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10.1152/ajpendo.00177.2001.
Matzinger, Oscar, Philippe Schneiter, and Luc lipid oxidation to total energy expenditure in endur-
Tappy. Effects of fatty acids on exercise plus insulin-induced ance-trained vs. sedentary individuals is observed at
glucose utilization in trained and sedentary subjects. Am J both the same relative and same absolute workloads (1,
Physiol Endocrinol Metab 282: E125–E131, 2002; 10.1152/ 17). Endurance training may affect several key steps in
ajpendo.00177.2001.—Fatty acids are known to decrease in-
lipid metabolism to attain such an increase in lipid
sulin-mediated glucose utilization in humans, both at rest
and during exercise. To evaluate the effect of endurance oxidation by skeletal muscle: an enhanced lipolysis of
training in this process, we infused lipids or saline in groups triglyceride stored in adipose tissue and/or within the
of sedentary and highly trained subjects. Whole body glucose muscle fibers, an enhanced uptake of circulating lipids
utilization and substrate oxidation were monitored during a by working muscle, and an enhanced -oxidation of
2.5-h hyperinsulinemic clamp. During the last 30 min, a fatty acids may all possibly be involved (19). How these
cycling exercise was superimposed. During hyperinsulinemia metabolic adaptations to endurance training affect the
at rest, whole body glucose utilization and glucose oxidation interactions between glucose and lipid metabolism re-
were higher in trained subjects than in sedentary subjects. mains, however, unknown. The aim of this study was
Compared with the control experiments with the antilipolytic therefore to assess the effects of endurance training on
agent acipimox, lipid infusion stimulated lipid oxidation to the inhibition of whole body glucose metabolism by
the same extent in trained as in sedentary subjects. It re-
duced whole body glucose utilization by 37% in trained and
lipids at rest and during exercise.
by 41% in sedentary subjects. During exercise, lipid infusion
increased more lipid oxidation in trained than in sedentary METHODS
subjects and reduced whole body glucose utilization by 43 ⫾
Subjects
4% in trained and by 22 ⫾ 4% in sedentary subjects (P ⬍
0.01). The present data indicate that lipid infusion has sim- Nine endurance-trained cyclists (group T) and seven
ilar effects on lipid oxidation and whole body glucose utiliza- healthy sedentary volunteers (group S) were selected to take
tion during hyperinsulinemia at rest in trained and seden- part in this study. All subjects underwent a medical evalua-
tary subjects. During exercise, however, it increases more tion including history, physical examination, and electrocar-
lipid oxidation and produces a more important reduction in diogram. They were all in good physical health, were not
glucose utilization in trained than in sedentary subjects. taking any medication, were nonsmokers, and had no famil-
These results suggest that endurance training enhances the ial history of diabetes or obesity (Table 1).
inhibitory effect of lipids on whole body glucose metabolism The endurance-trained cyclists were selected on the basis
during exercise. of having biked ⬎4,000 km/yr for the previous 2 yr. The
insulin; exercise; whole body glucose utilization; lipid oxida- sedentary volunteers did not perform any kind of sport (in-
tion cluding physical activity at work) for the previous 2 yr.
The experimental protocol was approved by the ethics
committee of the Lausanne University Medical School, and
all participants provided informed written consent. Percent
IT HAS BEEN KNOWN FOR A LONG TIME that infusion of a lipid
body fat was estimated from skinfold thickness measure-
emulsion impairs glucose tolerance (15) and decreases ments with the use of standard formulas (10).
insulin-mediated glucose disposal (12) in healthy hu- Maximal oxygen uptake was measured on an electronically
mans. Lipids inhibit both glucose oxidation and stor- braked cycle ergometer during an incremental exhaustive
age (33) and exert this effect primarily in skeletal exercise test. For the trained subjects, exercise started at a
muscle (24). These effects are observed not only at rest power output of 150 W, which was increased by 30 W every
but also during exercise (16, 28) and during the recov- minute until exhaustion. The same procedure was used for
ery period after an exercise (6). sedentary subjects, except that exercise was started at a
Endurance training has profound effects on skeletal power output of 50 W. Respiratory gases were analyzed via
open-circuit indirect calorimetry as described (20) and were
muscle substrate utilization. It results in an increased recorded on line.
lipid utilization by working muscles at low to moderate
exercise intensity (17). This increased contribution of
The costs of publication of this article were defrayed in part by the
Address for reprint requests and other correspondence: L. Tappy, payment of page charges. The article must therefore be hereby
Institut de physiologie, Rue du Bugnon 7, CH-1005 Lausanne, Swit- marked ‘‘advertisement’’ in accordance with 18 U.S.C. Section 1734
zerland (E-mail: Luc.Tappy@iphysiol.unil.ch). solely to indicate this fact.
http://www.ajpendo.org 0193-1849/02 $5.00 Copyright © 2002 the American Physiological Society E125
E126 METABOLIC EFFECTS OF FATTY ACIDS AND TRAINING
Table 1. Subjects’ characteristics during exercise in the presence of very low FFA plasma
levels. All subjects received 250 mg of the antilipolytic agent
Sedentary Group Trained Group acipimox (Olbetam; Pharmacia & Upjohn, Dübendorf, Swit-
zerland) at the beginning of the test and again 2 h later to
n 7 9
Age, yr 23.4 ⫾ 3.2 24.3 ⫾ 3.3
efficiently suppress plasma FFA concentrations.
Body mass, kg 61.5 ⫾ 9.6 68.2 ⫾ 5.1
Height, cm 174.6 ⫾ 5.9 178.7 ⫾ 5.6 Analytical Procedures
BMI, kg/m2 20.3 ⫾ 2.1 21.4 ⫾ 0.9
Body fat, % 14.7 ⫾ 3.8 10.4 ⫾ 2.3 Plasma glucose was determined by the oxidase method,
FFM, kg 52.4 ⫾ 8.4 61.1 ⫾ 4.7 using a Beckman Glucose Analyzer II (Beckman Instru-
V̇O2max, ml/min 2541 ⫾ 217 4591 ⫾ 170 ments, Fullerton, CA). Plasma FFA concentrations were
determined by a colorimetric assay kit (Wako, Freiburg,
Values are means ⫾ SD. BMI, body mass index; FFM, fat-free Germany). Plasma lactate concentrations were measured
mass; V̇O2 max, maximal oxygen uptake.
enzymatically (18). Plasma insulin concentrations were mea-
sured by radioimmunoassay (kit from Biodata Guidonia,
Montecello, Italy, with ⬍14% cross-reactivity with proinsu-
Experimental Protocol lin). Urinary urea concentration was analyzed enzymatically
using a Beckman urea analyzer (Beckman Instruments).
Each subject took part in two different protocols separated Plasma [6,6-2H2]glucose was measured by gas chromatogra-
by ⱖ2 wk. The order in which the two protocols were per- phy-mass spectrometry, as described (32).
formed was randomly assigned. During the 3 days preceding The rates of glucose appearance (Ra) and disappearance
each protocol, subjects were requested not to perform heavy (Rd) were calculated from plasma [6,6-2H2]glucose enrich-
physical activity. They were also asked not to consume any ment using hot infusate equations (14).
drinks containing caffeine or alcohol during the 24 h preced- Endogenous glucose production was calculated as glucose
ing each protocol. Ra ⫺ the rate of exogenous dextrose infusion.
In both protocols, subjects were studied in the morning The percent reduction in glucose Rd induced by lipids
after an overnight fast. After having voided, subjects lay between protocols 1 (lipids, L) and 2 (acipimox, Acx) was
quietly supine in bed. Intravenous catheters were placed calculated as
percutaneously in an antecubital vein of each arm. One
catheter was used for infusion of [6,6-2H2]glucose, insulin, RdAcx ⫺ RdL
% reduction ⫽ 䡠 100
dextrose, and a soybean lipid emulsion (20% Lipovenös, Fre- RdAcx
senius, Stans, Switzerland). The contralateral catheter was
used for periodic collection of blood samples. The heated hand Statistical Analysis
technique was used, with a thermostabilized box heated
at 50°C, to obtain partially arterialized blood samples. All results are expressed as means ⫾ SE unless stated
Throughout the experiments, respiratory gas exchanges were otherwise. Comparisons between groups were performed by
multiple way analysis of variance. Post hoc comparisons were
monitored by open-circuit indirect calorimetry by means of a
made using Fisher’s protected least significant difference.
transparent hood ventilated with ⬃40 l/min (16). A primed
Statistical significance was set at ␣ ⫽ 0.05.
(4 mg/kg bolus), continuous infusion of [6,6-2H2]glucose,
(40 g 䡠 kg⫺1 䡠 min⫺1; MassTrace, Woburn, MA) was started
RESULTS
immediately after the insertion of the venous cannula. Sixty
minutes later, a hyperinsulinemic euglycemic (0.4 mU 䡠 Plasma Hormones and Substrate Concentrations
kg⫺1 䡠 min⫺1) clamp (glucose ⫽ 5 mmol/l) was started (time 0).
Exogenous glucose was labeled with 1.25% [6,6-2H2]glucose During the initial 2 h at rest, plasma glucose was
(hot infusate technique) to calculate whole body glucose rate clamped at the following values: trained subjects dur-
of disappearance (14). ing lipid infusion (TL), 5.54 ⫾ 0.29 mmol/l; trained
Two hours after the beginning of the clamp, the subjects subjects after acipimox (TAcx), 5.44 ⫾ 0.35 mmol/l;
were transferred to an ergometric bicycle (Schiller ergometer
sedentary subjects during lipid infusion (SL), 5.55 ⫾
CE 0.124; Baar, Switzerland) where they remained seated for
the next 35 min. A hood was fitted over their heads to allow 0.23 mmol/l; and sedentary subjects after acipimox
collection of expiratory gases and was ventilated with ambi- (SAcx), 5.57 ⫾ 0.63 mmol/l. During the next 30 min,
ent air at a rate of 250 l/min. After 5 min of preparation and with a cycling exercise at a power output of 100 W, the
adaptation of the subject, a cycling exercise at a power output following plasma glucose concentrations were main-
of 100 W was performed during 30 consecutive minutes. tained: TL, 5.29 ⫾ 0.54 mmol/l; TAcx, 5.32 ⫾ 0.62
Because there was a significant degree of hyperventilation mmol/l; SL, 5.6 ⫾ 0.52 mmol/l; and SAcx, 5.58 ⫾ 0.4
during the initial period of exercise, only the last 10 min of mmol/l. Steady-state plasma insulin concentrations at
exercise were recorded. Plasma bicarbonate concentrations rest were similar under all four conditions (TL, 260.8 ⫾
remained steady during this period. 10.9 pmol/l; TAcx, 223.3 ⫾ 7.1 pmol/l; SL, 275.1 ⫾ 6.8
Protocol 1: lipid infusion. This test was performed to as- pmol/l; SAcx, 256.5 ⫾ 6.5 pmol/l). They were minimally
sess insulin-mediated glucose disposal at rest and during
affected by exercise (Fig. 1). Steady-state plasma FFA
exercise in presence of elevated plasma free fatty acid (FFA)
concentrations (condition L). A continuous infusion of 20% concentrations were similarly increased to high physi-
Lipovenös (1 ml/min) was started 60 min before the begin- ological values in TL (0.395 ⫾ 0.12 mmol/l) and SL
ning of insulin infusion and was continued throughout the (0.415 ⫾ 0.28 mmol/l); they were suppressed to the
test to maintain elevated plasma FFA concentrations. same extent in both groups with acipimox (TAcx,
Protocol 2: administration of acipimox. This test (condition 0.033 ⫾ 0.004 mmol/l; SAcx, 0.035 ⫾ 0.003 mmol/l; P ⬍
Acx) was performed to assess insulin sensibility at rest and 0.0001 vs. TL and SL; Fig. 2).
AJP-Endocrinol Metab • VOL 282 • JANUARY 2002 • www.ajpendo.org
METABOLIC EFFECTS OF FATTY ACIDS AND TRAINING E127
During the initial 2-h period of hyperinsulinemia, Several explanations can be proposed for the en-
while subjects were resting quietly in the supine posi- hanced effect of lipids on glucose metabolism in en-
tion, insulin-mediated glucose disposal was 65% higher durance-trained individuals. Infused lipids initially
in trained vs. sedentary subjects during lipid infusion combine with circulating apolipoproteins to form li-
and 55% higher after acipimox. This observation was poproteins similar to very-low-density lipoproteins in
expected and reflects the well-known effect of physical the circulation (5). The triglycerides present in these
fitness and endurance training to increase insulin sen- particles are subsequently hydrolyzed to fatty acids by
sitivity (4, 7). Infusion of lipids, which produced similar lipoprotein lipase in the capillaries of skeletal muscle
increases in plasma FFA concentrations and in lipid and adipose tissue. Endurance training significantly
oxidation rates in trained and sedentary subjects, also increases the synthesis of lipoprotein lipase in skeletal
produced the same relative inhibition of insulin-medi- muscle (21, 30) and, hence, is expected to enhance the
ated glucose disposal in both groups of subjects. This proportion of infused triglycerides, which are taken up
indicates that elevated plasma FFA concentrations are as FFA by skeletal muscle. A role of lipoprotein lipase
equally effective in impairing insulin actions in trained in insulin sensitivity is indeed supported by the recent
and sedentary subjects at rest. observation of transgenic mice overexpressing lipopro-
The mechanisms by which elevated FFAs produce tein lipase being markedly insulin resistant (13).
insulin resistance are still controversial. It was pro- It is recognized that FFAs enter the skeletal muscle
posed by Randle et al. (26) that an elevated concentra- cell by a carrier-mediated process (3). Three puta-
tion of FFA stimulates FFA oxidation in skeletal and tive fatty acid transporters have been identified so far
cardiac muscle. According to the hypothesis enunciated [fatty acid translocase (FAT/CD36), plasma membrane
by these investigators, fat oxidation gives rise to in- fatty acid binding protein (FABPPM), fatty acid trans-
creased intracellular concentrations of acetyl-CoA, port protein]. If cellular FFA uptake was increased as
ATP, and citrate, which in turn inhibit glycolysis and a consequence of endurance training, it might result in
the entry of pyruvate into the tricarboxylic acid cycle. an increase in intracellular long-chain fatty acyl-CoA
It results in an increase in intracellular glucose 6-phos- concentrations, the putative mediator of glucose trans-
phate, which in turn inhibits hexokinase and cellular port inhibition. An upregulation of fatty acid transport-
glucose uptake. Several observations, however, sug- ers by exercise training has indeed been suggested.
gest that FFA may decrease insulin sensitivity through Several reports indicate that chronic muscle stimula-
other mechanisms unrelated with lipid oxidation. tion increases FABP (24) and FAT/CD36 (3) or FABP
Boden et al. (2) observed that an infusion of lipids in and FAT/CD36 (26) in rats. Other studies, however,
healthy humans rapidly increased glucose oxidation at failed to observe an effect of training on these param-
the expense of lipid oxidation; inhibition of nonoxida- eters (11, 34). Our present observation indicates that
tive glucose disposal, however, was delayed by several similar FFA concentrations are equally effective in
hours, suggesting that this effect was not directly re- reducing insulin-mediated glucose metabolism in
lated to lipid oxidation. Furthermore, glucose 6-phos- trained and sedentary subjects at rest and exert an
phate concentrations were not decreased in skeletal enhanced inhibition only during exercise. If the effects
muscle biopsies obtained 6 h after the beginning of of FFA were primarily exerted through an increase in
lipid infusions. Roden et al. (27) studied skeletal mus- intracellular long-chain fatty acyl-CoA, this would im-
cle metabolism with nuclear magnetic resonance spec- ply an acute increase in skeletal muscle FFA transport
troscopy in healthy subjects during lipid infusion. They during muscle contraction. Such an effect of muscle
observed that lipids suppressed glycogen synthesis and contraction on FFA uptake has indeed been suggested
decreased the intracellular concentrations of glucose (11) but remains to be demonstrated.
6-phosphate. Interestingly, it was also reported that Lipid oxidation was significantly higher in endur-
skeletal muscle glucose 6-phosphate concentrations ance-trained individuals. This may be secondary to an
are not increased in humans or Rhesus monkeys with increased uptake of FFA in skeletal muscle. An en-
type 2 diabetes (25). In view of these observations, it is hanced activity of the enzyme carnitine palmitoyl-
proposed that FFAs exert a direct inhibitory effect in transferase I may also be involved (31). Interestingly,
the insulin resistance induced by lipids. Inhibition of lipid oxidation was higher in endurance-trained indi-
insulin receptor substrate 1 associated with phospha- viduals during exercise even when acipimox was used
tidylinositol 3-kinase activity may be involved in this to inhibit adipose tissue lipolysis. This observation is
effect (9). consistent with the report that endurance training
During exercise, lipid infusion resulted in similar increases oxidation of intramuscular triglycerides (29).
plasma FFA concentrations in trained and sedentary Altogether, our results indicate that the inhibitory
subjects, but in markedly higher lipid oxidation rates effects of lipids on whole body glucose utilization are
in trained subjects. This reflects the well-known effect enhanced in endurance-trained subjects during exer-
of training on muscle fuel oxidation (17). The major cise plus hyperinsulinemia but not during hyperinsu-
novel observation of this study was that, despite simi- linemia alone. As discussed earlier, an increased up-
lar plasma FFA concentrations, the reduction by lipids take of FFA in skeletal muscle due to stimulation of
of whole body glucose disposal during exercise was lipoprotein lipase and/or FABP appears the most likely
about twice as important in trained as in sedentary explanation for this effect. The hypothesis that an
subjects. increased lipid oxidation per se inhibits glucose uptake
AJP-Endocrinol Metab • VOL 282 • JANUARY 2002 • www.ajpendo.org
E130 METABOLIC EFFECTS OF FATTY ACIDS AND TRAINING
has never been actually disproved; it appears, however, palmitoyltransferase-1 promotes intramyocellular lipid accumu-
unlikely in regard to the observation that chronic in- lation and insulin resistance in rats. Diabetes 50: 123–130, 2001.
9. Dresner A, Laurent D, Marcucci M, Griffin ME, Dufour S,
hibition of lipid oxidation causes accumulation of in- Cline GW, Slezak LA, Andersen DK, Hundal RS, Rothman
tramyocellular triglycerides and insulin resistance in DL, Petersen KF, and Shulman GI. Effects of free fatty acids
rats (8). In the present study, the inhibitory effects of on glucose transport and IRS-1-associated phosphatidylinositol
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during exercise but not at rest suggests that muscle 10. Durnin JVGA and Womersley J. Body fat assessment for
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als. It remains, however, possible that our observation Endurance training increases FFA oxidation and reduces tri-
was merely due to the fact that endurance training per acylglycerol utilization in contracting rat soleus. Am J Physiol
Endocrinol Metab 278: E778–E785, 2000.
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muscle capillary density (22) and GLUT-4 content (23) RA. Effect of fatty acids on glucose production and utilization in
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