Departments of 1 Medicine and 2 Psychiatry, University of Pittsburgh, Pittsburgh, Pennsylvania 15261; and 3 Division of Kinesiology, Department of Social and Preventive Medicine, Laval University, Ste-Foy, Quebec, Canada G1K 7P4
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ABSTRACT |
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The current study was undertaken to
investigate fatty acid metabolism by skeletal muscle to examine
potential mechanisms that could lead to increased muscle triglyceride
in obesity. Sixteen lean and 40 obese research volunteers had leg
balance measurement of glucose and free fatty acid (FFA) uptake
(fractional extraction of [9,10
3H]oleate) and indirect
calorimetry across the leg to determine substrate oxidation during
fasting and insulin-stimulated conditions. Muscle obtained by
percutaneous biopsy had lower carnitine palmitoyl transferase (CPT)
activity and oxidative enzyme activity in obesity (P < 0.05). During fasting
conditions, obese subjects had an elevated leg respiratory quotient
(RQ, 0.83 ± 0.02 vs. 0.90 ± 0.01;
P < 0.01) and reduced fat oxidation
but similar FFA uptake across the leg. During insulin infusions, fat
oxidation by leg tissues was suppressed in lean but not obese subjects;
rates of FFA uptake were similar. Fasting values for leg RQ correlated
with insulin sensitivity (r = 0.57, P < 0.001). Thirty-two
of the obese subjects were restudied after weight loss (WL,
14.0 ± 0.9 kg); insulin sensitivity and insulin suppression of fat
oxidation improved (P < 0.01), but
fasting leg RQ (0.90 ± 0.02 vs. 0.90 ± 0.02, pre-WL vs.
post-WL) and muscle CPT activity did not change. The findings suggest
that triglyceride accumulation in skeletal muscle in obesity derives
from reduced capacity for fat oxidation and that inflexibility in
regulating fat oxidation, more than fatty acid uptake, is related to
insulin resistance.
arteriovenous balance; indirect calorimetry; fatty acid metabolism
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INTRODUCTION |
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SKELETAL MUSCLE has an increased content of triglyceride in obesity (37, 38). The amount of triglyceride in skeletal muscle, although quite small relative to that in adipose tissue, is nevertheless significantly associated with insulin resistance (24, 38, 45, 53). However, the mechanisms that account for increased skeletal muscle lipid deposition in obesity are uncertain. Rates of de novo lipogenesis within skeletal muscle are low (49), and although muscle content of malonyl-CoA, a precursor for fatty acid synthesis, may be increased in obesity, this is thought to function more as a signal for fatty acid partitioning (44, 46). Accordingly, skeletal muscle accretion of triglyceride in obesity might result from either increased fatty acid uptake, out of proportion to normal rates of lipid oxidation, or, alternatively, from diminished fat oxidation. The primary objective of the current study was to test these alternative hypotheses.
It is now well established that during fasting conditions, skeletal muscle in lean, healthy individuals relies on lipid oxidation for the majority of resting energy production, as originally reported by Andres and colleagues (Andres and Cadar, Ref. 2, and Baltzan et al., Ref. 3) on the basis of regional indirect calorimetry across the forearm. During postabsorptive conditions, skeletal muscle has a high fractional extraction of fatty acids and thus is an important site for systemic utilization of fatty acids (55). Some of the fatty acids taken up by muscle enter tissue lipid pools of triglyceride or phospholipids (8, 14, 45), although it is less clear whether fatty acids must initially enter tissue triglyceride before oxidization (11) or enter mitochondria directly, as recently suggested by the isotopic studies of Sidossis et al. (51). There are several biochemical determinants of the capacity for fatty acid utilization in skeletal muscle. In animal studies, the patterns of fatty acid utilization are related to fiber type, with slow-twitch oxidative muscle having a higher capacity for fatty acid uptake and lipid oxidation than fast-twitch glycolytic muscle fibers (8, 14, 37). In animal models of obesity, skeletal muscle content of malonyl-CoA, a potent allosteric inhibitor of carnitine palmitoyl transferase I (CPT I) in skeletal muscle, has been found to be increased (44, 47). Other potential determinants might be the patterns of expression of various fatty acid-binding proteins (6, 21, 57), although relatively little is known at present concerning human skeletal muscle and the effect of obesity. Intriguingly, some of these same skeletal muscle characteristics are associated with insulin resistance, specifically, a lower oxidative enzyme capacity (54), an increased proportion of glycolytic type II muscle fibers (31), and increased malonyl-CoA content (44). Moreover, defects in the activity of CPT, the enzyme complex regarded as rate limiting for oxidation of long-chain fatty acids (35), are associated with lipid accumulation within skeletal muscle (50).
On the basis of these considerations, it is biologically plausible that skeletal muscle patterns of fatty acid utilization during fasting conditions might associate with obesity-related insulin resistance, and the second objective of the current study was to explore this hypothesis. Whereas it is generally accepted that rates of lipid oxidation are increased in obesity during insulin-stimulated conditions, and, indeed, impaired suppression of lipid oxidation is a prominent manifestation of insulin resistance (16, 30), much less is known regarding a potential link between fasting patterns of muscle free fatty acid (FFA) utilization and insulin resistance. Another important consideration is whether potential impairments within the pathways of fatty acid utilization in skeletal muscle in obesity are primary defects or arise secondarily, after an individual has become obese. This is a difficult issue to effectively address by cross-sectional comparisons of lean and obese subjects. A prospective clinical study indicated that a decreased reliance on lipid oxidation is a risk factor for weight gain (59), and collateral analyses of skeletal muscle enzyme activities implicated skeletal muscle in impaired lipid oxidation (17, 60). A reduced reliance on lipid oxidation has also been identified as a risk factor for weight regain after weight loss (7). These data raise the possibility that a potential impairment in capacity for lipid oxidation might be a primary defect in obesity. Weight loss can substantially improve insulin-resistant glucose metabolism in skeletal muscle (20), indicating a substantial acquired or secondary component of obesity-related insulin-resistant glucose metabolism. Thus the third objective of the current study was to assess whether weight loss, undertaken by dietary restriction and without change in baseline levels of physical fitness, can also modulate patterns of skeletal muscle metabolism of fatty acids, and how this would compare with the effect on glucose metabolism.
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METHODS |
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Subjects.
Sixteen lean (L) and forty obese (O) volunteers were recruited by
advertisement in a community newspaper. All potential research volunteers underwent a thorough medical evaluation, including a 2-h
75-g oral glucose tolerance test, before participation. To be eligible,
research volunteers were required to be within the ages of 20 and 45 yr, to have normal glucose tolerance, fasting triglyceride, and
cholesterol values <300 mg/dl, and to be normotensive without
anti-hypertensive medications. Women taking oral contraceptives were
excluded, as were subjects taking lipid-lowering medication. Additional
criteria were that neither L nor O volunteers engaged regularly in 2
exercise sessions weekly and that weight was stable (±2 kg) for
3
mo before enrollment. Informed, written consent was obtained from each
subject. The research plan was reviewed and approved by the University
of Pittsburgh Institutional Review Board.
Metabolic assessments.
Subjects were admitted to the University of Pittsburgh General Clinical
Research Center 1 day before studies. Research subjects were instructed
to ingest 200 g of carbohydrate and avoid strenuous exertion for 3 days preceding studies. On the evening before physiological investigations, subjects received a standard dinner (10 kcal/kg; 50%
carbohydrate, 30% fat, 20% protein) and then fasted until completion
of the metabolic measurements on the following day. In the morning, for
the study of substrate exchange across the leg, catheters for blood
sampling were inserted in a radial artery and femoral vein, as
previously described (10, 25). To measure uptake of FFA across the leg,
an infusion of
[9,10-3H]oleate (New
England Nuclear, Boston, MA), at 0.4 µCi/min, was begun in a forearm
vein, with 1 h for isotope equilibration before arteriovenous sampling.
During a 40-min period of basal (fasting) determinations, nine paired
sets of arterial and femoral venous blood samples were obtained in
iced, heparinized syringes for immediate measurement of blood
O2 and
CO2 content; each set was obtained
at 5-min intervals. At 10-min intervals, arterial and venous blood was
obtained for measurement of glucose, plasma FFA, and FFA specific
activity and for determination of arterial insulin. Venous occlusion
strain-gauge plethysmography was used to measure resting blood flow to
the leg; the mean of five tracings was used to estimate resting limb
blood flow. After completion of fasting measurements, a percutaneous
muscle biopsy of the vastus lateralis muscle was performed. Muscle
samples were immediately frozen in liquid
N2 and kept at
80°C for
later assay.
Weight loss intervention.
Subjects who completed the above metabolic assessments and who had a
body mass index (BMI) 30 kg/m2
were invited to participate in a 4-mo outpatient weight loss (WL)
program. The goal of the WL intervention was to produce a WL of
10-15 kg and to do so by dietary restriction of calories and
without an increase in patterns of physical activity. The WL program
combined a very low calorie diet (VLCD) with an intensive program of
behavioral intervention, followed by a period of weight stabilization,
as previously described (58). The WL program was initiated within
several days of the completion of baseline physiological assessments.
Briefly, during the first 10 wk of this program, subjects were
instructed to consume a VLCD (800 kcal/day), and this was followed by 2 wk of gradual refeeding up to isocaloric requirements and then 4 wk of
weight stabilization. During the VLCD, subjects consumed a combination
of liquid formula (Optifast, Novartis) and lean meat, fish, and fowl.
During weeks 11-13, subjects were
instructed to consume 1,200 kcal/day, with a gradual reintroduction of
fruits, vegetables, and grains to the diet. During
weeks 14-17, subjects were
instructed to consume a weight-maintaining diet, with 30% of calories
as fat, 15% as protein, and 55% as complex carbohydrates to avoid
effects of acute fasting or calorie restriction on post-WL
physiological assessments. Subjects were seen weekly for 16 wk by a
nutritionist/behaviorist. To avoid potential confounding effects of
exercise on muscle biochemistry and physiology, subjects were carefully
instructed to maintain pre-WL levels of physical activity. Vitamin and
mineral supplementation was provided during the VLCD. Serum potassium
was monitored at 2 wk and then repeated at 4-wk intervals, with
measurement of uric acid and other blood chemistries and periodic
electrocardiograms. Metabolic reassessments, which entailed all of the
parameters described previously, were repeated at the conclusion of the
WL intervention and the 4-wk interval of weight stabilization.
Body composition and measurement of maximal aerobic power.
At baseline and after WL, muscle composition was assessed using
cross-sectional computed tomography (CT) imaging of the mid-thigh. Systemic fat mass (FM) and fat-free mass (FFM) were assessed using dual-energy X-ray absorptiometry (Lunar model DPX-L, Madison, WI).
Details for both methods have been previously described (24). To assess
maximal aerobic power
(O2 max), an
incremental, modified Bruce protocol on an electronically braked cycle
ergometer (Bosch ERG 601, Aachen, Germany) was used with
continuous monitoring of heart rate. The test for
O2 max was done
1
wk before studies of substrate metabolism (pre-WL and post-WL) were performed.
Analyses. For analysis of FFA radioactivity, plasma FFA were extracted into isopropyl alcohol-heptane-1 NH2SO4 (40:10:1), dried using vacuum evaporation (Savant Instruments, Farmingdale, NY), and reconstituted with scintillation fluid, and radioactivity was measured using liquid scintillation counting, as previously described (10, 12, 14). Before extraction, [14C]oleate was added to each sample as an internal standard, with a mean recovery of [14C]oleate >97%. Plasma FFA were measured using an enzymatic, colorimetric kit (Wako NEFA, Wako Chemical, Nuess, Germany). Samples for blood gas analysis were obtained in iced, heparinized syringes and immediately analyzed at the bedside using a blood gas analyzer to measure pH and plasma CO2 (IL BG3, Instruments Lab, Waltham, MA) and a co-oximeter (IL 482) to measure hemoglobin (Hb), Hb saturation, and blood O2 content. Blood CO2 content was calculated from measured plasma CO2 by use of a regression equation with measured values for Hb, Hb saturation, and pH (13). The mean of the nine arterial or femoral venous samples from basal and insulin-stimulated conditions was used for calculations. Blood glucose was measured, in duplicate with an automated glucose oxidase reaction (YSI 2300 Stat Plus glucose analyzer, Yellow Springs Instruments, Yellow Springs, OH), and the means of five basal and five insulin-stimulated samples were used for limb balance calculations. Serum insulin was determined using a commercially available radioimmunoassay kit (Pharmacia, Uppsala, Sweden).
For the determination of enzyme activity in skeletal muscle, small pieces of the muscle sample (~10 mg) were homogenized in a glass-glass Duall homogenizer with 39 vol of ice-cold extracting medium (0.1 M Na+-K+-phosphate, 2 mM EDTA, pH = 7.2). Homogenate was transferred into 1.5-ml polypropylene tubes, and this suspension was magnetically stirred on ice for 15 min and sonicated six times for 5 s at 20 W, on ice, with pauses of 85 s between pulses. The resulting homogenate was used for determination of activity levels of cytochrome-c oxidase (COX; EN 1.9.3.1) and carnitine O-palmitoyltransferase (CPT; EN 2.3.1.21). Spectrophotometric techniques were conducted at 30°C, according to methods previously used (10, 54). Values of these enzyme activities are expressed in units of micromoles of substrate per minute per gram of wet weight tissue (µM · minCalculations.
Leg uptake of glucose was calculated as the product of the
arteriovenous differences and blood flow. Uptake of FFA across the leg
was calculated as the product of plasma flow, arterial FFA
concentration, and the fractional extraction of
[9,10-3H]oleate across
the leg (53). Fractional extraction of
[9,10-3H]oleate across
the leg was calculated as the quotient of the arteriovenous difference
(dpm/ml) divided by arterial radioactivity (dpm/ml). Plasma flow to the
leg was calculated as blood flow × (1 Hct). Uptake of
O2 across the leg
(
O2) and production of
CO2
(
CO2) were calculated as
the product of arteriovenous differences for
O2 and
CO2 and blood flow. Values of leg
O2 and
CO2 were used in indirect
calorimetry equations to estimate glucose and lipid oxidation across
the leg, as previously described (26).
Statistical analyses.
Data are presented as means ± SE, unless otherwise indicated.
Two-way analysis of variance (ANOVA) was used to examine for effects of
group (O vs. L) and gender with respect to parameters of leg balance
studies, leg respiratory quotient (RQ), body composition, and insulin
sensitivity. Repeated-measures ANOVA was used to examine for the effect
of WL on these measures. Linear regression and step-wise multiple
regression were used to examine for correlation among adiposity,
O2 max, leg balance
of substrates, and leg RQ. Statistics were performed using Sigma Stat
2.0 (Jandel Scientific Software, San Rafael, CA).
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RESULTS |
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Skeletal muscle composition.
Body composition of lean and obese men and women are shown in Table
1. As per study design, obese subjects had
a greater mean weight and BMI than lean subjects and had greater FM and FFM. As measured by cross-sectional CT at the midthigh, obese subjects
had more subcutaneous adipose tissue and a greater cross-sectional area
of skeletal muscle (both P < 0.01).
However, skeletal muscle in obese subjects had a lower attenuation
value than that in lean subjects (39.2 ± 0.7 vs. 36.0 ± 0.8 Hounsfield units; P < 0.01). Based
on the histogram distribution of these attenuation values, obese
subjects had increased "low-density" skeletal muscle (i.e., Hounsfield units 0-30), as also shown in Table 1. Lean and obese subjects had similar values for aerobic fitness, with respective values
for O2 max of 43 ± 0.9 vs. 39 ± 0.8 ml/kg FFM; values in each group are
consistent with a sedentary status.
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Fasting metabolism measured by leg balance and enzyme activities.
Fasting values for plasma insulin were higher in obese subjects (46 ± 7 vs. 111 ± 16 pmol/l; P < 0.01), with similar arterial blood glucose (4.56 ± 0.11 vs. 4.68 ± 0.22 mmol/l). Fasting values for the arteriovenous difference of
glucose across the leg were similar in lean and obese subjects, as
shown in Table 2. Also, resting basal rates
of blood flow in the leg were similar, and thus fasting rates of
glucose uptake across the leg (LGU) were similar in lean and obese
subjects. Fasting rates of glucose oxidation across the leg, measured
by regional indirect calorimetry, were greater in obese compared with
lean subjects (P < 0.01). In both lean and obese subjects, rates of glucose oxidation exceeded rates for
uptake of blood glucose. The negative values for net storage are
indicative of glycogenolysis during postabsorptive conditions. The
negative values for net glucose storage were greater in obesity (0.12 ± 0.10 vs.
0.35 ± 0.06 µmol · min
1 · 100 ml leg tissue
1;
P < 0.05).
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Leg indirect calorimetry. During both fasting and insulin-stimulated conditions, nine arterial and nine femoral venous blood gas determinations were obtained during 40 min of steady-state conditions. Arterial Hb saturation was similar in lean and obese subjects during basal conditions (0.96 ± 0.02 vs. 0.95 ± 0.02) and had a mean within-subject coefficient of variation (CV) of 0.5%. Femoral venous Hb saturation was similar in lean and obese subjects (0.72 ± 0.02 vs. 0.70 ± 0.01), although the within-subject CV was greater at 5.2%. Arterial and venous Hb saturation was not affected by insulin infusion. Femoral venous pH was significantly lower than arterial values (P < 0.001), and the mean within-subject CV for measurement of pH was below 0.5% for both arterial and venous samples. The within-subject CVs for measurement of arterial and femoral venous CO2 were 1.9 and 1.7%, respectively, and did not change during insulin infusions compared with basal conditions.
During fasting conditions, the RQ across the leg was lower in lean compared with obese subjects (0.83 ± 0.02 vs. 0.90 ± 0.01, P < 0.01), as shown in Table 3 and Fig. 1. On the basis of values for leg RQ, lean subjects derived a substantially greater percentage of energy expenditure (EE) from lipid oxidation (59 ± 7 vs. 35 ± 4%; L and O, P < 0.01), as shown in Fig. 1. Basal rates of EE across the leg did not differ between lean and obese subjects.
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Insulin-stimulated metabolism measured by leg balance.
Arterial glucose was maintained at euglycemic values during insulin
infusions in lean and obese subjects (4.88 ± 0.08 vs. 5.03 ± 0.06 mmol/l). During insulin infusions, arterial insulin was higher in
obese subjects (483 ± 18 vs. 596 ± 25 pmol/l;
P < 0.01), consistent with reduced
insulin clearance in obesity. During steady-state insulin-stimulated
conditions, obese subjects manifested systemic insulin resistance (9.6 ± 0.6 vs. 6.0 ± 0.4 mg · min1 · kg
FFM
1;
P < 0.001) and insulin-resistant
glucose metabolism across the leg (P < 0.001). Values for leg glucose uptake, oxidation, and nonoxidative
glucose metabolism are shown in Table 4.
During insulin infusions, lean subjects had twofold greater
arteriovenous differences for glucose compared with obese subjects and
slightly higher, although not significantly greater, blood flow than
obese subjects. Rates of leg glucose uptake in lean subjects were twice the value in obese subjects. During insulin infusions, lean subjects had significantly higher rates of glucose oxidation than obese subjects
(P < 0.01). Rates of glucose uptake
exceeded rates of glucose oxidation in both groups. In lean subjects,
rates of glucose oxidation accounted for 40 ± 5% of glucose uptake,
whereas in obese subjects the percentage of glucose uptake accounted
for by glucose oxidation was 55 ± 5%. Nonoxidative glucose
metabolism across the leg during insulin infusion was significantly
higher in lean subjects (2.03 ± 0.32 vs. 0.78 ± 0.15 µmol · min
1 · 100 ml leg tissue
1;
P < 0.001). Insulin-stimulated LGU
had a positive correlation with systemic glucose metabolism
(r = 0.65;
P < 0.001) and a negative correlation with BMI (r =
0.53;
P < 0.001).
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Association between insulin sensitivity and fasting metabolism.
The second objective of this study was to address the potential
relation between insulin-resistant glucose metabolism and fasting or
insulin-stimulated patterns of fatty acid uptake and oxidation. A
decreased reliance on lipid oxidation during fasting conditions was
associated with resistance to insulin stimulation of glucose
metabolism; as shown in Fig. 2, fasting
values for leg RQ were negatively correlated with insulin sensitivity
(r = 0.57;
P < 0.001). Thus, in addition to
group differences in fasting leg RQ, there was significant correlation
between the individual variation in the severity of obesity-related
insulin resistance and fasting patterns of glucose and lipid oxidation in leg tissues. However, fasting levels of fatty acids and fasting rates of fatty acid uptake across the leg did not correlate
significantly with insulin resistance.
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Effect of WL on muscle FFA metabolism.
The third objective of the current project was to examine the effect of
WL on fasting patterns of fatty acid metabolism by leg muscle and on
insulin-stimulated patterns of glucose metabolism. The time course of
the WL is shown in Fig. 3; as shown, 4 wk
of weight stabilization preceded reassessments of metabolism.
Thirty-two subjects completed the WL intervention. Mean WL was 14.0 ± 0.9 kg, of which 10.3 ± 0.8 kg were loss of FM. Detailed
studies of changes in body composition and in relation to changes in
insulin-stimulated glucose metabolism have been previously reported
(24). After WL, measurements of
O2 max were repeated
and were unchanged compared with pre-WL values (39 ± 0.8 vs.
40 ± 1.1 ml/kg FFM).
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DISCUSSION |
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One of the striking physiological characteristics of skeletal muscle is metabolic flexibility (48), expressed by a high capacity to modulate rates of energy production, blood flow, and substrate utilization. Part of this metabolic plasticity of skeletal muscle is the capacity to utilize either carbohydrate or fatty acids. In obesity, there is a well-characterized impairment in the capacity of skeletal muscle to modulate glucose uptake in response to insulin (15). The present studies were undertaken to address whether another aspect of obesity-related "insulin resistance" could be perturbations of fatty acid metabolism during fasting conditions. The chief impetus for this query derives from the emerging concept that fat deposition within skeletal muscle is increased in obesity and is associated with the severity of insulin resistance (23, 38, 53). These findings raise the question of how lipid accumulates within skeletal muscle in obesity. During resting postabsorptive conditions, as after an overnight fast, it is generally considered that the predominant substrate oxidized by skeletal muscle is lipid, provided substantially by a high rate of uptake of plasma FFA (2, 55).
In the current study, during fasting conditions, these patterns were reaffirmed in lean subjects. However, in obese subjects, despite rates of fatty acid uptake that were equivalent to those of lean subjects, fasting rates of fatty acid oxidation by leg tissues were significantly lower. The values for the RQ across the leg denoted a reduced reliance on lipid oxidation in obesity, such that only one-third of energy production was accounted for by fat oxidation, whereas nearly twice this proportion was found in muscle of lean volunteers. Skeletal muscle in the obese subjects had lower attenuation value on CT, a biophysical characteristic suggestive of increased lipid content (9). Fasting rates of fatty acid uptake across the leg were greater than fasting rates of lipid oxidation, indicating a modest net surplus of fatty acid uptake, as has been well described in animal studies (8, 14). These rates of "net storage" of fatty acids were greater in obesity. Thus the paradigm we would propose on the basis of these novel physiological observations is that, in obesity, skeletal muscle accrues triglyceride due to a reduced rate of lipid oxidation in the face of equivalent fatty acid uptake. Furthermore, fasting patterns of fatty acid metabolism by muscle correlated with the severity of insulin-resistant glucose metabolism and, in obesity, fat oxidation in muscle is resistant to modulation by physiological hyperinsulinemia. It was also observed that weight loss only partially rectifies these patterns, with lesser effects on fatty acid metabolism compared with glucose metabolism, raising the provocative question as to whether abnormal fatty acid metabolism by muscle is a primary rather than acquired metabolic impairment in obesity or obesity-prone individuals.
A decreased reliance on lipid oxidation has previously been identified as a metabolic risk factor for weight gain (59), and this was related to a decreased oxidative enzyme capacity of skeletal muscle (17, 60). The findings of the current study provide further support that decreased oxidative enzyme capacity of skeletal muscle and reduced activity of CPT may be a mechanism responsible for reduced fasting rates of fatty acid oxidation in obesity, despite more than sufficient uptake of plasma fatty acids and despite an expanded tissue triglyceride content. Lower oxidative enzyme capacity in muscle in obesity has been previously reported (32), as has lower CPT activity (10), and in prior studies, we had reported a positive correlation between oxidative enzyme capacity of muscle and insulin-stimulated glucose metabolism (10, 54); this has been confirmed by others (28). In studies with rat skeletal muscle, it has been well established that oxidative muscle fibers have an increased capacity for the uptake and oxidation of fatty acids compared with glycolytic muscle fibers (8, 14, 37). Marked defects of CPT in skeletal muscle can produce clinically symptomatic impairment of fat oxidation, manifest especially during fasting and exercise, as well as lipid accumulation within muscle (50). However, the severity of the impairment in CPT found among obese subjects in the current study is not this extreme but nevertheless might impede fatty acid oxidation.
The concept that perturbed skeletal muscle fatty acid metabolism may contribute to skeletal muscle insulin resistance in certainly not new (34, 40), although the hypothesis that insulin resistance is associated with decreased fasting fatty acid oxidation is a novel reformulation. It has been well established, including work from our laboratory, that experimental infusions of fatty acids can induce insulin resistance (5, 25). However, several recent studies indicate that glucose inhibits fat oxidation (33, 52), a so-called "reverse Randle cycle," which could be pertinent to the observation that insulin-resistant skeletal muscle in animal models of obesity has increased malonyl-CoA (44, 46, 47). Under the stimulation of insulin, utilization of fatty acids by skeletal muscle is normally suppressed (25, 26). In obesity, this effect of insulin to suppress lipid oxidation is blunted (16, 30), which does fit the classic concept of fatty acid-induced insulin resistance (40). Incomplete suppression of lipid oxidation during insulin stimulation was observed among the obese volunteers in the current study, and rates of muscle lipid oxidation during insulin infusion correlated with the severity of insulin-resistant glucose metabolism. Yet, these observations do not indicate that fatty acid oxidation within insulin-resistant muscle is persistently "increased." Although insulin infusion did not suppress muscle lipid oxidation in obesity (compared with strong suppression in lean individuals), a salient point to emphasize is that, in obesity, rates of fat oxidation in skeletal muscle during insulin infusion were unchanged from the fasting condition and were lower than in lean individuals during fasting. Rates of fatty acid uptake during insulin infusions did not have a significant association with insulin resistance, whereas, in stepwise regression analysis, greater amounts of low-density muscle and an elevated fasting leg RQ contributed independently to account for nearly one-half of the variability in insulin resistance. The amount of low-density muscle also correlated (negatively) with the suppression of fat oxidation by insulin. The tissue composition data reinforce the emerging concept that muscle triglyceride in obesity is reflective of the severity of insulin resistance and may be a link between perturbed metabolism of fatty acids and insulin-resistant glucose metabolism. Thus, in regard to the nature of substrate competition, muscle in obesity most plainly manifested a severe inflexibility in the modulation of fatty acid oxidation, with neither suppression by insulin infusion nor an appropriate enhancement in response to an overnight fast.
Another important component of the metabolic inflexibility and perturbed patterns of fatty acid oxidation in obesity was the observation that a poor reliance on fatty acid oxidation by skeletal muscle during fasting conditions significantly predicted the severity of insulin-resistant glucose metabolism, as was shown in Fig. 1. To our knowledge, this is the first report of a correlation between fasting patterns of substrate oxidation in muscle and insulin-resistant glucose metabolism. The observation, although only associative in nature rather than truly mechanistic, is important because it extends the "phenotype of insulin resistance" in skeletal muscle beyond defects of insulin-stimulated metabolism to a broader concept of an organ system poorly performing one of its key homeostatic functions of substrate utilization. This concept may be central to understanding the role of skeletal muscle in the pathogenesis of obesity and obesity-related comorbid conditions, such as type II diabetes mellitus.
The third objective of the current study was to examine the effect of weight loss, and more narrowly defined, weight loss achieved through restricted calorie intake and without changes in physical activity patterns or maximal aerobic capacity. A substantial weight loss was achieved and then was followed by a 1-mo period of careful weight stabilization before reassessments of metabolism. The positive effects of this weight loss on insulin-resistant glucose metabolism, and on reductions in visceral adiposity, muscle adiposity, and metabolic factors such as hyperinsulinemia, lipoproteins, and blood pressure have been previously reported (24). The data of the current study concern primarily the effects on patterns of fatty acid uptake and oxidation in skeletal muscle. With respect to fasting patterns of skeletal muscle fatty acid metabolism, the effect of weight loss was relatively modest. Skeletal muscle oxidative enzyme activity was slightly diminished, and activity of CPT was unchanged (and remained lower than in lean subjects). Not unexpectedly (1, 29), rates of resting energy expenditure measured by limb balance were lower than in the obese state. The rates of fatty acid uptake were slightly reduced. However, the leg RQ was unchanged from pre-WL values, and thus reliance of skeletal muscle upon fat oxidation during fasting conditions was not improved. Persistent impairment of fatty acid metabolism has been previously reported after weight loss (4, 7, 41). These data would suggest that these defects could be primary impairments, leading to obesity rather than merely resulting from obesity. Furthermore, it is interesting to speculate on what might have happened had the intervention included aerobic exercise. In lean sedentary subjects, aerobic exercise training promotes an increase in oxidative enzyme capacity, and this is accompanied by an increased rate of fatty acid oxidation during exercise conditions (22, 56).
Two changes that did occur in muscle fatty acid metabolism after weight loss were that insulin infusion stimulated a significant rise in leg RQ (compared with fasting values) and a significant suppression of fat oxidation, and there was an overall increase in muscle attenuation values on CT imaging. Furthermore, after weight loss, rates of fatty acid uptake during insulin-stimulated conditions were nearly equivalent to rates of fat oxidation, whereas the rate of fat oxidation had exceeded fatty acid uptake during insulin infusions before weight loss. This change in insulin-stimulated patterns of muscle fatty acid metabolism is indicative of more complete suppression of lipolysis of muscle triglyceride.
Many of the observations of the current study are based on limb balance methods, including the use of regional indirect calorimetry, and it is important to review some of the limitations of these methods. One of the advantages of limb balance is to "isolate" peripheral tissue metabolism from systemic patterns, which is of particular value for studies of fasting metabolism wherein the contribution of skeletal muscle is relatively modest. The original observations of a high reliance on fatty acid oxidation by human skeletal muscle in lean, healthy individuals were made by Andres and colleagues (Andres and Cadar, Ref. 2, and Baltzan et al., Ref. 3) by use of the limb balance method; the current data on lean subjects closely conform to the patterns presented in those previous studies. Furthermore, the mean rates of lipid and glucose oxidation across the leg found in the current study are highly consistent with several prior reports from our laboratory published over the past five years (10, 27, 33). Nevertheless, it is important, as previously suggested by Frayn et al. (19), that data on regional indirect calorimetry be interpreted within the context of substrate exchange. This was comprehensively followed in the current study, in that values for leg RQ were one aspect of an integrated physiological context of fatty acid and glucose uptake, tissue composition, and muscle biochemistry. In this context, an elevated fasting value for leg RQ and a resistance to modulate values for leg RQ by insulin infusion were significantly correlated with obesity, with altered muscle composition in obesity (in a pattern denoting increased lipid content), and with insulin-resistant patterns of glucose uptake. The tissues of the leg that could be responsible for the leg RQ patterns include skeletal muscle, adipose tissue, skin, and bone. Adipose tissue has a relatively high value for RQ, of ~1.0, (18), and conceivably the increased adiposity of the leg in obese subjects caused the higher values for leg RQ. However, adipose tissue has a substantially lower rate of oxygen consumption than skeletal muscle, being estimated at approximately one-tenth of the rate of oxygen consumption by resting skeletal muscle. In the current study, rates of energy expenditure across the leg were similar in lean and obese subjects despite the greater adiposity in obese subjects, and there was no significant correlation between the amount of thigh adiposity and rates of energy expenditure across the leg. Furthermore, there was no significant correlation between leg adipose tissue and values for leg RQ, whereas the values for leg RQ did relate to several independently measured parameters of leg glucose metabolism, and these are widely accepted as predominantly reflective of muscle metabolism. Moreover, the enzyme activities and determinations of muscle composition are independent markers that skeletal muscle has a reduced efficiency for the oxidation of fat in obesity. Another potential consideration concerns the determinations of blood flow, or more precisely the tissue distribution of blood flow, which is important both for calculation of limb balance exchanges of substrate and for interpolation of respective tissue contributions (e.g., muscle and adipose tissue) to metabolism. Venous occlusion strain-gauge plethysmography, as used in the current study, provides a measurement of flow to all tissue of the extremity and therefore does not solely represent skeletal muscle blood flow (43).
In summary, the current study indicates that skeletal muscle in obesity is more disposed to partition fatty acids toward esterification during fasting conditions and manifests a lesser reliance on fatty acid oxidation compared with skeletal muscle of lean individuals. Biochemical markers are consistent with these findings, as reduced oxidative enzyme capacity and a diminished activity of CPT were found in obesity. The diminished capacity for fatty acid oxidation in obesity may contribute more directly to accretion of triglyceride within muscle than fatty acid uptake per se, because rates of the latter were not increased in obesity. Also, fasting patterns of fatty acid oxidation by muscle in obesity were found to associate with insulin-resistant glucose metabolism and yet, unlike glucose metabolism, did not improve substantially after weight loss, although improvement in insulin suppression of muscle lipid oxidation was observed. These intervention data suggest that an important area of future research should be to better determine whether the fasting impairment of fat oxidation in skeletal muscle is indeed a primary metabolic defect disposing to obesity and to weight regain after weight loss. In conclusion, the current study supports the concept that perturbations of fatty acid metabolism in skeletal muscle are integral components of the phenotype of obesity-related insulin resistance.
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ACKNOWLEDGEMENTS |
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We are grateful for the participation of the research volunteers and acknowledge the help and cooperation of the nursing and nutritional staffs at the General Clinical Research Center and the Obesity and Nutrition Research Center of the University of Pittsburgh. We acknowledge specifically the special efforts of Nancy Mazzei, Amy Meier, Susan Andreko, Dr. Monica Nuturajhan, and Freddy Troost. We are also grateful for the support of Novartis Pharmaceuticals in providing Optifast for the weight loss intervention.
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FOOTNOTES |
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This research was supported by funding from National Institutes of Health (NIH) R01 DK-49200-02, General Clinical Research Center Grant 5M01RR-00056, and Obesity and Nutrition Research Center Grant 1P30DK-46204. B. Goodpaster was supported by NIH National Research Service Award DK-07052-23.
The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. §1734 solely to indicate this fact.
Address for correspondence and reprint requests: D. E. Kelley, E-1140 Biomedical Science Tower, Dept. of Medicine, Univ. of Pittsburgh, Pittsburgh, PA 15261 (E-mail: kelley{at}med1.dept-med.pitt.edu).
Received 22 February 1999; accepted in final form 17 August 1999.
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