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Originally published In Press as doi:10.1074/jbc.M410448200 on February 11, 2005

J. Biol. Chem., Vol. 280, Issue 17, 17260-17265, April 29, 2005
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Exercise Capacity of Mice Genetically Lacking Muscle Glycogen Synthase

IN MICE, MUSCLE GLYCOGEN IS NOT ESSENTIAL FOR EXERCISE*

Bartholomew A. Pederson{ddagger}§, Carlie R. Cope{ddagger}, Jill M. Schroeder{ddagger}, Micah W. Smith{ddagger}, José M. Irimia{ddagger}, Beth L. Thurberg||, Anna A. DePaoli-Roach{ddagger}, and Peter J. Roach{ddagger}**

From the {ddagger}Department of Biochemistry and Molecular Biology and Indiana University Center for Diabetes Research, Indiana University School of Medicine, Indianapolis, Indiana 46202-5122 and ||Department of Pathology, Genzyme Corporation, Framingham, Massachusetts 01701-9322

Received for publication, September 10, 2004 , and in revised form, February 11, 2005.


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 EXPERIMENTAL PROCEDURES
 RESULTS
 DISCUSSION
 REFERENCES
 
The glucose storage polymer glycogen is generally considered to be an important source of energy for skeletal muscle contraction and a factor in exercise endurance. A genetically modified mouse model lacking muscle glycogen was used to examine whether the absence of the polysaccharide affects the ability of mice to run on a treadmill. The MGSKO mouse has the GYS1 gene, encoding the muscle isoform of glycogen synthase, disrupted so that skeletal muscle totally lacks glycogen. The morphology of the soleus and quadriceps muscles from MGSKO mice appeared normal. MGSKO-null mice, along with wild type littermates, were exercised to exhaustion. There were no significant differences in the work performed by MGSKO mice as compared with their wild type littermates. The amount of liver glycogen consumed during exercise was similar for MGSKO and wild type animals. Fasting reduced exercise endurance, and after overnight fasting, there was a trend to reduced exercise endurance for the MGSKO mice. These studies provide genetic evidence that in mice muscle glycogen is not essential for strenuous exercise and has relatively little effect on endurance.


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
EXPERIMENTAL PROCEDURES
 RESULTS
 DISCUSSION
 REFERENCES
 
The two major repositories of glycogen, the polymeric storage form of glucose, are in the liver and skeletal muscle (1). In humans, these carbohydrate reserves are an important determinant of endurance upon sustained exercise, and muscle glycogen has long been viewed as a critical energy source during muscular activity (2–4). Depletion of muscle glycogen results in fatigue and impaired muscle performance and is a major determinant of endurance (2–5). Likewise, the ineffective utilization of muscle glycogen, as in patients with McArdle disease, leads to impaired exercise tolerance (6). In their "glycogen shunt" hypothesis, Shulman and Rothman (7) propose that glycogenolysis is the predominant source of energy for muscle contraction with glycogen acting essentially as an intermediate for blood glucose to enter glycolysis. Increasing muscle glycogen by manipulating diet and exercise regimens, a procedure termed "carbohydrate loading" or "glycogen supercompensation" (8), is adopted by endurance athletes to delay the onset of fatigue (4, 9–11).

Although the importance of adequate muscle glycogen to sustain exercise in humans has been well documented, caution is needed in extrapolating findings in rodents to humans. For instance, the amount of muscle glycogen, expressed as a fraction of body mass, is ~10-fold lower in mice than in humans (12, 13), whereas the corresponding values for liver glycogen are comparable (14). Thus, the relative role of these two glycogen storage depots may be different between the two species. The relative importance of muscle and liver glycogen stores as fuel sources for exercise has been studied extensively in rats (15–17). Exhaustive exercise either by treadmill running or swimming resulted in a reduction of muscle glycogen by 70 or >90%, respectively (15, 16). Both exercise methods reduced liver glycogen >90%. Using less strenuous exercise regimens, muscle glycogen stores were depleted 40–70%, depending on muscle type, whereas liver glycogen stores were reduced ~85% (17). Although significant amounts of muscle glycogen were consumed, the authors suggest that, in contrast to humans, rats may be more dependent on liver glycogen stores for exercise (17).

Several genetically modified mouse lines with altered muscle metabolism have been analyzed for exercise endurance. Mice lacking the type 1 protein phosphatase glycogen-targeting subunit, RGL (GM) (18) have ~10% of wild type muscle glycogen levels and exhibit a 60% decrease in work capacity (19). Overexpression of RGL resulted in a 3–4-fold increase in skeletal muscle glycogen but had no effect on exercise tolerance (19). Mice with muscle-specific disruption of the gene encoding the GLUT4 glucose transporter have normal muscle glycogen levels but are impaired in their ability to exercise (20). Recently, mouse models have been described in which genetic manipulation affected the oxidative capacity of muscles and physical endurance (21, 22). Overexpression of PPAR{delta}1 caused a significant switch to more oxidative muscle fibers and increased exercise endurance (22). Conversely, disruption of the PPAR{delta} gene led to a significant reduction in run time (22). In a different model, mice lacking PPAR{alpha} deplete liver but not muscle glycogen more rapidly than wild type littermates when subjected to exhaustive exercise (23). This liver glycogen depletion correlates with reduced exercise performance in the null animals (23). Loss of muscle HIF-1{alpha} suppressed exercise-induced expression of a number of genes and caused a change to more oxidative muscle metabolism in the null animals (21). This metabolic modification correlated with increased exercise capacity, but repeated bouts of activity ultimately led to increased muscle damage compared with controls.

Bulk synthesis and degradation of glycogen are catalyzed by glycogen synthase and glycogen phosphorylase, respectively, in concert with branching and debranching enzymes. The enzymology of glycogen metabolism is tissue-specific. For example, glycogen synthase (EC 2.4.1.11 [EC] ), the enzyme responsible for forming the basic {alpha}-1,4 polymeric linkages of glycogen, is encoded by the GYS2 gene in liver and the GYS1 gene in skeletal muscle and most other tissues. We recently obtained from Lexicon Genetics Incorporated a genetically modified mouse (MGSKO) in which the GYS1 gene is disrupted (24). The homozygous null animals are devoid of glycogen in skeletal muscle, heart, and several other tissues (24). The MGSKO mouse model provides an interesting genetic model with which to assess the role of muscle glycogen in exercise endurance. We hypothesized that MGSKO mice might be impaired in their ability to perform exhaustive exercise. In addition, the inability to synthesize glycogen in the muscle allows us to test the notion that glucose is first converted to glycogen and subsequently degraded before entering glycolysis (7).


   EXPERIMENTAL PROCEDURES
TOP
 ABSTRACT
 INTRODUCTION
 EXPERIMENTAL PROCEDURES
RESULTS
 DISCUSSION
 REFERENCES
 
Mouse Background and Husbandry—MGSKO heterozygous mice were generated from the Lexicon Genetics Omnibank library of gene-trapped ES cells (24). Breeders, generated by mating these heterozygotes with C57BL/6J animals, were then mated to produce the null animals (75% C57BL/6J) utilized in this study. All mice were maintained in temperature- and humidity-controlled conditions with a 12-h light,12-h dark cycle and were allowed food and water ad libitum. Animals were maintained in the Association for Assessment of Accreditation of Laboratory Animal Care (AAALAC)-approved animal facility at Indiana University. All procedures were approved by the Indiana University Animal Care and Use Committee.

Exercise Protocol—For exercise studies, mice were trained for 4 days (3 min/day) on a treadmill (Exer6M, Columbus Instruments). On the first day, the treadmill incline was set to 5°, and the speed was set at 8 m/min and was increased by 1 m/min during the training session. For each successive training bout, the incline was increased by 5°. The initial speed was also increased to 10, 11, and 12 m/min on successive training days. For the experimental run, fed mice were run at 9:30 a.m. on a treadmill set at a 20° incline with an initial belt speed of 12 m/min. The speed was increased by 1 m/min at 2, 5, 10, 20, 30, 40, 50, and 60 min after the initiation of the exercise. For mice fasted for 6 h, food was removed at 8 a.m., and mice were exercised at 2 p.m. For 16-h overnight fasting, food was removed at 5:30 p.m., and mice were run the following morning at 9:30 a.m. A mild electrical stimulus (16–28 V) was applied to mice that stepped off of the treadmill belt. Mice were run to exhaustion, as judged by refusal of mice to remain on the treadmill belt. Work performed (J) = body weight (kg) x running speed (m/min) x running time (min) x grade x 9.8 (J/kg x m).

Locomotor Activity—Ambulatory movement of mice was monitored in the X and Y (horizontal) planes in cages equipped with infrared beams (Columbus Instruments). Data presented represent the sum of double beam interruptions in both planes for the 12-h dark cycle and 10 h of the light cycle.

Blood Metabolite Levels—Blood glucose and lactate were measured before and immediately after exercise from tail vein blood with a DEX glucometer (Bayer, Mishiwaka, IN) and Lactate Pro (Arkray, Inc., Kyoto, Japan), respectively.

Preparation of Samples for Biochemical Analyses—Mice were sacrificed by cervical dislocation decapitation. Hind limb skeletal muscle and liver were rapidly excised, quick-frozen in liquid nitrogen, and stored at –80 °C. Glycogen content in tissue was determined in samples of frozen tissue (~30 mg) by measuring amyloglucosidase-released glucose from glycogen by the method of Bergmeyer et al. (25) as described previously by Suzuki et al. (18). Data are presented as mean values ± S.E. Statistical significance was determined with the unpaired Student's t test.

Microscopy—Soleus and quadriceps muscles were isolated from 10-month-old MGSKO and wild type littermates. Muscles were rapidly cut into 1-mm cubes and fixed in 3% glutaraldehyde in 0.2 mol/liter sodium cacodylate buffer, pH 7.3, followed by post-fixation in osmium tetroxide in 0.2 mol/liter sodium cacodylate buffer (Electron Microscopy Sciences, Fort Washington, PA). The tissues were infiltrated overnight and embedded in epon-araldite. 1-micron sections were stained with periodic acid-Schiff procedure and counterstained with Richardson's solution. This results in high resolution light microscopy in which abnormal pools of glycogen are well preserved and appear purple against a blue tissue counterstain of myocyte cytoplasm. Images were collected with a Nikon DXM1200 digital camera and acquired with the Nikon Act 1 photo image capture software for the DXM1200 digital camera, version 1.12 (Nikon Inc. Instrument Group, Melville, NY). Serial sections were cut from these same blocks for electron microscopy. Epon blocks were sectioned at 7 nm, and sections were mounted onto 200-mesh copper grids. Each grid was stained with 1% aqueous uranyl acetate solution for 20 min followed by 0.4% lead citrate/NaOH solution for 30 s. The grids were examined in a Philips EM 300 electron microscope (Philips Manufacturing). Images were collected onto Kodak electron microscope film 4489 and printed on Kodabromide photographic paper.


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 EXPERIMENTAL PROCEDURES
 RESULTS
DISCUSSION
 REFERENCES
 
MGSKO Mice—The MGSKO mouse has the GYS1 gene disrupted and hence lacks glycogen synthase and glycogen in several tissues including skeletal muscle, heart, brain, kidney, and lung. The lack of cardiac glycogen appears to cause a developmental problem, and only ~10% of the null mice survive birth (24). Surviving mice, however, are ostensibly normal with hearts that are functional as judged by echocardiography and that are not grossly abnormal (24). We also examined skeletal muscle by microscopy to see whether the absence of glycogen had any gross morphological consequences. Examination of soleus and quadricep muscle sections from the MGSKO mice by high resolution light microscopy did not reveal any abnormalities as compared with wild type littermates (Fig. 1). The same was true at the level of electron microscopy for the quadriceps (Fig. 1).



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  		FIG. 1.
Skeletal muscle morphology of WT and MGSKO mice. High resolution light microscopy (see "Experimental Procedures") preserves the normal banding pattern of the myofibrils in WT (a and c) and MGSKO (b and d) quadriceps (a and b) and soleus (c and d) samples; magnification, x1000. Electron microscopy (see "Experimental Procedures") of quadriceps muscle isolated from wild type (e) and MGSKO (f) mice are shown. Magnification, x8500.

 
Activity and Exercise of MGSKO Mice—From observation of MGSKO animals, there was no obvious difference in movements compared with wild type littermates. To test whether there were more subtle differences in locomotor activity, mice were monitored for an extended period in cages outfitted with infrared beams in the X and Y dimensions. Activity was gauged by the frequency with which the photobeams were interrupted (Fig. 2). Over a period of 22 h, there was no significant difference in total activity between MGSKO and wild type mice. MGSKO mice tended to be more active during the light cycle and less active during the dark cycle (Fig. 2), but the differences were small.



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  		FIG. 2.
Locomotor activity in wild type and MGSKO mice. Total ambulatory movement (see "Experimental Procedures") for wild type (open bars) and MGSKO (closed bars) mice is shown for light and dark cycles as well as total movement over 22 h. n = 8–9 five-month-old male mice.

 
Because of the potential importance of glycogen for sustained strenuous exercise, fed male and female mice were subjected to treadmill running until exhaustion using the protocol described under "Experimental Procedures" whereby the treadmill speed was progressively increased (Fig. 3, Tables I and II). There was no significant difference in the running time (48 ± 4 min for WT versus 56 ± 6 min for MGSKO, n = 9–13) or the work performed by male mice (Fig. 3a). Female MGSKO mice ran ~25% longer than wild type littermates (48 ± 5 min for WT versus 63 ± 4 min for MGSKO, n = 9, p = 0.041). Both female and male MGSKO mice have lower body weights (~10% reduction for males and ~5% reduction for females) as compared with age-matched wild type littermates.2 When this difference in body weight is taken into account in the calculation of work performed, the difference between genotypes was not significant (Fig. 3b). Sex differences in running appear to depend strongly on the mouse strain studied (26). Resting blood glucose was not significantly different between MGSKO and wild type mice (Fig. 4, a and b), and exercise caused a similar decrease in both genotypes (Fig. 4, a and b). Blood lactate during exercise reflects anaerobic glycolysis and can be a contributory factor for exercise tolerance. Basal blood lactate levels were lower in the MGSKO mice (Fig. 4, c and d) and were increased by exercise. However, the increase was much smaller in the MGSKO animals (Fig. 4, c and d). The exercise regimen decreased muscle glycogen in wild type mice from 5.6 ± 1.1 to 0.4 ± 0.1 µmol of glucose/g (n = 4, p = 0.004). Previous work in rats (16, 17) has shown that to reach such low levels of muscle glycogen, glycogen must be depleted from red, intermediate, and white fibers. Glycogen depletion in white muscle only occurs when the workload exceeds the capacity of red and intermediate fibers (16, 17). Thus it appears that our treadmill protocol subjected the mice to a relatively intense exercise bout. In these fed animals, liver glycogen did not compensate for the absence of muscle glycogen in the MGSKO mice because it decreased by the same amount in both genotypes (Fig. 5).



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  		FIG. 3.
Treadmill exercise of wild type and MGKSO mice. Work in wild type (open bars) and MGSKO (closed bars) mice is shown. Work performed was calculated for 5–9-month-old male (a) and female (b) mice exercised to exhaustion under fed, 6-h fasted, or 16-h overnight (O/N) fasted conditions as described under "Experimental Procedures." n = 9–13. *, p < 0.05; **, p < 0.01 compared with the respective genotype in the fed condition.

 


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  		TABLE I
Treadmill exercise of 6-h day fasted wild type and MGSKO mice

Mice, 6–9 months of age, were day-fasted 6 h prior to being subjected to exhaustive exercise on a treadmill as described under "Experimental Procedures." Blood glucose and lactate were monitored before and immediately after exercise.

 


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  		TABLE II
Treadmill exercise of overnight fasted wild type and MGSKO mice

Mice, 5–8 months of age, were fasted 16 h prior to being subjected to exhaustive exercise on a treadmill as described under "Experimental Procedures." Blood glucose and lactate were monitored before and immediately after exercise. n = 7–13 except body weight of male and female MGSKO exercised mice in which case n = 3–4.

 



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  		FIG. 4.
Effect of exercise on blood glucose and lactate in fed wild type and MGSKO mice. Before and immediately after exercise, glucose (a and b) and lactate (c and d) were measured in blood collected from 5–9-month-old male (a and c) and female (b and d) wild type (open bars) and MGSKO (closed bars) animals. n = 9–13. *, p < 0.01; **, p < 0.001 compared with the respective genotype before exercise. #, p < 0.001 compared with wild type in the same exercise state.

 



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  		FIG. 5.
Effect of exercise on liver glycogen in fed wild type and MGSKO mice. Livers harvested from 13–14-month-old male wild type (open bars) and MGSKO (closed bars) mice before and immediately after exercise were analyzed for tissue glycogen content as described under "Experimental Procedures." n = 4–8. *, p < 0.01 compared with respective genotype before exercise.

 
Nutritional Status and Exercise Endurance—Because liver glycogen is consumed during the exercise program, levels were reduced by fasting prior to treadmill exercise to test whether muscle glycogen would assume a greater importance as a determinant of run time. To deplete liver glycogen, mice were "day-fasted" for 6 h, i.e. 8 a.m.–2 p.m., to elicit a modest decrease or fasted 16 h overnight to elicit a large decrease in glycogen levels in this organ. In contrast to liver, muscle glycogen stores of the wild type mice are not affected by a 16-h overnight fast (5.6 ± 1.1 fed versus 7.4 ± 1.2 µmol of glucose/g fasted; n = 4–7). After a 6-h fast, the work performed by both wild type and MGSKO animals was decreased compared with fed animals (Fig. 3), reaching statistical significance for both male and female MGSKO mice (~35%, p <0.05). An overnight fast reduced liver glycogen to ~10% of the levels in fed mice (32 ± 6, WT fasted, 40 ± 9, MGSKO fasted, versus 373 ± 33, WT fed, 297 ± 29 µmol of glucose/g of tissue, MGSKO fed; n = 5–8) and correlated with a significant reduction in the exercise capacity of the animals (Fig. 3). Wild type mice performed ~65% of the work achieved in the fed state, whereas MGSKO mice were capable of only ~40% of their fed work performance (Fig. 3). Post-exercise blood glucose levels were lower in all fasted mice compared with fed mice, but there were no differences between genotypes (Tables I and II, Fig. 4). Overnight fasting reduced basal lactate levels in both genotypes such that there was now no difference between wild type and MGSKO animals (Table II). Lactate levels at the completion of exercise were reduced with both 6 and 16 h of fasting to a greater extent in wild type than MGSKO mice (Tables I and II).


   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 EXPERIMENTAL PROCEDURES
 RESULTS
 DISCUSSION
REFERENCES
 
Although the prevailing view is that muscle glycogen is an important determinant for exercise capacity in humans (3, 4), such may not be true for rodents. Studies with rats suggest that quantitatively liver glycogen may be more important than muscle glycogen for sustaining exercise (15–17). Work with several mouse models with genetically manipulated muscle glucose metabolism has not given a definitive answer on the significance of muscle glycogen as discussed in the Introduction. However, in both rats and mice, muscle glycogen is utilized during exercise and thus contributes as a source of fuel for contraction. The MGSKO mice, which have no skeletal muscle glycogen, offer a robust genetic model with which to test the importance of muscle glycogen. In fact, these animals exhibited normal physical activity and were not significantly impaired in their performance of exhaustive exercise. Only after overnight starvation to deplete the liver glycogen pool did a trend to lesser endurance in the MGSKO animals emerge. It is possible that lack of muscle glycogen might have a greater impact on performance under other exercise conditions, such as those forcing anaerobic muscular activity, as in the case of sprinting for humans. However, arranging such an experimental protocol with mice is difficult. Because 90% of MGSKO pups die shortly after birth, we cannot formally exclude the possibility that the subset of animals studied here is able to exercise normally because of the presence of some factor that allowed for their survival in the first place. Indeed, we have found evidence for adaptive responses as discussed below. However, the fact remains that normal exercise performance is maintained in the absence of muscle glycogen. It will be of interest to analyze in vitro measures of muscle function. The only other measured parameter that differed between wild type and MGSKO mice was blood lactate both before and after exercise. The reduced blood lactate in MGSKO mice is likely due to reduced anaerobic glycolysis in the absence of muscle glycogen although we cannot formally exclude increased hepatic uptake of lactate to be used as a gluconeogenic precursor by the liver.

Glucose equivalents normally provided by muscle glycogen could have been replaced by the breakdown of liver glycogen in MGSKO animals, simply based on considerations of major energy deposits in the body. However, there is also the possibility that impaired muscle glycogen metabolism affects liver deposits indirectly via interleukin-6 (IL-6). It has been reported that exercise causes muscle to increase secretion of IL-6, which in turn signals to the liver to increase glycogen breakdown (27, 28). Furthermore, IL-6 production by the muscle is increased as glycogen is depleted (29, 30). We therefore examined IL-6 levels in MGSKO mice and found no significant effects of the loss of muscle glycogen on either basal or exercise-induced serum IL-6 levels.3 In fact liver glycogen usage during exercise was the same in wild type and MGSKO mice, indicating that the short-fall in energy due to the lack of muscle glycogen must come from an alternative source. Possibilities are increased oxidation of glucose (correlating with lowered blood lactate) from liver glycogen or the oxidation of fatty acids. Elevated ATPase and increased phosphorylation of AMP kinase and acetyl-CoA carboxylase in skeletal muscle from MGSKO animals is consistent with this latter hypothesis.4 Another mouse model with increased oxidative capacity, PPAR{delta}-overexpressing animals, has increased exercise performance compared with wild type littermates. This suggests that a switch to more oxidative metabolism has the potential to overcome the loss of muscle glycogen as a fuel in MGSKO mice. The observation that MGSKO animals are using glucose provided by liver glycogen to fuel exercise also argues against the necessity of glucose being converted to glycogen in muscle prior to entering glycolysis as proposed by Shulman and Rothman (7).

Making the assumption that 30% (31) of the body weight of a mouse is muscle and knowing the weight of the liver, one can estimate the amount of glycogen used during the exhaustive exercise bout. Wild type mice used ~350 µmol of glucose equivalents, 70 µmol from muscle and 280 µmol from liver glycogen, whereas MGSKO mice utilized ~250 µmol of glucose equivalents from liver. In a fed normal mouse weighing ~30 g, total glucose equivalents of glycogen are 50–80 µmol and 400–500 µmol in muscle and liver, respectively. Therefore, in mice there is 5–10-fold more glycogen in the liver of a fed animal than in skeletal muscle. A similar ratio of liver to muscle glycogen has been reported in rats (17). In contrast, humans store 3–8-fold more glycogen in skeletal muscle than in liver (4). There is, therefore, a fundamental difference in the distribution of glycogen in mice and rats versus humans, a fact that may help explain why the manipulation of muscle glycogen had little impact on the ability of mice to exercise, whereas in humans the importance of glycogen is well established as, for example, by McArdle patients. The incremental reduction of liver glycogen with increasing time of fasting correlated with a decreased ability to perform work. This effect was greatest in MGSKO mice, and after a 16-h fast there was a strong trend (p = 0.057) for null mice to perform less work than wild type littermates. Thus, liver, rather than muscle, glycogen content at the onset of exercise may be a better determinant of the exercise capacity of mice. Muoio et al. (23) also noted that when mice were run to exhaustion on a treadmill under low intensity exercise conditions, fatigue correlated with liver rather than muscle glycogen depletion. Consistent with this observation, the rate of liver glycogen depletion in PPAR{alpha}-null mice was increased as compared with wild type littermates and correlated with earlier fatigue upon exhaustive treadmill exercise (23). This is also consistent with the suggestion by Reitman et al. (15) that liver glycogen may be more important than muscle glycogen for exercise in rats.

In conclusion, the MGSKO mouse provides genetic evidence that there is no obligate requirement of glycogen for even quite demanding muscular activity in mice. Furthermore, in mice the synthesis of muscle glycogen is not a necessary step for glucose to enter glycolysis. Only under conditions where liver glycogen is low may lack of muscle glycogen possibly become limiting for exercise capacity.


   FOOTNOTES
 
* This work was supported by in part by National Institutes of Health Grant DK27221. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. Back

§ Supported by a mentor-based postdoctoral research award from the American Diabetes Association (to P. J. R.). Back

Supported by a grant from the Fondo de Investigación Sanitaria of the Instituto de Salud Carlos III, Red de centros en Metabolismo y Nutrición (C03/08), Madrid, Spain. Present address: Unitat de Bioquímica, Departament de Ciències Fisiològiques I, Institut d'Investigaciones Biomèdiques August Pi i Sunyer, Universitat de Barcelona, Barcelona, Spain. Back

** To whom correspondence should be addressed: Dept. of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, IN 46202-5122. Tel.: 317-274-1582; Fax: 317-274-4686; E-mail: proach{at}iupui.edu.

1 The abbreviations used are: PPAR, peroxisome proliferator-activated receptor; WT, wild type; IL-6, interleukin-6. Back

2 B. A. Pederson, M. W. Smith, and P. J. Roach, unpublished observations. Back

3 B. A. Pederson, M. W. Smith, C. R. Cope, J. M. Schroeder, and P. J. Roach, unpublished results. Back

4 G. E. Parker, B. A. Pederson, and P. J. Roach, unpublished observations. Back


   ACKNOWLEDGMENTS
 
Locomotor activity was assessed at the Vanderbilt University School of Medicine Mouse Metabolic Phenotyping Center (supported in part by National Institutes of Health Grant U24 DK59637). We thank Drs. J. Elmendorf, L. Goodyear, R. A. Harris, J. C. Lawrence, and O. McGuinness for helpful discussions andCharlie Vaccaro at Genzyme for technical assistance with the electron microscopy.



   REFERENCES
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 ABSTRACT
 INTRODUCTION
 EXPERIMENTAL PROCEDURES
 RESULTS
 DISCUSSION
 REFERENCES
 

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