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Effect of exercise training on metabolic flexibility in response to a high-fat diet in obese individuals

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Obese individuals typically exhibit a reduced capacity for metabolic flexibility by failing to increase fatty acid oxidation (FAO) upon the imposition of a high fat diet (HFD). Exercise training increases FAO in the skeletal muscle of obese individuals, but whether this intervention restores metabolic flexibility is unclear. The purpose of this study was to compare FAO in the skeletal muscle of lean and obese subjects in response to a HFD before and after exercise training. Twelve lean (mean ± SEM) (age 21.8 ± 1.1y; BMI 22.6 ± 0.7 kg/m(2)) and 10 obese (age 22.4 ± 0.8y; BMI 33.7 ± 0.7 kg/m(2)) men consumed a eucaloric HFD (70% of energy from fat) for 3d. After a washout period, 10 consecutive days of aerobic exercise (1h/d, 70% VO(2)peak) were performed with the HFD repeated during days 8-10. FAO and indices of mitochondrial content were determined from muscle biopsies. In response to the HFD, lean subjects increased complete FAO (27.3 ± 7.4%, p=0.03) in contrast to no change in their obese counterparts (1.0 ± 7.9%). After 7 days of exercise, citrate synthase activity and FAO increased (p<0.05) regardless of body habitus; addition of the HFD elicited no further increase in FAO. These data indicate that obese, in contrast to lean, individuals do not increase FAO in skeletal muscle in response to a HFD. The increase in FAO with exercise training, however, enables the skeletal muscle of obese individuals to respond similarly to their lean counterparts when confronted with short-term excursion in dietary lipid.
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Effect of exercise training on metabolic flexibility in response to a high-fat
diet in obese individuals
Gina M. Battaglia,
1,2,3
Donghai Zheng,
1,2,3
Robert C. Hickner,
1,2,3
and Joseph A. Houmard
1,2,3
1
Department of Kinesiology, College of Health and Human Performance, East Carolina University, Greenville, North
Carolina;
2
Human Performance Laboratory, College of Health and Human Performance, East Carolina University,
Greenville, North Carolina; and
3
East Carolina Diabetes and Obesity Institute, East Carolina University, Greenville,
North Carolina
Submitted 12 July 2012; accepted in final form 7 October 2012
Battaglia GM, Zheng D, Hickner RC, Houmard JA. Effect of exercise
training on metabolic flexibility in response to a high-fat diet in obese
individuals. Am J Physiol Endocrinol Metab 303: E1440 –E1445, 2012. First
published October 9, 2012; doi:10.1152/ajpendo.00355.2012.—Obese indi-
viduals typically exhibit a reduced capacity for metabolic flexibility
by failing to increase fatty acid oxidation (FAO) upon the imposition
of a high-fat diet (HFD). Exercise training increases FAO in the
skeletal muscle of obese individuals, but whether this intervention can
restore metabolic flexibility is unclear. The purpose of this study was
to compare FAO in the skeletal muscle of lean and obese subjects in
response to a HFD before and after exercise training. Twelve lean
(means SE) (age 21.8 1.1 yr, BMI 22.6 0.7 kg/m
2
) and 10
obese men (age 22.4 0.8 yr, BMI 33.7 0.7 kg/m
2
) consumed a
eucaloric HFD (70% of energy from fat) for 3 days. After a washout
period, 10 consecutive days of aerobic exercise (1 h/day, 70%
V
˙O
2peak
) were performed, with the HFD repeated during days 8 –10.
FAO and indices of mitochondrial content were determined from
muscle biopsies. In response to the HFD, lean subjects increased
complete FAO (27.3 7.4%, P0.03) in contrast to no change in
their obese counterparts (1.0 7.9%). After 7 days of exercise, citrate
synthase activity and FAO increased (P0.05) regardless of body
habitus; addition of the HFD elicited no further increase in FAO.
These data indicate that obese, in contrast to lean, individuals do not
increase FAO in skeletal muscle in response to a HFD. The increase
in FAO with exercise training, however, enables the skeletal muscle
of obese individuals to respond similarly to their lean counterparts
when confronted with short-term excursion in dietary lipid.
skeletal muscle; fat oxidation; mitochondria; physical activity
THE PREVALENCE OF OBESITY has been increasing rapidly and is
strongly associated with the development of insulin resistance,
the metabolic syndrome, and type 2 diabetes (10). An impor-
tant indicator of metabolic health is metabolic flexibility,
which is the ability to adjust substrate utilization to changes in
substrate availability (16). For example, in lean individuals,
fatty acid oxidation (FAO) at the whole body level increases
with the imposition of a high-fat diet (HFD); to the contrary,
obese individuals display an impaired capacity to increase
FAO in the face of an elevation in dietary lipid (1, 11, 15, 21).
In the skeletal muscle of lean individuals, a HFD also increased
the transcription of genes involved in fatty acid transport and
oxidation in contrast to minimal or no changes in their obese
counterparts (3, 6, 20). This inability to increase FAO when
lipid presence is elevated creates a condition of positive fat
balance, which in skeletal muscle may lead to ectopic lipid
accumulation (21), lipid peroxidation (23), and excessive in-
creases in lipid intermediates such as diacylglycerol and cer-
amide, resulting in intracellular lipotoxicity (18).
Our research has demonstrated that obese and formerly
severely obese (BMI 40 kg/m
2
) individuals who lost weight
increased lipid oxidation in skeletal muscle to the same extent
as lean subjects with 10 days of endurance-oriented exercise
training (2). However, it is not evident whether exercise train-
ing restores metabolic flexibility with respect to adjusting
appropriately (i.e., similar to lean subjects) to an increase in
dietary lipid. The purposes of the present study were to deter-
mine 1) whether the skeletal muscle of young, obese individ-
uals lacks metabolic flexibility in terms of increasing FAO in
response to a HFD and 2) whether exercise training can correct
any impairment in metabolic flexibility evident with obesity.
METHODS
Subjects. Twelve lean (BMI 25 kg/m
2
) and 10 obese (BMI
30 kg/m
2
) male subjects aged 18 –30 yr volunteered to participate.
Subjects were not involved in an aerobic training program, as deter-
mined by a physical activity questionnaire and verbal questioning, and
were asked to not change their physical activity patterns throughout
the duration of the study. Participants filled out a medical history to
confirm that they were free from disease, did not smoke, and were not
taking any medications known to influence carbohydrate or lipid
metabolism. Subjects were weight stable (2 kg over the past 3 mo)
and nonsmokers. The experimental procedure and associated risks
were explained in written and oral format, and informed consent was
obtained. The study was approved by the East Carolina Policy and
Review Committee on Human Research and was in accordance with
the Declaration of Helsinki.
Study design. Each participant consumed a eucaloric HFD for 3
days while sedentary. After a 2- to 3-wk washout period, subjects
exercised for 10 consecutive days and consumed a eucaloric HFD
from days 8 to 10 of exercise training (Fig. 1). A 2-wk washout has
been used in other studies examining the effects of a HFD and
exercise (5, 27). Skeletal muscle biopsies were obtained from the
vastus lateralis after a 12-h overnight fast on the morning that the
HFD was initiated and on the morning after the 3 days of the HFD.
Blood samples were taken at the initial screening and biopsy visits.
Diet. The HFD consisted of 70% fat, 15% carbohydrate, and 15%
protein and was calculated to be eucaloric and maintain body mass. In
our preliminary studies, this fat proportion and duration (3 days)
increased FAO in skeletal muscle by 38% in four lean subjects (data
not shown), and another group reported that a similar diet increased
pyruvate dehydrogenase kinase 4 (PDK4) content and activity in
skeletal muscle (20). Energy content for each individual was deter-
mined from the Harris-Benedict equation (13), and mean macronutri-
ent content (per kg body mass) was 2.5 g/kg fat, 1.2 g/kg carbohy-
drate, and 1.0 g/kg protein; 21% of the energy intake from fat
consisted of saturated fats. Subjects were weighed before and after the
Address for correspondence: J. A. Houmard, Human Performance Labora-
tory, Ward Sports Medicine Bldg., East Carolina University, Greenville, NC
27858 (e-mail: houmardj@ecu.edu).
Am J Physiol Endocrinol Metab 303: E1440–E1445, 2012.
First published October 9, 2012; doi:10.1152/ajpendo.00355.2012.
0193-1849/12 Copyright ©2012 the American Physiological Society http://www.ajpendo.orgE1440
HFD and at the beginning of exercise training to ensure that body
weight did not change throughout the duration of the study. The 3-day
diet regimen was described to each subject in detail, emphasizing the
importance of consuming only the items indicated. Some meals were
from fast-food chains, and subjects ordered the exact items and
returned dated receipts to ensure compliance. The remainder of the
food items were prepackaged and labeled in the appropriate amount
for each given day and provided to the participants. Subjects logged
their intake. On the day prior to commencement of the HFD, subjects
were provided an isocaloric diet consisting of 25% fat, 15% protein,
and 60% carbohydrates. All diets and food logs were analyzed by
Nutritionist Pro Nutrition Analyst Software (Axxya Systems, Staf-
ford, TX) to ensure correct macronutrient composition.
Exercise training. An incremental maximal exercise test on an
electronically braked cycle ergometer was performed to determine
peak oxygen uptake (V
˙O
2peak
) during the screening process. Partici-
pants then exercised 60 min/day at 70% V
˙O
2peak
for 10 consecutive
days. All training was supervised and performed in the laboratory
setting; heart rate was monitored throughout each training session and
V
˙O
2
measurements were taken periodically to ensure proper work-
load. Net energy utilized during exercise training was determined
using indirect calorimetry and the resulting energy added to the diets
during days 8 –10 of exercise. Exercise was performed 14 –18 h before
the muscle biopsies on days 7 and 10.
Muscle analyses. Fatty acid oxidation was measured as described
previously (2, 14, 17). Briefly, 50 60 mg of muscle tissue was
collected in 200 l of a buffer containing 250 mM sucrose, 1 mM
EDTA, and 10 mM Tris·HCl, pH 7.4. Samples were minced with
scissors to remove excess fat and connective tissue and diluted 20-fold
with additional buffer. Tissue was placed on ice and homogenized
with a Teflon pestle for 30 s. Forty microliters of homogenate was
added to the top well of a sealed, modified 48-well plate that contained
a channel connecting to the adjacent trap well, which allowed for the
passage of CO
2
liberated by the complete oxidation of [1-
14
C]palmi-
tate. The bottom trap well contained 1 N sodium hydroxide to collect
the
14
CO
2
given off by the oxidation procedure. To initiate the
reaction, 160 l of a reaction buffer composed of the following was
added to the top wells: 0.2 mM palmitate ([1-
14
C]palmitate at 0.5
Ci/ml), 100 mM sucrose, 10 mM Tris·HCl, 5 mM potassium phos-
phate, 80 mM potassium chloride, 1 mM magnesium chloride, 0.1
mM malate, 2 mM ATP, 1 mM dithiothreitol, 0.2 mM EDTA, 1 mM
L-carnitine, 0.5 mM coenzyme A, and 0.5% fatty acid-free bovine
serum albumin, pH 7.4. The samples were incubated in a 37°C water
bath for 30 min, at which point 100 l of 70% perchloric acid was
added to terminate the reaction. The plate was placed on a shaker for
1 h to ensure complete transfer of CO
2
into the bottom well. Label
incorporation into
14
CO
2
was determined by scintillation counting
using 4 ml of Uniscient BD (National Diagnostics, Atlanta, GA).
Incomplete oxidative products (acid-soluble metabolites) remaining in
the top well were measured as described previously (17).
A 10- to 15-mg piece of muscle was homogenized at 4°C using a
Bullet Blender (Next Advance, Averill Park, NY) in a lysis buffer
containing 50 mM HEPES, 12 mM sodium pyrophosphate, 100 mM
sodium fluoride, 10 mM EDTA, 1% Triton X-100, and 0.1% SDS and
supplemented with protease and phosphatase inhibitors (Sigma-Al-
drich). Samples were rotated end over end on a rotating wheel for 1
h at 4°C and centrifuged at 21,000 gfor 20 min at 10°C. Protein
concentrations were determined using the bicinchoninic acid assay
(Pierce Biotechnology, Rockford, IL). Five micrograms of protein
was separated by SDS-PAGE and electrotransfered to polyvi-
nylidened flouride membranes (Millipore, Billerica, MA) and probed
overnight for cytochrome coxidase IV (1:1,000; Cell Signaling
Technology, Beverly, MA) and with a cocktail containing antibodies
against the following proteins (1:1,000): complex I subunit NDUFB8,
complex II subunit 30 kDa, complex III subunit core 2, complex IV
subunit II, and ATP synthase subunit-(Mitosciences, Eugene, OR).
Membranes were incubated for1hatroom temperature with the
corresponding secondary antibody, and the immunoreactive proteins
were detected using enhanced chemiluminescence (ChemiDoc XRS
Imaging System; Bio-Rad Laboratories, Hercules, CA). Samples were
normalized to a crude muscle homogenate sample on each gel to
normalize for blotting efficiency across gels.
A 10- to 15-mg piece of muscle was diluted 20-fold in a buffer
containing 100 mM KH
2
PO
4
and 0.05% bovine serum albumin and
homogenized at 4°C using the Bullet Blender. Homogenates went
through four freeze-thaw cycles before experimentation. This homog-
enate was used for determining citrate synthase (CS) and -hydroxy-
acetyl coenzyme A dehydrogenase (HAD) activity. Protein content
was measured using the bicinchoninic acid assay. CS activity was
assessed with reagents provided in a kit (Sigma CS0720), which used
a colorimetric reaction to measure the reaction rate of acetyl coen-
zyme A and oxaloacetic acid. Activity of HAD was measured using
methods described previously (26), and rates were determined by
calculating the rate of disappearance of NADH after the addition of
acetoacetyl coenzyme A.
Statistical analyses. Two-way repeated-measures analysis of vari-
ance was used to compare the data. Post hoc analyses were performed
using contrast-contrast analysis. Statistical significance was set at P
0.05, and all data are expressed as means SE. Because of limitations
in tissue size, all measurements could not be obtained for all individ-
uals; the nfor each variable is indicated.
RESULTS
Anthropometric data are presented in Table 1. Body mass,
BMI, fasting insulin, and homeostatic model assessment of
insulin resistance were significantly higher in the obese sub-
Table 1. Subject characteristics
Lean (n12) Obese (n10)
Age, yr 21.8 1.1 22.4 0.8
Height, cm 178.9 2.0 179.1 2.2
Mass, kg 72.2 2.4 108.4 3.3*
BMI, kg/m
2
22.6 0.7 33.7 0.7*
Body fat, % 17.7 1.8 37.5 1.8*
Fasting glucose, mmol/l 4.7 0.1 4.7 0.1
Fasting insulin, mol/l 44 8788*
HOMA-IR 1.3 0.2 2.4 0.3*
Plasma cholesterol, mmol/l 3.97 0.21 4.62 0.31
Plasma triglycerides, mmol/l 0.82 0.10 1.37 0.19*
V
˙O
2peak
,mlkg
1
min
1
36.7 1.2 27.2 1.2*
V
˙O
2peak
, l/min 2.6 0.2 2.9 0.2
Results are expressed as means SE. HOMA-IR, homeostatic model
assessment of insulin resistance. *Significantly different (P0.05) from lean.
Fig. 1. Study design. Subjects were screened and tested for maximal aerobic
capacity (V
˙O
2max
) before commencement of the study. Within 4 wk of
screening, subjects underwent a fasting muscle biopsy of the vastus lateralis,
consumed an isocaloric 70% high-fat diet (HFD) for 3 days (3d), and then had
another muscle biopsy on the morning after the final day of the HFD. After a
2- to 3-wk washout period, subjects began exercise training for 10 consecu-
tive days (10d), 1 h/day, at 70% peak oxygen consumption. On the morning of
day 8, subjects had a muscle biopsy and began consuming the HFD during
days 8–10 of exercise training. The day after the exercise training and second
HFD was finished, subjects underwent their final muscle biopsy.
E1441EXERCISE, METABOLIC FLEXIBILITY, AND OBESITY
AJP-Endocrinol Metab doi:10.1152/ajpendo.00355.2012 www.ajpendo.org
jects (P0.01). Blood lipids, glucose, and insulin did not
change as a result of the HFD or exercise training and were not
associated with FAO or mitochondrial content (data not shown).
All subjects remained weight stable throughout the course of the
study, and there were no changes in body mass in either group
(data not shown). The diet composition was similar between lean
and obese subjects (72% fat, 15% carbohydrate, and 13% protein)
and provided a significant increase in dietary fat over their normal
consumption determined from 3-day food logs performed before
commencement of the study (35% fat, 48% carbohydrate, and
17% protein).
Fatty acid oxidation in skeletal muscle. Fatty acid oxidation
in response to the high-fat diet and exercise training are
presented in Fig. 2. The lean subjects increased complete
palmitate oxidation (
14
CO
2
production) by 27% in response to
the 3-day HFD (P0.03), indicating metabolic flexibility in
response to an increase in dietary lipid. However, there was
essentially no alteration in FAO in the obese group (1%
increase vs. prediet values; Fig. 2), indicating a lack of meta-
bolic flexibility. Exercise training (P0.02) and 10 days of
exercise plus the 3-day HFD (P0.002) increased FAO above
preexercise levels in both groups; however, in relation to meta-
bolic flexibility, there was no significant increase in FAO with the
addition of the HFD after the 7 days of exercise (Fig. 2). Total
FAO (overall average 1,450.8 nmol·mg protein
1
·min
1
) and
acid-soluble metabolites (overall average 1,157.3 nmol·mg
protein
1
·min
1
) did not change with the HFD or exercise train-
ing and were not different between the lean and obese groups
(data not shown).
Skeletal muscle enzyme activities/protein content. Enzyme
activities for CS and HAD are presented in Fig. 3, Aand B,
respectively. In the sedentary state, CS activity exhibited a
pattern similar to complete FAO (Fig. 2), with a tendency for
the lean subjects to increase (12.3 7.3%, P0.17) in
response to the HFD and the obese subjects to have an
attenuated response (2.3 8.9% decrease from prediet
values). Seven days of exercise training increased CS activity
in both groups over the sedentary condition (P0.02), with no
further change at 10 days of exercise plus the HFD (P0.03
compared with sedentary prediet) (Fig. 3A). The trends for
HAD responses to the HFD and exercise training were similar
to CS, with a HFD plus exercise increase that approached
statistical significance (P0.07 compared with sedentary
prediet; Fig. 3B). Protein content of complexe II, III, and IV
and ATP synthase subunits did not change with the HFD or
exercise training and were not different between lean and obese
individuals (Fig. 4).
DISCUSSION
A decrement in metabolic flexibility with obesity was first
observed by Kelley et al. (15), who reported an inability to
increase carbohydrate oxidation in response to euglycemic/
hyperinsulinemic conditions. In terms of lipid availability, both
whole body fat oxidation (1) and the transcription of genes
A
B
Fig. 3. Citrate synthase (CS; A) and hydroxy coenzyme A dehydrogenase
(HAD; B) prediet, after 3d HFD, after 7d exercise, and after 10d exercise 3d
HFD. CS activity was determined from 12 lean and 9 obese subjects, whereas
HAD was determined from 10 lean and 8 obese subjects. Results are expressed
as means SE. ‡Significant treatment effect for 7d exercise compared with
the prediet condition (P0.02); §significant treatment effect for the 10d
exercise HFD compared with the prediet condition (P0.03).
Fig. 2. Complete palmitate oxidation (
14
CO
2
production from palmitate) in
skeletal muscle biopsies prediet, following a 3d HFD in the sedentary condi-
tion, after 7 days of exercise, and after a 3d HFD 10d exercise in lean (n
9) and obese (n8) men. Results are expressed as means SE. *Significantly
different from obese after the 3d HFD (P0.02); †significantly increased
compared with the prediet condition for lean (P0.02); ‡significant treatment
effect for 7 days (7d) of exercise compared with the prediet condition (P
0.02); §significant treatment effect for the 10d exercise HFD compared with
the prediet condition (P0.01).
E1442 EXERCISE, METABOLIC FLEXIBILITY, AND OBESITY
AJP-Endocrinol Metab doi:10.1152/ajpendo.00355.2012 www.ajpendo.org
regulating fat oxidation in skeletal muscle (3) increased in lean
individuals, whereas their obese counterparts exhibited damp-
ened responses with the imposition of a HFD. The ability to
adjust FAO appropriately in response to excursions in dietary
lipid is a critical component of metabolic health because
inflexibility may lead to positive fat balance (11), ectopic lipid
accumulation (29), and weight gain (21). In terms of interven-
tion, FAO in skeletal muscle increases in both lean and obese
individuals with relatively short-term (10-day) endurance-ori-
ented exercise training (2); however, it is not evident whether
exercise training can rescue (i.e., induce a response similar to
that seen in lean subjects) the impairment in metabolic flexi-
bility evident with obesity. The main findings of the present
study were that 1) relatively young, obese individuals lack
metabolic flexibility in terms of increasing FAO in skeletal
muscle in response to a HFD and 2) exercise training increases
FAO in skeletal muscle, which enables obese individuals to
respond to an increase in dietary lipid in a manner similar to
lean subjects.
In the current study the lean, but not obese, group increased
complete FAO in skeletal muscle in response to the 3-day HFD
(Fig. 2), which corresponds with other studies at the whole
body level (1, 29). We have reported previously that obese
individuals exhibited a diminished capacity to increase the
expression of genes that regulate fatty acid transport and
utilization in response to a HFD (3). The current findings
provide the additional information that this impairment in gene
expression with obesity likely contributes, at least in part, to
the inability to upregulate FAO in the face of increased lipid
availability (Fig. 2). However, although the patterns of change
in CS, which can reflect mitochondrial content (30), and FAO
were similar in the lean subjects (Figs. 2 and 3), it is likely that
factors involved with enhanced mitochondrial function also
contributed to the increases in FAO. PDK4, an enzyme that
inhibits activity of the pyruvate dehydrogenase complex, re-
sponds rapidly to increases in lipid presence that would in turn
partition substrates toward FAO (8). A HFD increased PDK4
protein content and overall PDK activity in lean individuals
significantly after only 1 day (20), and PDK4 mRNA was
increased in lean but not obese individuals after a 5-day 60%
fat diet (3). Thus, an inability to increase PDK4 content with
obesity may help explain the differential response to the HFD
(Fig. 2); however, this is conjecture, because limitations in
tissue size prevented us from determining PDK4 content. Also,
one of the limitations of this study was that sufficient tissue
could not be obtained for all analyses, which may have com-
promised the power for detecting statistical differences in
measurements such as CS activity.
A novel feature of the current study was the inclusion of
short-term aerobic exercise training as a possible means for
AB
CD
Fig. 4. Protein content of mitochondrial elec-
tron transport chain enzyme subunits prediet,
after 3d HFD, after 7d exercise, and after 10d
exercise 3d HFD in 9 lean and 8 obese
subjects. A: ATP synthase subunit-.B: com-
plex III core 2. C: cytochrome coxidase IV
(COX IV). D: complex II 30 kDa. Results are
expressed as means SE.
E1443EXERCISE, METABOLIC FLEXIBILITY, AND OBESITY
AJP-Endocrinol Metab doi:10.1152/ajpendo.00355.2012 www.ajpendo.org
improving metabolic flexibility. The 7 days of exercise training
increased skeletal muscle FAO to the same extent in both
groups of subjects (Fig. 2), indicative of no resistance to the
intervention with obesity. Similar increases in FAO were
reported in lean, obese, and post-gastric bypass subjects (2) and
in lean and obese Caucasian and African-American women (9)
with 10 days of exercise, suggesting that FAO in skeletal
muscle increases rapidly regardless of body habitus. However,
to our knowledge, no studies have directly examined the effect
of exercise training on metabolic flexibility in relation to an
increase in dietary lipid. We observed that with the addition of
the HFD neither the lean nor obese groups significantly in-
creased FAO above that which was evident after exercise
training alone (Fig. 2); this lack of a response indicates tech-
nically that metabolic flexibility, i.e., the ability to increase
FAO with respect to increased lipid availability, was not
enhanced. However, it is important to note that exercise train-
ing increased FAO equivalent to or beyond the increment seen
in response to the HFD alone (Fig. 2). These findings suggest
that a high absolute capacity for FAO can render the skeletal
muscle of the obese effective in dealing with increased dietary
lipid and minimizing positive lipid balance, although an en-
hanced ability to adjust utilization (metabolic flexibility) per se
is not evident.
With exercise training, CS and HAD activities mirrored the
pattern of FAO changes, with CS activity elevated compared
with the sedentary condition at both 7 and 10 days (Fig. 3).
Endurance-oriented exercise training has been shown to be a
potent means for rapidly (7–14 days) improving the maximal
activity and content of mitochondrial proteins (4, 25, 28) in
lean individuals. Although previous research in rodents have
shown an additive effect of exercise training and a HFD on CS
and HAD activities (7, 24), these enzymes did not change
either with the addition of a HFD in endurance-trained humans
(12) or in the present study (Fig. 3), implying either a species
difference or that the increase in mitochondrial content with
exercise training in humans is sufficient to adjust to subsequent
increases in dietary lipid. Similarly, rats bred for high intrinsic
running capacity had higher skeletal muscle lipid oxidation
rates compared with their low intrinsic running capacity coun-
terparts, which was due primarily to increased oxidative ca-
pacity and mitochondrial content in the white muscle fibers
(22). However, the current data cannot dismiss the possibility
that improvements in mitochondrial function also contributed
to the enhanced capacity for FAO.
Electron transport chain content was not altered with the HFD
or exercise training and did not differ with obesity (Fig. 4). The
temporal pattern of gene expression likely varies, because
Perry et al. (19) showed that CS and HAD activities increased
after 6 days of training, whereas cytochrome coxidase subunit
IV content did not increase until 10 days. However, the training
protocol of our study was moderate (1 h at 70% V
˙O
2peak
)
compared with the one employed by Perry et al. (19). There-
fore, the higher intensity of the former may have elicited a
more robust response in mitochondrial content compared with
our study.
In conclusion, 3 days of a HFD increased lipid oxidation in
the skeletal muscle of lean but not obese individuals, which
was indicative of an impairment in metabolic flexibility with
obesity. Endurance-oriented exercise training increased lipid
oxidation and CS activity in skeletal muscle regardless of body
habitus, with no incremental improvement with the addition of
a HFD. These findings suggest that the increase in FAO in
skeletal muscle with endurance-oriented exercise training en-
ables obese individuals to respond similarly to their lean
counterparts when confronted with an increase in dietary lipid
intake.
ACKNOWLEDGMENTS
We thank Angela Clark and Rita Bowden for assisting with specimen
collection and the undergraduate student assistants at East Carolina University
for assisting with exercise training and testing.
GRANTS
Funding for this work was provided by a grant from the National Institute
of Diabetes and Digestive and Kidney Diseases (DK-056112, J. A. Houmard).
DISCLOSURES
The authors have no conflicts of interest, financial or otherwise, to declare.
AUTHOR CONTRIBUTIONS
G.M.B. and J.A.H. did the conception and design of the research; G.M.B.,
D.Z., R.C.H., and J.A.H. performed the experiments; G.M.B. and D.Z. ana-
lyzed the data; G.M.B., D.Z., and J.A.H. interpreted the results of the
experiments; G.M.B. and J.A.H. prepared the figures; G.M.B. and J.A.H.
drafted the manuscript; G.M.B. and J.A.H. edited and revised the manuscript;
G.M.B. and J.A.H. approved the final version of the manuscript.
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... Individuals living with obesity inefficiently alternate between fat and carbohydrate oxidation at rest and during submaximal exercise, which is often referred to as metabolic inflexibility (Battaglia et al., 2012;Kelley et al., 1999;Mittendorfer et al., 2009). In a study by Kelley et al. (1999) measuring fuel oxidation using blood gas measures across a catheterized leg, a significantly higher respiratory quotient (RQ) value was observed in fasted individuals living with obesity (0.90 ± 0.01) compared to individuals without obesity (0.83 ± 0.02; p < 0.01) (Kelley et al., 1999). ...
... Increasing exercise levels is suggested to improve substrate oxidation in individuals living with obesity (Battaglia et al., 2012;Goodpaster et al., 2003;Jabbour & Iancu, 2017;Kanaley et al., 2001;Malin et al., 2013;Potteiger et al., 2008;Whyte et al., 2010). Continuous moderate-to-vigorous physical activity (MVPA) training has been thoroughly studied (Battaglia et al., 2012;Goodpaster et al., 2003;Kanaley et al., 2001;Malin et al., 2013;Potteiger et al., 2008), suggesting significant increases in fat oxidation at rest and during submaximal exercise. ...
... Increasing exercise levels is suggested to improve substrate oxidation in individuals living with obesity (Battaglia et al., 2012;Goodpaster et al., 2003;Jabbour & Iancu, 2017;Kanaley et al., 2001;Malin et al., 2013;Potteiger et al., 2008;Whyte et al., 2010). Continuous moderate-to-vigorous physical activity (MVPA) training has been thoroughly studied (Battaglia et al., 2012;Goodpaster et al., 2003;Kanaley et al., 2001;Malin et al., 2013;Potteiger et al., 2008), suggesting significant increases in fat oxidation at rest and during submaximal exercise. To date, few studies have investigated the impact of sprint interval training (SIT) on substrate oxidation in individuals living with obesity (Jabbour & Iancu, 2017;Whyte et al., 2010), which could be of interest due to the reduced time constraint (Korkiakangas et al., 2009). ...
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Metabolic flexibility is the ability to adapt substrate oxidation according to metabolic demand. Exercise increases fat oxidation responses in individuals living with obesity; however, limited research exists on the relationship between substrate oxidation and insulin sensitivity after sprint interval training (SIT). The primary objective was to investigate changes in substrate oxidation at rest and during submaximal exercise, and in insulin sensitivity after 4 weeks of SIT in individuals living with or without obesity. The secondary objective was to investigate correlations between changes in substrate oxidation and insulin sensitivity following SIT. Adults living with obesity (n = 16, body mass index (BMI) = 34.1 kg/m2 ± 3.8) and without obesity (n = 18, BMI = 22.9 kg/m2 ± 1.6) took part in a 4-week SIT intervention. Participants completed three sessions of SIT per week, consisting of repeated sets of a 30-s Wingate separated by 4 m of active recovery. Substrate oxidation at rest and during submaximal exercise was measured using VCO2 /VO2 . Insulin sensitivity was calculated using the Matsuda index. No difference in substrate oxidation at rest was observed for either group (p > 0.05), while a significant increase in fat oxidation was observed in individuals living with obesity [F(1,31) = 14.55, p = 0.001] during the submaximal exercise test. A significant decrease in insulin sensitivity was observed among individuals without obesity [F(1,31) = 5.010, p = 0.033]. No correlations were observed between changes in substrate oxidation and insulin sensitivity (p > 0.05). Following SIT, individuals living with obesity increased submaximal fat oxidation compared to individuals without obesity. No correlations were observed between substrate oxidation and insulin sensitivity. Thus, SIT impacts fat oxidation during exercise in individuals living with obesity while having no such influence on insulin sensitivity.
... Diet has a considerable role in metabolic flexibility, depending on the type of nutrients and the period of fasting [77]. It is well known that a decrease in circulating dietary carbohydrates and lipids and a decline in insulin/glucagon ratio during fasting induce a switch toward fatty acid oxidation [77]. ...
... Diet has a considerable role in metabolic flexibility, depending on the type of nutrients and the period of fasting [77]. It is well known that a decrease in circulating dietary carbohydrates and lipids and a decline in insulin/glucagon ratio during fasting induce a switch toward fatty acid oxidation [77]. In line with these studies, other reports have shown that subjects under a high-fat diet were able to increase fatty acid oxidation at the expense of the glycolytic rate, though this effect was not observed in obese individuals. ...
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In general, metabolic flexibility refers to an organism’s capacity to adapt to metabolic changes due to differing energy demands. The aim of this work is to summarize and discuss recent findings regarding variables that modulate energy regulation in two different pathways of mitochondrial fatty metabolism: β-oxidation and fatty acid biosynthesis. We focus specifically on two diseases: very long-chain acyl-CoA dehydrogenase deficiency (VLCADD) and malonyl-CoA synthetase deficiency (acyl-CoA synthetase family member 3 (ACSF3)) deficiency, which are both characterized by alterations in metabolic flexibility. On the one hand, in a mouse model of VLCAD-deficient (VLCAD−/−) mice, the white skeletal muscle undergoes metabolic and morphologic transdifferentiation towards glycolytic muscle fiber types via the up-regulation of mitochondrial fatty acid biosynthesis (mtFAS). On the other hand, in ACSF3-deficient patients, fibroblasts show impaired mitochondrial respiration, reduced lipoylation, and reduced glycolytic flux, which are compensated for by an increased β-oxidation rate and the use of anaplerotic amino acids to address the energy needs. Here, we discuss a possible co-regulation by mtFAS and β-oxidation in the maintenance of energy homeostasis.
... The concept of metabolic flexibility (opposed to metabolic inflexibility) indicates the ability to adjust the utilization of substrates depending on different conditions (e.g., changes in their availability) (8,62). The typical alterations observed in NAFLD patients (high triglycerides, FFAs, and insulin) led to the hypothesis that it could be a condition characterized by metabolic inflexibility (8). ...
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Metabolic (dysfunction)-associated fatty liver disease (MAFLD) is the definition recently proposed to better circumscribe the spectrum of conditions long known as non-alcoholic fatty liver disease (NAFLD) that range from simple steatosis without inflammation to more advanced liver diseases. The progression of MAFLD, as well as other chronic liver diseases, toward cirrhosis, is driven by hepatic inflammation and fibrogenesis. The latter, result of a “chronic wound healing reaction,” is a dynamic process, and the understanding of its underlying pathophysiological events has increased in recent years. Fibrosis progresses in a microenvironment where it takes part an interplay between fibrogenic cells and many other elements, including some cells of the immune system with an underexplored or still unclear role in liver diseases. Some therapeutic approaches, also acting on the immune system, have been probed over time to evaluate their ability to improve inflammation and fibrosis in NAFLD, but to date no drug has been approved to treat this condition. In this review, we will focus on the contribution of the liver immune system in the progression of NAFLD, and on therapies under study that aim to counter the immune substrate of the disease.
... For example, following an eucaloric high fat diet, fat oxidation was increased by 27% in lean individuals while no change was observed in obese individuals 9 . In other experiments, obesity-prone individuals, as identified from personal and family history, who consume hypercaloric diets, show a down-regulation in nocturnal fat oxidation compared to obesity-resistant individuals 10,11 . ...
Article
Indian adults tend to inappropriately accumulate body fat even at low Body Mass Index (BMI). Usually, fat that is stored in the fed state is mobilized for energy during nocturnal fasting, thus achieving daily fat balance. This is called metabolic flexibility, which may be lost in some individuals leading to body fat accumulation. Measuring fat balance requires 24h measurement of fat oxidation, but nocturnal fat oxidation could be a reasonable surrogate. The variability of nocturnal fat oxidation is also unknown. A retrospective analysis on 24h fat oxidation in adult men (n=18) was carried out to test the former hypothesis, while the variability of nocturnal fat oxidation was measured prospectively in 5 adult men, who were fed the same diet for 2 days prior to the measurement. Whole-body indirect calorimetry was used for measuring Respiratory Quotient (RQ), energy expenditure and fat oxidation. In 24h analyses, nocturnal (0.44 ± 0.21 g/kg) was significantly higher than diurnal fat oxidation (0.24 ± 0.21 g/kg) and was 64.5% of the total 24h value. Nocturnal fat oxidation was positively correlated with 24h fat oxidation (r = 0.937; p<0.01) and inversely correlated with 24h fat balance (r = -0.850; p<0.01). Metabolic flexibility, measured as the Fed: Fasted RQ ratio, was negatively correlated with BMI (r = -0.226; p=0.366). The intra- and inter-individual variability of 12h nocturnal fat oxidation was low, at 4.7% and 7.2%, respectively. Nocturnal fat oxidation has a low variability when prior diets over 2 days are constant and the Fed: Fasted RQ ratio is an index of metabolic flexibility, which relates to BMI in young adults.
... This adaptation indicates an improved capacity to acutely and more quickly metabolise large amounts of carbohydrates consumed at breakfast. This finding is in agreement with previous reports of a positive effect of training on features of MetFlex, such as ΔRQ under insulin-stimulated conditions [8,23,24] and in vitro skeletal muscle palmitate oxidation [25] in individuals with type 2 diabetes and insulin resistance. While we observed a significant improvement in MetFlex after training, this was only evident when assessed by the meal challenge and not under the insulin-stimulated conditions of the hyperinsulinaemiceuglycaemic clamp. ...
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Aims/hypothesis The aim of this study was to assess metabolic flexibility (MetFlex) in participants with type 2 diabetes within the physiologically relevant conditions of sleeping, the post-absorptive (fasting) state and during meals using 24 h whole-room indirect calorimetry (WRIC) and to determine the impact of aerobic training on these novel features of MetFlex. Methods Normal-weight, active healthy individuals (active; n = 9), obese individuals without type 2 diabetes (ND; n = 9) and obese individuals with type 2 diabetes (n = 23) completed baseline metabolic assessments. The type 2 diabetes group underwent a 10 week supervised aerobic training intervention and repeated the metabolic assessments. MetFlex was assessed by indirect calorimetry in response to insulin infusion and during a 24 h period in a whole-room indirect calorimeter. Indices of MetFlex evaluated by WRIC included mean RQ and RQ kinetic responses after ingesting a standard high-carbohydrate breakfast (RQBF) and sleep RQ (RQsleep). Muscle mitochondrial energetics were assessed in the vastus lateralis muscle in vivo and ex vivo using ³¹P-magnetic resonance spectroscopy and high-resolution respirometry, respectively. Results The three groups had significantly different RQsleep values (active 0.823 ± 0.04, ND 0.860 ± 0.01, type 2 diabetes 0.842 ± 0.03; p < 0.05). The active group had significantly faster RQBF and more stable RQsleep responses than the ND and type 2 diabetes groups, as demonstrated by steeper and flatter slopes, respectively. Following the training intervention, the type 2 diabetes group displayed significantly increased RQBF slope. Several indices of RQ kinetics had significant associations with in vivo and ex vivo muscle mitochondrial capacities. Conclusions/interpretation Twenty-four hour WRIC revealed that physiological RQ responses exemplify differences in MetFlex across a spectrum of metabolic health and correlated with skeletal muscle mitochondrial energetics. Defects in certain features of MetFlex were improved with aerobic training, emphasising the need to assess multiple aspects of MetFlex and disentangle insulin resistance from MetFlex in type 2 diabetes. Trial registration ClinicalTrials.gov NCT01911104. Funding This study was funded by the ADA (grant no. 7-13-JF-53). Graphical abstract
... It is known that both intermittent fasting and exercise training can help improve metabolic flexibility in high-fat diet conditions [34,35]; however, little is known about how these lifestyles affect metabolic flexibility in response to an acute exercise bout in a healthy population. When we examined transcriptional markers of lipid metabolism and glucose metabolism, entrainment with exercise and delayed feeding post exercise yielded lower levels of fatty acid binding protein, hormone sensitive lipase and fatty acid synthase after acute exercise, while there were no differences in the transcription of genes regulating glucose metabolism. ...
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Time-restricted feeding (TRF) is becoming a popular way of eating in physically active populations, despite a lack of research on metabolic and performance outcomes as they relate to the timing of food consumption in relation to the time of exercise. The purpose of this study was to determine if the timing of feeding/fasting after exercise training differently affects muscle metabolic flexibility and response to an acute bout of exercise. Male C57BL/6 mice were randomized to one of three groups for 8 weeks. The control had ad libitum access to food before and after exercise training. TRF-immediate had immediate access to food for 6 h following exercise training and the TRF-delayed group had access to food 5-h post exercise for 6 h. The timing of fasting did not impact performance in a run to fatigue despite TRF groups having lower hindlimb muscle mass. TRF-delayed had lower levels of muscle HSL mRNA expression and lower levels of PGC-1α expression but displayed no changes in electron transport chain enzymes. These results suggest that in young populations consuming a healthy diet and exercising, the timing of fasting may not substantially impact metabolic flexibility and running performance.
... Metabolic flexibility is the ability of the organism to adjust fuel utilization according to a multi-factorial network that includes substrate sensing, trafficking, storage, availability, and demand (Smith et al., 2018), and is a key indicator of mitochondrial dysfunction via its link to type 2 diabetes mellitus (Galgoni et al., 2008), metabolic syndrome (Fonseca, 2005), insulin resistance (Kelley et al., 1999;Kelley and Mandarino, 2000), obesity (Kelley et al., 1999) and health (Duchan, 2004;Nicolson, 2007;Galgani et al., 2008a,b;Galgani et al., 2008). Metabolic flexibility is known to be heavily influenced by lifestyle changes, including diet, weight loss, and increased physical activity (Achten and Jeukendrup, 2004;Battaglia et al., 2012;Corpeleijn et al., 2009). ...
Article
Purpose Metabolic flexibility is compromised in individuals suffering from metabolic diseases, lipo- and glucotoxicity, and mitochondrial dysfunctions. Exercise studies performed in cold environments have demonstrated an increase in lipid utilization, which could lead to a compromised substrate competition, glycotoxic-lipotoxic state, or metabolic inflexibility. Whether metabolic flexibility is altered during incremental maximal exercise to volitional fatigue in a cold environment remains unclear. Methods Ten young healthy participants performed four maximal incremental treadmill tests to volitional fatigue, in a fasted state, in a cold (0 °C) or a thermoneutral (22.0 °C) environment, with and without a pre-exercise ingestion of a 75-g glucose solution. Metabolic flexibility was assessed via indirect calorimetry using the change in respiratory exchange ratio (ΔRER), maximal fat oxidation (ΔMFO), and where MFO occurred along the exercise intensity spectrum (ΔFatmax), while circulating lactate and glucose levels were measured pre and post exercise. Results Multiple linear mixed-effects regressions revealed an increase in glucose oxidation from glucose ingestion and an increase in lipid oxidation from the cold during exercise (p < 0.001). No differences were observed in metabolic flexibility as assessed via ΔRER (0.05 ± 0.03 vs. 0.05 ± 0.03; p = 0.734), ΔMFO (0.21 ± 0.18 vs. 0.16 ± 0.13 g min⁻¹; p = 0.133) and ΔFatmax (13.3 ± 19.0 vs. 0.6 ± 21.3 %V̇O2peak; p = 0.266) in cold and thermoneutral, respectively. Conclusions Following glucose loading, metabolic flexibility was unaffected during exercise to volitional fatigue in a cold environment, inducing an increase in lipid oxidation. These results suggest that competing pathways responsible for the regulation of fuel selection during exercise and cold exposure may potentially be mechanistically independent. Whether long-term metabolic influences of high-fat diets and acute lipid overload in cold and warm environments would impact metabolic flexibility remain unclear.
Chapter
This chapter summarizes how fatty acid (FA) oxidation is regulated in skeletal muscle during exercise and the role of obesity in regulation of FA oxidation in skeletal muscle. The substrates fueling increased FA oxidation in skeletal muscle during exercise are mainly circulating FAs, although hydrolysis of circulating triacylglycerol (TG) in very-low-density lipoproteins (VLDL-TG) and especially lipolysis of intramuscular TG (IMTG) also appear to contribute to some extent. Several steps are involved in FA uptake and oxidation in skeletal muscle and could all be of importance in the regulation of FA oxidation during exercise. Besides trans-sarcolemmal FA uptake via fatty acid transporters, it appears that intramyocellular carnitine content plays an important regulatory step in regulation of substrate selection during exercise. Interestingly, individuals with obesity exhibit a compromised ability to oxidize FAs and to increase FA oxidation in response to lipid exposure (reduced metabolic flexibility). Skeletal muscle mitochondrial function appears to be related to this defect. It remains controversial whether this impaired FA oxidative capacity in obesity diminishes the ability to increase and properly regulate FA oxidation during an acute, single exercise bout. However, despite these initial impairments in FA oxidation capacity in the obese situation, endurance exercise training can rescue the capacity for FA oxidation and the metabolic flexibility in the skeletal muscle of individuals with obesity at least to equivalent levels of their lean counterparts.
Article
A metabolically flexible state exists when there is a rapid switch between glucose and fatty acids during the transition between the fed and fasting state. This flexibility in fuel choice serves to prevent hyperglycemia following a meal and simultaneously ensures an adequate amount of blood glucose is available for delivery to the brain and exclusively glycolytic tissues during fasting. The modern era is characterized by chronic overnutrition in which a mixture of fuels is delivered to the mitochondria in an unabated manner thereby uncoupling the feast and famine situation. The continuous influx of fuel leads to accumulation of reducing equivalents in the mitochondria and an increase in the mitochondrial membrane potential. These changes create a microenvironment fostering the generation of reactive oxygen species and other metabolites leading to deleterious protein modification, cell injury, and ultimately clinical disease. Insulin resistance may also play a primary role in this deleterious effect. The imbalance between mitochondrial energy delivery and use is made worse with a sedentary lifestyle. Maneuvers that restore energy balance across the mitochondria activate pathways that remove or repair damaged molecules and restore the plasticity characteristic of normal energy metabolism. Readily available strategies to maintain energy balance across the mitochondria include exercise, various forms of caloric restriction, administration of sodium-glucose cotransporter-2 inhibitors, cold exposure, and hypobaric hypoxia.
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Healthspan is the period of our life without major debilitating diseases. In the modern world where unhealthy lifestyle choices and chronic diseases taper the healthspan, which lead to an enormous economic burden, finding ways to promote healthspan becomes a pressing goal of the scientific community. Exercise, one of humanity’s most ancient and effective lifestyle interventions, appears to be at the center of the solution since it can both treat and prevent the occurrence of many chronic diseases. Here, we will review the current evidence and opinions about regular exercise promoting healthspan through enhancing the functionality of our organ systems and preventing diseases.
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Context The prevalence of obesity and overweight increased in the United States between 1978 and 1991. More recent reports have suggested continued increases but are based on self-reported data.Objective To examine trends and prevalences of overweight (body mass index [BMI] ≥25) and obesity (BMI ≥30), using measured height and weight data.Design, Setting, and Participants Survey of 4115 adult men and women conducted in 1999 and 2000 as part of the National Health and Nutrition Examination Survey (NHANES), a nationally representative sample of the US population.Main Outcome Measure Age-adjusted prevalence of overweight, obesity, and extreme obesity compared with prior surveys, and sex-, age-, and race/ethnicity–specific estimates.Results The age-adjusted prevalence of obesity was 30.5% in 1999-2000 compared with 22.9% in NHANES III (1988-1994; P<.001). The prevalence of overweight also increased during this period from 55.9% to 64.5% (P<.001). Extreme obesity (BMI ≥40) also increased significantly in the population, from 2.9% to 4.7% (P = .002). Although not all changes were statistically significant, increases occurred for both men and women in all age groups and for non-Hispanic whites, non-Hispanic blacks, and Mexican Americans. Racial/ethnic groups did not differ significantly in the prevalence of obesity or overweight for men. Among women, obesity and overweight prevalences were highest among non-Hispanic black women. More than half of non-Hispanic black women aged 40 years or older were obese and more than 80% were overweight.Conclusions The increases in the prevalences of obesity and overweight previously observed continued in 1999-2000. The potential health benefits from reduction in overweight and obesity are of considerable public health importance.
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We examined the time course of metabolic adaptations to 15 days of a high-fat diet (HFD). Sixteen endurance-trained cyclists were assigned randomly to a control (CON) group, who consumed their habitual diet (30% ± 8% mJ fat), or a HFD group, who consumed a high-fat isocaloric diet (69% ± 1% mJ fat). At 5-day intervals, the subjects underwent an oral glucose tolerance test (OGTT); on the next day, they performed a 2.5-hour constant-load ride at 70% peak oxygen consumption (VO2peak), followed by a simulated 40-km cycling time-trial while ingesting a 10% 14C-glucose + 3.44% medium-chain triglyceride (MCT) emulsion at a rate of 600 mL/h. In the OGTT, plasma glucose concentrations at 30 minutes increased significantly after 5 days of the HFD and remained elevated at days 10 and 15 versus the levels measured prior to the HFD (P < .05). The activity of carnitine acyltransferase (CAT) in biopsies of the vastus lateralis muscle also increased from 0.45 to 0.54 μmol/g/min over days 0 to 10 of the HFD (P < .01) without any change in citrate synthase (CS) or 3-hydroxyacyl-coenzyme A dehydrogenase (3-HAD) activities. Changes in glucose tolerance and CAT activity were associated with a shift from carbohydrate (CHO) to fat oxidation during exercise (P < .001), which occurred within 5 to 10 days of the HFD. During the constant-load ride, the calculated oxidation of muscle glycogen was reduced from 1.5 to 1.0 g/min (P < .001) after 15 days of the HFD. Ingestion of a HFD for as little as 5 to 10 days significantly altered substrate utilization during submaximal exercise but did not attenuate the 40-km time-trial performance.
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Chronic metabolic diseases develop from the complex interaction of environmental and genetic factors, although the extent to which each contributes to these disorders is unknown. Here, we test the hypothesis that artificial selection for low intrinsic aerobic running capacity is associated with reduced skeletal muscle metabolism and impaired metabolic health. Rat models for low- (LCR) and high- (HCR) intrinsic running capacity were derived from genetically heterogeneous N:NIH stock for 20 generations. Artificial selection produced a 530% difference in running capacity between LCR/HCR, which was associated with significant functional differences in glucose and lipid handling by skeletal muscle, as assessed by hindlimb perfusion. LCR had reduced rates of skeletal muscle glucose uptake (∼30%; P = 0.04), glucose oxidation (∼50%; P = 0.04), and lipid oxidation (∼40%; P = 0.02). Artificial selection for low aerobic capacity was also linked with reduced molecular signaling, decreased muscle glycogen, and triglyceride storage, and a lower mitochondrial content in skeletal muscle, with the most profound changes to these parameters evident in white rather than red muscle. We show that a low intrinsic aerobic running capacity confers reduced insulin sensitivity in skeletal muscle and is associated with impaired markers of metabolic health compared with high intrinsic running capacity. Furthermore, selection for high running capacity, in the absence of exercise training, endows increased skeletal muscle insulin sensitivity and oxidative capacity in specifically white muscle rather than red muscle. These data provide evidence that differences in white muscle may have a role in the divergent aerobic capacity observed in this generation of LCR/HCR.
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In lean individuals, increasing dietary lipid can elicit an increase in whole body lipid oxidation; however, with obesity the capacity to respond to changes in substrate availability appears to be compromised. To determine whether the responses of genes regulating lipid oxidation in skeletal muscle differed between lean and insulin resistant obese humans upon exposure to a high-fat diet (HFD). A 5-d prospective study conducted in the research unit of an academic center. Healthy, lean (n = 12; body mass index = 22.1 ± 0.6 kg/m(2)), and obese (n=10; body mass index = 39.6 ± 1.7 kg/m(2)) males and females, between ages 18 and 30. Participants were studied before and after a 5-d HFD (65% fat). Skeletal muscle biopsies (vastus lateralis) were obtained in the fasted and fed states before and after the HFD and mRNA content for genes involved with lipid oxidation determined. Skeletal muscle acylcarnitine content was determined in the fed states before and after the HFD. Peroxisome proliferator activated receptor (PPAR) α mRNA content increased in lean, but not obese, subjects after a single high-fat meal. From Pre- to Post-HFD, mRNA content exhibited a body size × HFD interaction, where the lean individuals increased while the obese individuals decreased mRNA content for pyruvate dehydrogenase kinase 4, uncoupling protein 3, PPARα, and PPARγ coactivator-1α (P ≤ 0.05). In the obese subjects medium-chain acylcarnitine species tended to accumulate, whereas no change or a reduction was evident in the lean individuals. These findings indicate a differential response to a lipid stimulus in the skeletal muscle of lean and insulin resistant obese humans.
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