glycerol and FFA turnover indicates that the effect is mediated by suppression of lipolysis and not by stimulation of FFA reesterification.

Insulin Sensitivity in Septic Cancer‐Bearing Patients

Resistance to insulin's effect on glucose metabolism is a well-documented phenomenon. The magnitude of resistance to insulin's antilipolytic action is usually less than the resistance to insulin's action on glucose metabolism. In sepsis, resistance to the antilipolytic effect of insulin may be more prominent than resistance to insulin's action on glucose metabolism. Therefore, free fatty acid (FFA) turnover, FFA concentration, glucose tissue uptake, and endogenous glucose production were measured in nine septic cancer-bearing patients and six healthy volunteers during a constant glucose load at two different insulin concentrations. During infusion of glucose alone, plasma insulin concentration in patients and control subjects were, respectively 33 +/- 7 mU/L and 23 +/- 4 mU/L. When plasma glucose was clamped at the low normal range these values were, respectively, 85 +/- 17 mU/L and 28 +/- 5 mU/L (p less than 0.05). Glucose tissue uptake and endogenous glucose production were not significantly different in patients and control subjects in both parts of the study. FFA turnover and FFA concentrations were significantly higher in the patients compared with the control subjects (p less than 0.001) in both parts of the study. It is concluded that in septic cancer-bearing patients, resistance to insulin's effect on FFA turnover is more pronounced than resistance to its inhibiting effect on endogenous glucose production and its stimulating effect on glucose tissue uptake.

How valid are isotopic measurements of fatty acid oxidation?

These studies were performed 1) to compare two isotopic methods (3H2O and 14CO2 production) of measuring free fatty acid (FFA) oxidation; 2) to determine whether isotopic estimates of fatty acid oxidation during hypoinsulinemia are plausible when compared with those obtained using indirect calorimetry; and 3) to examine whether the delay between the exit of [14C]FFA from plasma and the appearance of 14CO2 in breath is accounted for solely by bicarbonate kinetics. Studies in 11 healthy volunteers revealed that [14C]- and [3H]FFA tracers provide similar estimates of FFA turnover and oxidation. Isotopic estimates of fatty acid oxidation were less than those of indirect calorimetry under basal conditions but equaled or exceeded indirect calorimetry estimates after 3 h of acute hypoinsulinemia (somatostatin induced). After stopping tracer infusions, the half-life of plasma [14C]FFA was 3.7 +/- 0.1 min. The half-life of 14CO2 decay from [14C]bicarbonate was 37 +/- 1 min, and the half-life of 14CO2 decay after discontinuation of [14C]FFA infusion was 141 +/- 10 min. Intracellular preoxidative fatty acid pools (possibly triglycerides) most probably account for the marked delay between the exit of FFA tracers from plasma and the appearance of isotopic markers of oxidation in measurable spaces. This delay can result in erroneous estimates of "FFA oxidation." We conclude that tracer measurements of FFA oxidation are invalid under most circumstances.