Heart-type fatty acid-binding protein reciprocally regulates glucose and fatty acid utilization during exercise
Jane Shearer,1,3
Patrick T. Fueger,1,3
Jeffrey N. Rottman,2,3
Deanna P. Bracy,1,3
Bert Binas,4 and
David H. Wasserman1,3
Departments of 1Molecular Physiology and Biophysics, 2Cardiology, and 3Mouse Metabolic Phenotyping Center, Vanderbilt University, Nashville, Tennessee; 4Department of Pathobiology, College of Veterinary Medicine, Texas A & M University, College Station, Texas
Submitted 1 July 2004
; accepted in final form 23 September 2004
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ABSTRACT
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The role of heart-type cytosolic fatty acid-binding protein (H-FABP) in mediating whole body and muscle-specific long-chain fatty acid (LCFA) and glucose utilization was examined using exercise as a phenotyping tool. Catheters were chronically implanted in a carotid artery and jugular vein of wild-type (WT, n = 8), heterozygous (H-FABP+/, n = 8), and null (H-FABP/, n = 7) chow-fed C57BL/6J mice, and mice were allowed to recover for 7 days. After a 5-h fast, conscious, unrestrained mice were studied during 30 min of treadmill exercise (0.6 mph). A bolus of [125I]-15-(p-iodophenyl)-3-R,S-methylpentadecanoic acid and 2-deoxy-[3H]glucose was administered to obtain rates of whole body metabolic clearance (MCR) and indexes of muscle LCFA (Rf) and glucose (Rg) utilization. Fasting, nonesterified fatty acids (mM) were elevated in H-FABP/ mice (2.2 ± 0.9 vs. 1.3 ± 0.1 and 1.3 ± 0.2 for WT and H-FABP+/). During exercise, blood glucose (mM) increased in WT (11.7 ± 0.8) and H-FABP+/ (12.6 ± 0.9) mice, whereas H-FABP/ mice developed overt hypoglycemia (4.8 ± 0.8). Examination of tissue-specific and whole body glucose and LCFA utilization demonstrated a dependency on H-FABP with exercise in all tissues examined. Reductions in H-FABP led to decreasing exercise-stimulated Rf and increasing Rg with the most pronounced effects in heart and soleus muscle. Similar results were seen for MCR with decreasing LCFA and increasing glucose clearance with declining levels of H-FABP. These results show that, in vivo, H-FABP has reciprocal effects on glucose and LCFA utilization and whole body fuel homeostasis when metabolic demands are elevated by exercise.
skeletal muscle; metabolism; substrate balance; 2-deoxyglucose; 15-(p-iodophenyl)-3-R,S-methylpentadecanoic acid
LONG-CHAIN FATTY ACID (LCFA) transport across phospholipid membranes is facilitated by a number of fatty acid-binding proteins, including fatty acid translocase (FAT/CD36), fatty acid transport protein (FATP), and fatty acid-binding protein (FABP) in the plasma membrane (FABPpm) (5, 6). Once across cellular membranes, LCFA are tightly bound to cytosolic FABPs. In cardiac and skeletal muscle, heart-type cytosolic FABP (H-FABP) is present in abundance, representing 25% of total cytosolic protein (22). H-FABP functions to increase LCFA solubility, facilitate diffusion, and protect against LCFA toxicity. It also mediates LCFA trafficking by targeting LCFA to specific triacylglycerol depots, the maintenance of phospholipid pool mass, and phospholipid acyl chain composition (17, 23). In this capacity, H-FABP may influence not only LCFA metabolism but also the selection and utilization of other substrates, namely glucose. This is evident in types 1 and 2 diabetes, where there is increased H-FABP expression, presumably due to a greater reliance on fatty acid utilization (2, 12).
Despite the diverse role of H-FABP in mediating LCFA metabolism, a heterozygous germ line reduction of H-FABP (H-FABP+/) has no observable phenotype in the sedentary mouse (11, 15). This suggests that 50% of the protein is sufficient to meet basal metabolic demands. In contrast, a homozygous germ line deletion of H-FABP (H-FABP/) results in partial, but not complete, abolishment of LCFA utilization (3, 11). The most marked perturbation is in cardiac muscle, where there is a greater reliance on glucose and the development of cardiac hypertrophy. Skeletal muscle has qualitatively similar, but quantitatively lesser, effects compared with the heart, with increases in glucose oxidation and decreases in LCFA utilization (4). During contraction, isolated soleus muscle from H-FABP/ mice maintains the capacity to increase LCFA uptake, esterification, and oxidation in response to electrical stimulation (4). However, these parameters are still reduced compared with muscle from wild-type (WT) littermates. Despite their ability to increase LCFA utilization in response to electrical stimulation, H-FABP/ are intolerant to prolonged exercise (3). Explanations for this exercise intolerance are not known but are likely related to impairments in LCFA utilization in both cardiac and skeletal muscle (11).
The aim of the present study was to determine the role of H-FABP on tissue-specific and whole body substrate utilization when metabolic demands are elevated by exercise. Although previous studies have explored the effects of H-FABP/ in vitro, the role of reduced levels of H-FABP (H-FABP+/) in the context of the whole animal and its physiological function are incompletely understood. Using exercise as a phenotyping tool along with glucose and LCFA isotopic analogs to simultaneously assess substrate utilization, we demonstrate that H-FABP influences substrate utilization and that H-FABP/ mice have reduced exercise tolerance due to increased reliance on glucose and the development of overt hypoglycemia.
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METHODS
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Mouse maintenance and genotyping.
All procedures were approved by the Vanderbilt University Animal Care and Use Committee. Mice were produced on a 129/Balb/c background and were subsequently backcrossed for at least seven generations to C57BL/6J (3). This results in the absence of H-FABP in homozygous mice and a 50% reduction in heterozygous mice (3). Mice carrying the disrupted H-FABP allele (H-FABP+/) were subsequently bred, and, after a 3-wk weaning period, littermates were separated by sex and maintained in microisolator cages. Genotyping for the H-FABP germ line deletion was performed on genomic DNA obtained from a tail biopsy with the polymerase chain reaction, as previously described (4). Mice were fed a standard chow diet ad libitum and were studied at
4 mo of age. Experiments were performed on both male (M) and female (F) mice. Numbers of male and female mice per group are as follows: WT (n = 4 M/4 F), H-FABP+/ (n = 4 M/4 F), and H-FABP/ (n = 3 M/4 F).
Surgical procedures.
The surgical procedures were the same as those previously described (10). Mice were anesthetized with pentobarbitol sodium (70 mg/kg body wt). The left common carotid artery was catheterized for sampling with a catheter consisting of PE-10 and 0.025-in. OD Silastic tubing. The right jugular vein was catheterized for infusions with a Silastic catheter (0.025 in. OD). The free ends of the catheters were tunneled under the skin to the back of the neck, where they were attached via stainless steel connectors to tubing made of Micro-Renathane (0.033 in. OD), which were exteriorized and sealed with stainless steel plugs. Lines were flushed daily with
20 µl of saline containing 200 U/ml heparin and 5 mg/ml ampicillin. Animals were individually housed after surgery and body weight was recorded daily.
Isotopic analogs.
Glucose and LCFA tracers employed in the present study were 2-deoxy-[3H]glucose ([3H]DG) and [125I]-15-(p-iodophenyl)-3-R,S-methylpentadecanoic acid ([125I]BMIPP). [3H]DG was purchased from New England Nuclear (Boston, MA). BMIPP was a kind gift from Oak Ridge National Laboratories (Oak Ridge, TN). Radioiodination was performed according to the manufacturer's suggested protocol. Briefly, BMIPP was heated in the presence of Na125I solution (740 MBq/200 µl), propionic acid, and copper (II) sulfate. Na2S2O3 was then added and the organic phase ether extracted and sequentially back extracted with saturated NaHCO3 and water. After evaporation, the [125I]BMIPP was solubilized using sonication into ursodeoxycholic acid.
In vivo exercise experiments.
Mice were acclimated to treadmill running with a single 10-min bout of exercise (0.50.6 mph, 0% grade)
48 h before the experimental protocol. Experiments were conducted after a postoperative recovery period of
7 days, as previously described (13). The recovery period was sufficient for body weight to be restored within 10% of presurgery body weight. On the day of the study, conscious, unrestrained mice were placed in an
1-liter plastic container lined with bedding and fasted for 5 h. Approximately 1 h before an experiment, Micro-Renathane (0.033 in. OD) tubing was connected to the catheter leads and infusion syringes. Mice were then placed in the treadmill and allowed to acclimate before exercise (1 h). After this, a baseline arterial blood sample (150 µl) was drawn for the measurement of arterial blood glucose, hematocrit, plasma insulin, and nonesterified fatty acids (NEFAs). The remaining red blood cells were washed with 0.9% heparinized saline and reinfused. Mice then exercised on a motorized treadmill (0.6 mph, 0% grade) for 30 min. At t = 5 min, a 12-µCi bolus of [2-3H]DG and a bolus (2130 µCi) of [125I]BMIPP was administered into the jugular vein to obtain an index of glucose and LCFA uptake and clearance. At t = 7, 10, 15, and 20 min, arterial blood (
50 µl) was sampled to determine blood glucose, plasma [2-3H]DG, and [125I]BMIPP. At t = 30 min, a final arterial blood sample was obtained (150 µl) and was processed as the baseline blood sample with the addition of the determination of plasma [2-3H]DG and [125I]BMIPP. Mice were then anesthetized, and the heart and skeletal muscles [soleus, gastrocnemius, and superficial vastus lateralis (SVL)] were excised and rapidly freeze-clamped in liquid nitrogen. Individual skeletal muscles have been previously characterized for fiber type: soleus (
44% type I,
51% type IIA, and
5% type IID fibers), gastrocnemius (
6% type IIA,
11% type IID, and
83% type IIB fibers), and SVL (
3% type IIA,
10 type IID, and
87% type IIB fibers) muscles (1). All muscle samples were subsequently stored at 80°C until further analysis. All mice reported in the present study completed 30 min of treadmill exercise. Two H-FABP/, two H-FABP+/, and one WT mouse were excluded from the study because they could not complete the exercise test.
Plasma insulin and NEFAs.
Immunoreactive insulin was assayed with a double-antibody method (16). NEFAs were measured spectrophotometrically by an enzymatic colorimetric assay (NEFA C kit; Wako Chemicals, Richmond, VA).
Quantification of isotopic analogs.
[125I]BMIPP and [3H]DG were measured in the same plasma (15 µl) and tissue samples as previously described (18). Briefly, plasma and infusates were counted for [125I]BMIPP with a Beckman Gamma 5500 counter (Beckman Instruments, Fullerton, CA). After this, the plasma samples were deproteinized in 100 µl of 0.06 N Ba(OH)2 and 100 µl of 0.06 N Zn(SO)4 and subsequently centrifuged. The supernatant (100 µl) was extracted and diluted in 900 µl of H2O. 3H radioactivity was counted after addition of fluor (10 ml of Ultimate Gold; Packard Bioscience, Boston, MA) by use of a Packard Tri-Carb 2900TR Liquid Scintillation Analyzer (PerkinElmer, Boston, MA). Similarly, 125I radioactivity was determined in tissues before they were homogenized in 2 ml of 0.5% perchloric acid and centrifuged for 20 min. Supernatants (1.5 ml) were then neutralized using 5 M KOH, and 250 µl were determined by liquid scintillation counting (TRI-CARB 2900TR; Packard, Meriden, CT) with Ultima Gold (Packard) as scintillant. The relationship between gamma-radioactivity and beta-emissions for the specific counters was previously determined and used to correct 3H radioactivity for beta-emissions originating from 125I radioactivity (18).
Calculations: indexes of glucose and LCFA clearance and utilization.
Tissue-specific glucose clearance (Kg) and metabolic (Rg) indexes were calculated from the accumulation of [3H]DG-phosphate ([3H]DGP) and the integral of the plasma [3H]DG concentration after a [3H]DG bolus (10, 13). The relationships are defined as follows:
The subscripts p and m refer to concentrations in arterial plasma and muscle, respectively. The measurement of Rg has been described earlier (10, 13). In an analogous manner, LCFA clearance (Kf) and metabolic (Rf) indexes were calculated from the accumulation of [125I]BMIPP in muscle and the integral of the plasma [125I]BMIPP.
where [125I-BMIPP]m is the [125I]BMIPP concentration in the cell and [125I-BMIPP]p is the [125I]BMIPP concentration present in the plasma. The measurements of Kf and Rf have been previously described (8, 18). To determine whole body metabolic clearance rates (MCR) for glucose and LCFA from the plasma, the following equations were used. D represents total dose of the tracer normalized to radioactivity in the infusate.
Statistical analyses.
A one-way repeated-measures analysis of variance (ANOVA) was performed to compare differences in Kg, Kf, Rg, and Rf within specific tissues. To determine differences over time for blood glucose and NEFA, a two-way repeated-measures ANOVA was performed. A Student-Newman-Keuls post hoc test was used with significance levels of P
0.05. Data are reported as means ± SE. To establish a dose response of H-FABP, a linear regression analysis was employed, with WT = 1, H-FABP+/ = 0.5, and H-FABP/ = 0.
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RESULTS
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Baseline characteristics.
Presurgery weights of the animals in each group were as follows: 27.4 ± 1.9 g for WT, 25.5 ± 1.0 g for H-FABP+/, and 25.4 ± 1.8 g for H-FABP/. After 7 days of recovery, experimental animal weights for WT, H-FABP+/, and H-FABP/ were not different from presurgery weight or between genotypes with values of 26.9 ± 1.6, 25.8 ± 1.1, and 25.3 ± 1.5 g, respectively. Basal blood glucose levels were lower in H-FABP/ (8.1 ± 0.3 mM) compared with both WT (9.1 ± 0.3 mM) and H-FABP+/ (9.4 ± 0.4 mM). In contrast, plasma NEFAs were elevated in H-FABP/ (2.2 ± 0.3 mM) in relation to WT (1.3 ± 0.1 mM) and H-FABP+/ (1.3 ± 0.1 mM). For plasma insulin, no differences were observed between groups, with values of 8.9 ± 1.9, 6.9 ± 1.1, and 6.5 ± 1.3 µU/ml for WT, H-FABP+/, and H-FABP/, respectively. No differences between the sexes were noted for any parameter measured in the study.
Plasma measurements.
Blood glucose values during the experiment are reported in Fig. 1. Plasma glucose gradually increased in both WT and H-FABP+/ mice throughout exercise. In contrast, blood glucose fell gradually in the H-FABP/ mice. Levels reached a nadir of 4.8 ± 0.8 mM at 30 min. Plasma NEFA levels were elevated in H-FABP/ mice at baseline but declined to levels seen in H-FABP+/ and WT mice with exercise. After 30 min of exercise, mean plasma NEFA values were not different between groups, with values of 1.04 ± 0.15, 0.85 ± 0.11, and 1.12 ± 0.24 mM in WT, H-FABP+/, and H-FABP/, respectively.
Tissue clearance and utilization.
Absolute values for tissue Kf and Rf as well as for Kg and Rg are depicted in Tables 1 and 2. Analysis of individual tissues revealed Rf to be reduced in H-FABP/ compared with WT mice in all tissues with the exception of the SVL. Compared with H-FABP/, Rf was reduced in H-FABP+/ in the soleus and heart. Results of Kf followed the same trends, with the exception of the SVL, which showed increased clearance with H-FABP/ compared with WT mice. In contrast, Rg was elevated in H-FABP/ compared with WT mice in all tissues except SVL. H-FABP+/ was also greater in the heart compared with H-FABP/. Like Kf, results of Kg were similar to those of Rg. Linear regression analysis of clearance and utilization measurements revealed positive correlations with H-FABP for all muscles examined. To make comparisons between LCFA and glucose, values of Rg and Rf were plotted on a relative scale, with WT mice having an H-FABP content equal to 1.0 and with H-FABP+/ and H-FABP / having values of 0.5 and 0.0, respectively (Fig. 2).
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Table 1. Tissue-specific fatty acid Kf and Rf during 30 min of treadmill exercise in conscious, unrestrained mice
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Fig. 2. Relative tissue specific metabolic indexes of long-chain fatty acid (LCFA) (Rf) and glucose (Rg) utilization in soleus, gastrocnemius (Gastroc), superficial vastus lateralis (SVL), and heart during 30 min of treadmill exercise in conscious, unrestrained mice (78 mice per group). To make comparisons between glucose and LCFA, values of Rf and Rg were plotted on a relative scale. WT (+/+) mice have H-FABP content = 1.0, whereas H-FABP+/ = 0.5 and H-FABP/ = 0 (x-axis). To compare Rf and Rg, both values are shown relative to WT mice, which were set to an arbitrary value of 1 for each parameter (y-axis). *Significant difference (P < 0.05) from WT. #Significant difference (P < 0.05) from H-FABP+/. All values represent means ± SE.
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Whole body MCR.
Results of MCR are shown in Fig. 3. To compare glucose and LCFA MCRs, results were converted from milliliters per minute per 100 grams to relative units, with WT mice having an H-FABP content equal to 1.0 and with H-FABP+/ and H-FABP/ having values of 0.5 and 0.0, respectively. Compared with WT, glucose MCR was elevated in H-FABP/ whereas LCFA MCR was suppressed. No differences in MCR were apparent between WT and H-FABP+/ mice.

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Fig. 3. Relative whole body metabolic clearance rates of glucose (MCRg) and LCFA (MCRf). To make comparisons between glucose and LCFA for MCR, values were plotted on a relative scale. WT (+/+) mice have H-FABP content = 1.0, whereas H-FABP+/ = 0.5 and H-FABP/ = 0 (x-axis). To compare MCRf and MCRg, both values are shown relative to WT mice, which were set to an arbitrary value of 1 for each parameter (y-axis). Linear regression analysis showed a strong correlation for both glucose (y = 0.278x + 1.54, r2 = 0.98, P < 0.05) and LCFA (y = 0.315x + 0.81, P < 0.05). *Significant difference (P < 0.05) from WT. #Significant difference (P < 0.05) from H-FABP+/. All values represent means ± SE.
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DISCUSSION
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The studies performed herein show, using a novel chronically catheterized mouse model, that H-FABP has an important role in determining the relative usage of LCFA and glucose in working muscle. Using exercise to accelerate metabolism in WT, H-FABP+/ and H-FABP/ mice, we show that
50% of this protein is necessary to maintain LCFA flux. Both heterozygous and null mutations had reciprocal effects on glucose and LCFA utilization when metabolic demands were elevated in vivo. These effects were evident in the whole animal as well as in heart and individual muscles excised from mice.
Analysis of cardiac and skeletal muscles demonstrate reduced rates of LCFA and a compensatory increase in glucose utilization with declining H-FABP levels. In H-FABP/ mice, Rf was reduced in all muscles with the exception of the SVL, a muscle comprising highly glycolytic fibers (1). Reductions in Rf were greatest in the soleus and heart of H-FABP/ mice, with reductions of
75 and
80%, respectively, compared with WT mice. This result is consistent with previous studies on H-FABP demonstrating that the effects of H-FABP ablation are most pronounced in these two tissues (3, 4, 17). Albeit present to a lesser extent, reductions in Rf were also evident in the heart and soleus of H-FABP+/ mice. This is a novel finding and demonstrates that >50% of H-FABP is necessary to accommodate increased LCFA flux during exercise. To compensate for decreases in LCFA uptake, H-FABP+/ and H-FABP/ mice increase their reliance on glucose. The greatest compensation was in the heart, a finding not unexpected considering the heart normally derives 6080% of its energy from LCFA (14). Similar impacts of H-FABP were also noted for whole body MCR. In response to exercise, H-FABP/ mice developed overt hypoglycemia due to a decreased LCFA capacity. This finding explains the results of previous studies showing H-FABP/ mice to be exercise intolerant (3). Due to the sharp fall in blood glucose and the mild exercise intensity used in the experimental protocol (
70% O2 consumption), it appears that the majority of glucose was derived from blood glucose and not glycogen. Binas et al. (4) have characterized glycogen in H-FABP/ mice and shown that resting soleus muscle from H-FABP/ mice contains
34% less glycogen compared with WT mice; however, following electrical stimulation of muscles, the absolute amount of glycogen utilized did not differ between WT and H-FABP/ mice (4).
In the present study, we show that LCFA utilization during exercise was compromised in H-FABP/ mice but not completely abolished. Detailed phenotyping of these mice reveals normal expression and tissue content of other FABPs, including FAT/CD36 and FABPpm (4, 15, 19). However, it is possible that reduced levels of H-FABP negatively impact exercise-induced sarcolemmal recruitment of these proteins, resulting in the impaired fatty acid transport. To compensate for reduced levels of H-FABP, null mice selectively increase their mitochondrial density in subsarcolemmal space (4). It was hypothesized that this adaptation limits the diffusion distance of LCFA from the cytosolic membrane to mitochondria, thus enabling continued LCFA metabolism in the absence of H-FABP (4). This finding also suggests that H-FABP functions to target LCFA to the mitochondria. In agreement with this hypothesis, Murphy et al. (17) have shown that H-FABP may direct incoming LCFA to storage, oxidation, or esterification depending on the type of fatty acid. Specifically, in resting anesthetized mice, H-FABP/ resulted in an
52% decline in 20:4 n-6 uptake and an
40% reduction in 16:0 compared with WT littermates (17). Additionally, H-FABP/ preferentially impaired LCFA targeting of 16:0 destined to
-oxidation to a greater extent compared with esterification. This led the authors to conclude that H-FABP is an important determinant of the metabolic fate of individual fatty acids.
Results of the present study corroborate previous findings showing that normal levels of H-FABP have a fundamental, but not limiting, role in regulating LCFA utilization at rest (4, 15). However, we show that a full complement of H-FABP is required for augmented rates of LCFA utilization in cardiac and skeletal muscle with exercise. This may be one reason that the protein is expressed in such abundance, a finding that was unclear from previous in vitro studies. It may also explain why levels of H-FABP are elevated in situations wherein LCFA flux is augmented, such as diabetes, chronic exercise, and diets supplemented with (
-3) polyunsaturated fatty acids (2, 7, 12, 20). Although H-FABP may not limit basal metabolism, it compromises substrate utilization when metabolic demands are increased. Given this, reducing H-FABP may be a plausible pharmacological target in the treatment of pathophysiological states wherein glucose utilization is impaired such as type 2 diabetes. Indeed, recent studies have shown that a heterozygous reduction in H-FABP is sufficient to normalize elevated blood glucose levels caused by high-fat feeding (21). This increased sensitivity to insulin was due to the same phenomenon observed in the present study, a decreased capacity for LCFA utilization and increased reliance on glucose. However, the present results also caution that reducing H-FABP may lead to an increased risk of hypoglycemia in response to prolonged or intense exercise.
During the experimental protocol, all mice performed 30 min of treadmill exercise at 0.6 mph, which represents
70% of maximal oxygen consumption (9). Although the absolute amount of work performed by each animal was identical, the relative workload may be different between genotypes. Given this, it is possible that H-FABP+/ and H-FABP/ mice exercised at a higher relative exercise intensity compared with WT animals, resulting in increased rates of glucose utilization. Further exercise testing of the H-FABP mice will be needed to resolve this issue. Despite the diminished exercise-induced Rf in H-FABP/ and H-FABP+/ mice, LCFA levels still fell to the same level. An interesting finding from the present study is that, despite reduced Rf in H-FABP+/ and H-FABP/ mice, plasma LCFA (
1 mM) fell to the same levels. Considering the reduced Rf, it would have been reasonable to expect that LCFA levels would remain higher in H-FABP+/ and H-FABP/ mice. This result implies that there may be a compensatory mechanism for a deficit in H-FABP, whereby either the capacity for lipolysis is reduced or reesterification of LCFA is increased.
In conclusion, we demonstrate that, in vivo, reductions in H-FABP result in reciprocal effects on both tissue-specific and whole body LCFA and glucose utilization during exercise. Although FABP+/ mice have no discernible phenotype at rest, exercise reveals that >50% of this protein is required to accommodate high rates of LCFA flux into cardiac and skeletal muscle. This finding further elucidates the role of H-FABP and explains why this protein may be upregulated in metabolic situations wherein rates of LCFA utilization are elevated.
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GRANTS
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This work was supported by National Institute of Diabetes and Digestive and Kidney Diseases Grants DK-54902 and U24-DK-59637. J. Shearer is supported by a mentor-based fellowship from the American Diabetes Association.
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ACKNOWLEDGMENTS
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We acknowledge the technical contributions of Wanda Sneed, Angela Slater, and Freyja James.
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FOOTNOTES
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Address for reprint requests and other correspondence: D. Wasserman, Dept. of Molecular Physiology and Biophysics, 823 Light Hall, Vanderbilt University, Nashville, TN 37232-0615 (E-mail: david.wasserman{at}vanderbilt.edu)
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. Section 1734 solely to indicate this fact.
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