This Article Abstract Full Text (PDF) Services Download to citation manager PubMed PubMed Citation

Brief Food Restriction in Old Animals Decreases Triglyceride Content and Insulin-Stimulated Triglyceride Synthesis

Departments of Kinesiology and Biological Sciences, USC Diabetes Research Center, University of Southern California, Los Angeles.

Address correspondence to Lorraine P. Turcotte, PhD, Department of Kinesiology, University of Southern California, 3560 Watt Way, PED 107, Los Angeles, CA 90089-0652. E-mail: turcotte{at}usc.edu

	Abstract

Top Abstract Methods Results Discussion References

 
To determine the effects of brief food restriction on fatty acid (FA) metabolism in old muscle, hind limbs of 24-month F344/BN rats fed either ad libitum (AL) or 60% food restricted (FR) for 28 days were perfused under hyperglycemic-hyperinsulinemic conditions. Basal glucose and insulin levels were significantly lower (p <.05) in FR rats. Although palmitate uptake was not affected by food restriction, palmitate oxidation was 49% lower (2.2 ± 0.3 vs 4.3 ± 0.7 nmol · g^–1 · min^–1, p <.05) in FR versus AL animals, respectively. Compared to AL animals, FR animals had 25%–43% (p <.05) lower muscle triglyceride (TG) levels and hyperinsulinemic TG synthesis rates. Higher glucose uptake rates occurred in FR rats (p <.05). In conclusion, our results indicate that brief food restriction in old animals improves insulin sensitivity as it pertains to both glucose uptake and FA oxidation. Together with the decrease in nonoxidative FA disposal, the decreased FA oxidation under hyperinsulinemic conditions may significantly contribute to food restriction-induced reduction in muscle TG.

Food restriction has been shown to improve whole body and muscle insulin sensitivity for glucose metabolism in rats, rhesus monkeys, and humans, among others (8–10). Indeed, prolonged food restriction (4 months) has been shown to decrease TG levels by 50% in soleus muscles of young adult Otsuka Long Evans Tokushima Fatty (OLETF) rats, which was paralleled by a significant improvement in insulin sensitivity as measured by an increase in glucose infusion rate during a euglycemic-hyperinsulinemic clamp (11). But prolonged food restriction is not necessary to measure significant improvements in insulin sensitivity because an increase in insulin-stimulated glucose transport has been measured after as few as five days of food restriction (12). We have recently shown that, in young adult F344/BN rats, the commonly observed increase in insulin-stimulated glucose uptake with brief (1 month) food restriction (12) was associated with an increase in FA oxidation under hyperinsulinemic conditions and negatively correlated with muscle TG levels (13). These data suggest that alterations in FA metabolism under hyperinsulinemic conditions may significantly contribute to the food restriction-induced decrease in TG accumulation and improvement in the actions of insulin on glucose uptake. The effects of brief food restriction in old animals have not been extensively studied, but old animals are capable of responding to short-term dietary interventions. Glucose transport in incubated epitrochlearis muscle was shown to be significantly increased after 20 days of food restriction in old animals (14). In addition, brief food restriction decreased fasting blood glucose and insulin concentrations in older monkeys (15), effects that are also observed with brief food restriction in young rats (13). These data show that food restriction may be an effective dietary intervention to redress the loss of sensitivity to the actions of insulin on FA metabolism and glucose uptake in old muscle.

Thus, the purpose of the present study was to determine the effects of brief food restriction on FA metabolism in muscle of old animals under hyperglycemic-hyperinsulinemic conditions by measuring palmitate uptake and disposal in perfused hind-limbs. We chose to perfuse the hind limbs under hyperglycemic-hyperinsulinemic conditions to determine whether food restriction can redress the loss of sensitivity to the antioxidative actions of insulin on muscle FA metabolism previously documented in old rats (5). FABP_PM and HSL contents were also evaluated to assess the ability of the muscle to take up FA and hydrolyze muscle TG.

	METHODS

Top Abstract Methods Results Discussion References

 
Animals
Male Fischer 344/Brown Norway rats aged 22–23 months were obtained from the National Institute on Aging (Bethesda, MD), housed singly and maintained on a 12-h light/dark cycle. Animals were fed Harlan Teklad 8604 rodent diet (Teklad, Madison, WI), which has an average composition of 24% protein, 4% fat, 4% fiber, 8% ash, and 4.5% minerals. Daily food intake was measured during a 10-day baseline period as well as the experimental feeding period. Animals were randomly assigned to either an ad libitum (AL, n = 10) or 28-day FR (n = 10) group. FR rats received a daily food allotment at 6 PM equal to 60% of the baseline food intake rate, and the feeding period lasted for approximately 6–8 hours. The rats were 24 months old at the time of the experiment. Ethical approval for the present study was obtained from the Institutional Animal Care and Use Committee at the University of Southern California.

Hind-Limb Perfusion
Animals were fasted overnight and anesthetized intraperitoneally with ketamine/xylazine (40 mg/kg and 6 mg/kg body weight, respectively) between 10 AM and 1 PM. A basal blood sample was taken via a tail vein. Then, the animals were prepared for hind-limb perfusion as previously described (2,5). Before the perfusion catheters were inserted, heparin (150 IU) was administered into the inferior vena cava. The rats were killed with an intracardial injection of ketamine/xylazine (200 mg/kg and 30 mg/kg body weight, respectively) immediately before the catheters were inserted, and the preparation was placed in a perfusion apparatus, essentially as described (2,16).

The initial perfusate (300 ml) consisted of Krebs-Henseleit solution, 1- to 2-day-old washed bovine erythrocytes (hematocrit, 28%), 3.5% bovine serum albumin (Cohn fraction V; Sigma Chemical, St. Louis, MO), 20 mM glucose, 0.15 mM pyruvate, 1 mM palmitate, 1000 µU/ml insulin, 8 µCi of [1-¹⁴C]palmitate (ICN Pharmaceuticals, Costa Mesa, CA), and 10 µCi of [3-³H]glucose (NEN Life Science Products, Boston, MA). The perfusate (37°C) was continuously gassed with a mixture of 95% O₂/5% CO₂, which yielded arterial pH values of 7.2–7.3 and arterial pCO₂ and pO₂ values that were typically 30–34 and 141–188 mmHg, respectively, in both dietary groups. Mean perfusion pressures were 70 ± 6 and 77 ± 10 mmHg during unilateral hind-limb perfusion in the AL and FR animals, respectively.

To minimize the possible effects of heparin added during surgery on plasma FA availability due to lipoprotein lipase activation, 25 ml of perfusate were passed through the circulatory system to remove remaining heparin and were then discarded. Subsequently, the perfusate was recirculated at a flow of 7 ml/min. Immediately after the beginning of the perfusion, the left superficial fast-twitch white (predominantly type IIb) and the deep fast-twitch red (predominantly type IIa) sections of the gastrocnemius muscles, as well as the plantaris muscle (mixed fiber types), were taken out and freeze-clamped with aluminum clamps precooled in liquid nitrogen. The left iliac vessels were then tied off, and a clamp was fixed tightly around the proximal part of the leg to prevent bleeding. After an equilibration period of 20 minutes, the right leg was perfused at rest for 40 minutes at 7 ml/min (0.32 ± 0.01 and 0.34 ± 0.01 ml · min^–1 · g^–1 perfused muscle in AL and FR rats, respectively). Arterial perfusate glucose concentration was held steady throughout the perfusion with a small volume variable glucose infusion. Arterial and venous perfusate samples for the analysis of [¹⁴C]FA, ¹⁴CO₂, and [³H]glucose radioactivities as well as FA, glucose, and lactate concentrations were taken at 10, 20, 30, and 40 minutes. Arterial and venous perfusate samples for determinations of pCO₂, pO₂, and pH were taken at 10 and 30 minutes. Arterial samples for the determination of hemoglobin and hematocrit levels were taken 10 minutes prior to perfusion. At the end of the 40-minute perfusion period, muscle samples from the right leg of the animal were taken and treated as described above. In addition, the deep fast-twitch red vastus lateralis was taken out and freeze-clamped with aluminum clamps precooled in liquid nitrogen. The muscle mass perfused was determined by infusing a black ink solution into the arterial catheter and weighing the colored muscle mass at the end of the perfusions.

To correct for carbon loss, additional experiments were conducted to determine the acetate correction factor under our experimental conditions (5,17). Thus, subsamples of hind-limbs (n = 4 each for AL and FR animals) were perfused under identical perfusate conditions except that 5 µCi of [1-¹⁴C]acetate (ICN Pharmaceuticals) was added rather than [1-¹⁴C]palmitate and [3-³H]glucose. Arterial and venous perfusate samples were taken as described above and analyzed for [¹⁴C]acetate and ¹⁴CO₂ radioactivities.

Blood Sample Analyses
Basal venous blood samples were analyzed for glucose, FA, and insulin concentrations. Arterial and venous perfusate samples were analyzed for glucose, lactate, and FA concentrations as well as for [¹⁴C]FA, ¹⁴CO₂, and [³H]glucose radioactivities. Samples for glucose, lactate, and FA were put into 200 µM ethylene glycol-bis(ß-aminoethyl ether) (EGTA, pH = 7) and immediately analyzed as previously described in detail (2,5). Analysis for plasma palmitate and blood CO₂ radioactivities as well as for perfusate pCO₂, pO₂, pH, and hemoglobin were performed as previously described in detail (2,18).

Muscle Sample Analyses
Muscle TG concentration was determined by measuring glycerol levels after extraction and separation of the muscle samples, as previously described in detail (2,18). To measure the incorporation of [¹⁴C]palmitate into muscle TG, lipids from the extracted organic layer were separated by liquid chromatography as previously described in detail (2,5). Muscle glycogen concentration was determined by measuring glucose levels after hydrolysis of the muscle samples as previously described by others and us (2,19,20). To measure the incorporation of [³H]glucose into glycogen, an aliquot of the undiluted hydrolysate was mixed with liquid scintillation fluid (Research Products International, Mount Prospect, IL) and counted in a Tri-Carb liquid scintillation counter (5). Citrate synthase activity was measured as previously described by others and us (5,21).

Western Blot Analysis
Plantaris FABP_PM and red quadriceps HSL protein contents were determined by Western blotting. Solubilized muscle homogenate proteins were prepared and analyzed as previously described in details (2,18,22). Western blotting was performed using a polyclonal rabbit anti-FABP_PM (1:3000) and a polyclonal rabbit anti-HSL (1:5000, donated by Dr. F. B. Kraemer, Stanford University Medical Center, Palo Alto, CA). The secondary incubation was performed with goat anti-rabbit immunoglobulin G (H+L chains)–horseradish peroxidase followed by detection using enhanced chemiluminescence and exposure to film (Pierce, Rockford, IL). Films were scanned using a Hewlett Packard (Palo Alto, CA) ScanJet 6200C and quantitated using Scion Image (Scion Corp., Frederick, MD). Rat liver plasma membrane and rat soleus crude membrane preparations were used as standards, and results were expressed as relative density units. In all cases, multiple gels were analyzed.

Calculations and Statistics
Delivery, fractional and total uptake, and percent and total oxidation of palmitate were calculated as previously described in detail (2,18). Both percent and total palmitate oxidation were corrected for label fixation by using acetate correction factors of 1.224 and 1.147 for AL and FR animals, respectively. Oxygen and glucose uptake and lactate release were calculated as previously described (2,18) and expressed per gram of perfused muscle, which was measured to be 5.5% and 6.0% of body weight for unilateral hind-limb perfusion in AL and FR animals, respectively. The muscle TG fractional synthesis rate was calculated as muscle TG specific activity divided by the arterial FA specific activity (2). The rate of muscle TG synthesis was calculated as the product of muscle TG fractional synthesis rate and postperfusion muscle TG concentration (2). The glycogen synthesis rate was calculated as the ³H radioactivity recovered in glycogen divided by arterial glucose specific activity, taking into account fiber type composition (23) as previously described in detail (2,5).

The arterial and venous specific activities for palmitate and glucose did not vary over time and were not significantly different between groups. The arterial and venous specific activities averaged 34.1 ± 0.9 and 31.7 ± 1.0 µCi/mmol for palmitate and 1.9 ± 0.07 and 1.9 ± 0.07 µCi/mmol for glucose. Because FA uptake and oxidation rates did not change significantly during the last 30 minutes of perfusion, the averages of the values were used to make comparisons between groups.

Statistical evaluation of the muscle TG and glycogen data was performed using a two-way analysis of variance (ANOVA; Statistica, Tulsa, OK). Statistical analysis of glucose concentration, glucose uptake, lactate release, and lactate concentration was performed using an ANOVA with repeated measures. All other data were analyzed by a one-way ANOVA. Tukey's honestly significant difference test for post hoc multiple comparisons was performed when appropriate. Correlation coefficients were computed when applicable. In all instances, an value of 0.05 was used to determine significance.

	RESULTS

Top Abstract Methods Results Discussion References

 
Basal Metabolic Parameters
Baseline food intake was similar between AL and FR animals (16.7 ± 0.7 and 17.1 ± 0.9 g/day, respectively). Food intake during the experimental feeding period averaged 108 ± 1.6 and 60 ± 0.1% of baseline intake in AL and FR animals, respectively. Prior to perfusion, venous plasma glucose and insulin concentrations were significantly decreased (p <.05) by 23% and 48%, respectively, in FR versus AL animals (Table 1). However, preperfusion plasma FA concentration was not significantly different between groups. Body weight was decreased (p <.05) by 15% in FR compared to AL animals, but perfused muscle weight was similar between groups (Table 1).

View larger version (12K): [in this window] [in a new window]   Figure 1. Effects of food restriction (FR) on insulin-stimulated percent (A) and total (B) palmitate oxidation in perfused hind-limbs of old animals. Values are means ± SE for ad libitum-fed (AL; n = 10) and food-restricted (FR; n = 10) animals. Because there were no significant changes in values measured after 20, 30, and 40 minutes of perfusion, average values were used for each animal. Percent and total palmitate oxidation were corrected for label fixation as described in "Methods." *p <.05 compared with AL animals

View larger version (13K): [in this window] [in a new window]   Figure 2. Effects of food restriction on insulin-stimulated glucose uptake (A) and lactate release (B) in perfused hind-limbs of old animals. Values are means ± SE for ad libitum-fed (AL: n = 10) and food-restricted (FR; n = 10) animals. *p <.05 compared with AL animals. #p <.05 compared with 10-minute time point, FR animals only. +p <.05 compared with 10-minute time point, FR and AL animals

Muscle Metabolites
Preperfusion TG concentrations were significantly lower (p <.05) in FR animals in both the red (6.6 ± 0.4 and 4.5 ± 0.4 µmol · gwwt^–1 for AL and FR, respectively) and white (7.5 ± 0.8 and 4.5 ± 0.5 µmol · gwwt^–1 for AL and FR, respectively) gastrocnemius muscles than in AL animals (Figure 3A). Similar significant decreases were found in postperfusion red and white gastrocnemius muscles of FR versus AL animals (Figure 3A). We have previously demonstrated that our measurement of muscle TG concentration is not affected by adipose tissue infiltration, as assessed by the measurement of adipose-specific FABP or aP2 content in muscle (5). Indeed, we have shown that aP2 protein content in our muscle preparation is minimal compared to that observed in adipose tissue (<1%), providing evidence that our measurement can be used to quantify changes in TG concentration with experimental interventions (5). In addition, TG synthesis rates were significantly lower (p <.05) in FR animals in both red (2.2 ± 0.2 and 1.2 ± 0.2 nmol · g^–1 · min^–1 for AL and FR, respectively) and white gastrocnemius muscles (0.9 ± 0.1 and 0.4 ± 0.1 nmol · g^–1 · min^–1 for AL and FR, respectively) (Figure 3B).

View larger version (31K): [in this window] [in a new window]   Figure 3. Effects of food restriction on pre- and postperfusion muscle triglyceride (TG) concentration (A) and insulin-stimulated TG synthesis rates (B) in red and white gastrocnemius muscles of old animals. Values are means ± SE for ad libitum-fed (AL; n = 10) and food-restricted (FR; n = 10) animals. (A) Open and open dappled bars represent AL animals before and after perfusion, respectively. Solid and solid dappled bars represent FR animals before and after perfusion, respectively. (B) Open bars represent AL animals; solid bars represent FR animals. *p <.05 compared with AL animals at the same time point

View larger version (14K): [in this window] [in a new window]   Figure 4. Effects of food restriction on plantaris plasma membrane fatty acid binding protein (FABPPM) (A) and red gastrocnemius hormone-sensitive lipase (HSL) (B) content in old animals. Values are means ± SE for ad libitum-fed (AL; n = 10) and food-restricted (FR; n = 10) animals. FABPPM and HSL protein contents were measured by immunoblotting muscle homogenates and quantitated by scanning densitometry. FABPPM results are expressed as percent liver standard. HSL results are expressed as percent soleus standard

	DISCUSSION

Top Abstract Methods Results Discussion References

Plasma FA availability and blood flow are factors which can affect FA metabolism with the perfused hind-limb system. The perfused muscle mass, based on infused ink staining, was similar in FR and AL rats. Because blood flow and perfusate concentrations were kept constant, both groups had equivalent rates of FA and glucose delivery. In young animals perfused under the same hyperinsulinemic conditions, we have shown that brief food restriction is associated with an increase in FA uptake. However, it is important to note that, in old animals, FA uptake under hyperinsulinemic conditions and muscle FABP_PM and FAT/CD36 content are elevated (5). Because the purported role of FABP_PM and FAT/CD36 is to facilitate FA transport across the sarcolemmal membrane (24,25), the age-induced increase in the expression of FA transporter proteins may have been partially responsible for the high rates of FA uptake under these conditions. Thus, a decrease in FA uptake under hyperinsulinemic conditions could be considered a positive adaptation in old animals. In this study, palmitate uptake (p =.12) and FABP_PM content (p =.08) declined by 18%–21% with food restriction. Although these changes were not sufficient to observe a significant decrease in FA uptake, an increased duration of food restriction might have resulted in a further decline in FABP_PM protein level and FA uptake and be accompanied by a further improvement in insulin sensitivity as it pertains to both glucose uptake and FA oxidation.

Brief food restriction resulted in significant decreases in both the percent and total rate of FA oxidation. The decrease in FA oxidation appears to be a fuel selection choice as mitochondrial content is not only maintained with food restriction (26), but mitochondrial electron transport activity is increased (26) and mitochondrial deletion accumulation is decreased with food restriction (27). Thus, mitochondrial oxidative capacity should not be a limiting factor for FA oxidation in the FR animals as suggested in our study by the maintenance of citrate synthase activity with food restriction in the old animals. In addition, food restriction has been observed to attenuate age-associated changes in the activities of oxidative damage repair enzymes in muscle mitochondria, indicating that less oxidative damage occurs in mitochondria with food restriction in old animals (28). It is interesting to note that brief food restriction was associated with an increase in FA oxidation but no change in TG synthesis in young animals perfused under the same conditions (13). However, in the old animals, the high rate of FA oxidation under hyperinsulinemic conditions is a reflection of insulin resistance on FA oxidative metabolism because insulin has been shown to decrease FA oxidation (6,7). Thus, its decrease with food restriction may reflect an improvement in insulin action on FA oxidative metabolism. In line with this notion, the rate of FA oxidation observed in the FR animals was similar to those reported under identical experimental conditions in young ad libitum-fed animals (5,13).

The rate of TG synthesis was decreased with food restriction by 39%–43% in both red and white muscle fibers. HSL concentration has been shown to decrease with aging (2), and HSL content remained low in the FR animals indicating that food restriction may not have affected TG utilization in FR animals especially in view of the fact that insulin is an antilipolytic agent and that food restriction was associated with an increase in insulin action on FA oxidative metabolism. As food restriction significantly reduced TG levels, the reduction is most likely due to the decreased TG synthesis rate. TG synthesis can also be utilized as an index of nonoxidative FA disposal. Because high rates of nonoxidative FA disposal have been linked to an increase in apoptosis via ceramide production (29), a decrease in nonoxidative FA disposal with food restriction would be beneficial for the maintenance of muscle function in aged rats. Furthermore, in line with the well-established inverse relationship between insulin-stimulated glucose metabolism and muscle TG (3), the observed decrease in muscle TG levels was associated with an 18% increase in glucose uptake during the last 20 minutes of perfusion in FR animals.

In the presence of similar rates of oxygen consumption, the decreased rate of FA oxidation in FR animals suggests an increase in carbohydrate (CHO) oxidation. The rate of glycogen synthesis was similar between dietary groups. However, FR animals tended to accumulate less glycogen in both red (p =.16) and white (p =.14) muscle fibers than did AL animals. This may indicate a greater contribution of glucose derived from glycogen to oxidation in FR animals. Food restriction has been shown to completely prevent the age-related decline in gene expression of certain glycolytic enzymes such as glucose-6-phosphate isomerase and -enolase as well as to significantly increase the expression of other glycolytic enzymes such as pyruvate kinase and fructose bisphosphate aldolase (30). The increase in glycolytic enzyme expression with food restriction may favor CHO oxidation. Higher rates of CHO oxidation may have decreased FA oxidation via the "reverse glucose-fatty acid cycle" by which increased glucose oxidation inhibits FA oxidation by limiting its entry into the mitochondria via an increase in malonyl-CoA production (31,32). Alternatively, an increased sensitivity of carnitine palmitoyl transferase-1 to malonyl-CoA in FR animals could be responsible in part for the decrease in FA oxidation. Although a decreased rate of FA oxidation may appear to be an unfavorable adaptation with food restriction, in old animals the decrease in FA oxidation under hyperinsulinemic conditions represents a return to a more youthful balance between CHO and FA utilization (5). Furthermore, the increased CHO utilization in FR animals may be important in maintaining insulin action as it pertains to both glucose uptake and FA oxidation with advancing age.

Summary
The present study has shown that brief food restriction in old animals is an effective method to improve the actions of insulin on glucose uptake and FA oxidation. Brief food restriction resulted in decreased rates of FA oxidation and TG synthesis under hyperinsulinemic conditions, and this was associated with lower TG levels in both red and white muscle fibers and with an increase in glucose uptake. These findings indicate that brief food restriction in old animals leads to an improvement in insulin action on glucose uptake under hyperinsulinemic conditions that is due, at least in part, to both alterations in FA oxidative and nonoxidative disposal under those conditions and to a concomitant decrease in muscle TG levels.

	Acknowledgments

 
We thank Hubert Chan, Nicholas Chan, Felicity Macahilig, and William Wu for expert technical assistance and Dr. Fredric B. Kraemer (Stanford University Medical Center, CA) for providing the antibody for HSL.

This study was supported by grants from the American College of Sports Medicine and from the National Institute of Arthritis and Musculoskeletal and Skin Diseases (AR-45168).

	Footnotes

 
Decision Editor: James R. Smith, PhD

Received May 26, 2004

Accepted August 17, 2004

	References

Top Abstract Methods Results Discussion References

 

1. Calles-Escandon J, Arciero PJ, Gardner AW, Bauman C, Poehlman ET. Basal fat oxidation decreases with aging in women. J Appl Physiol. 1995;78:266-271.[Abstract/Free Full Text]
2. Tucker MZ, Turcotte LP. Impaired fatty acid oxidation in muscle of aging rats perfused under basal conditions. Am J Physiol Endocrinol Metab. 2002;282:E1102-E1109.[Abstract/Free Full Text]
3. Storlien LH, Jenkins AB, Chisholm DJ, Pascoe WS, Khouri S, Kraegen ED. Influence of dietary fat composition on development of insulin resistance in rats. Diabetes. 1991;40:280-289.[Abstract]
4. Toth MJ, Arciero PJ, Gardner AW, Calles-Escandon J, Poehlman ET. Rates of free fatty acid appearance and fat oxidation in healthy younger and older men. J Appl Physiol. 1996;80:506-511.[Abstract/Free Full Text]
5. Tucker MZ, Turcotte LP. Aging is associated with elevated muscle triglyceride content and increased insulin-stimulated fatty acid uptake. Am J Physiol Endocrinol Metab. 2003;285:E827-E835.[Abstract/Free Full Text]
6. Dyck DJ, Steinberg G, Bonen A. Insulin increases FA uptake and esterification but reduces lipid utilization in isolated contracting muscle. Am J Physiol Endocrinol Metab. 2001;281:E600-E607.[Abstract/Free Full Text]
7. Muoio DM, Dohm GL, Tapscott EB, Coleman RA. Leptin opposes insulin's effects on fatty acid partitioning in muscles isolated from obese ob/ob mice. Am J Physiol Endocrinol Metab. 1999;276:E913-E921.[Abstract/Free Full Text]
8. Cartee GD, Kietzke EW, Briggs-Tung C. Adaptations of muscle glucose transport with caloric restriction in adult, middle-aged, and old rats. Am J Physiol Regul Integr Comp Physiol. 1994;266:R1443-R1447.[Abstract/Free Full Text]
9. Kemnitz JW, Roecker EB, Weindruch R, Elson DF, Baum ST, Bergman RN. Dietary restriction increases insulin sensitivity and lowers blood glucose in rhesus monkeys. Am J Physiol Endocrinol Metab. 1994;266:E540-E547.[Abstract/Free Full Text]
10. Wing RR, Blair EH, Bononi P, Marcus MD, Watanabe R, Bergman RN. Caloric restriction per se is a significant factor in improvements in glycemic control and insulin sensitivity during weight loss in obese NIDDM patients. Diabetes Care. 1994;17:30-36.[Abstract]
11. Man ZW, Hirashima T, Mori S, Kawano K. Decrease in triglyceride accumulation in tissues by restricted diet and improvement of diabetes in Otsuka Long-Evans Tokushima Fatty rats, a non-insulin-dependent diabetes model. Metabolism. 2000;49:108-114.[Medline]
12. Cartee GD, Dean DJ. Glucose transport with brief dietary restriction: heterogenous responses in muscles. Am J Physiol Endocrinol Metab. 1994;266:E946-E952.[Abstract/Free Full Text]
13. Tucker MZ, Turcotte LP. Brief food restriction increases FA oxidation and glycogen synthesis under insulin-stimulated conditions. Am J Physiol Regul Integr Comp Physiol. 2002;282:R1210-R1218.[Abstract/Free Full Text]
14. Dean DJ, Cartee GD. Brief dietary restriction increases skeletal muscle glucose transport in old Fischer 344 rats. J Gerontol Biol Sci. 1996;51A:B208-B213.
15. Lane MA, Tilmont EM, De Angelis H, Handy A, Ingram DK, Kemnitz JW, Roth GS. Short-term caloric restriction improves disease-related markers in older male rhesus monkeys (Macaca mulatta). Mech Ageing Dev. 1999;112:185-196.
16. Ruderman NB, Houghton CRS, Hems R. Evaluation of the isolated perfused rat hindquarter for the study of muscle metabolism. Biochem J. 1971;124:639-651.[Medline]
17. Sidossis LS, Coggan AR, Gastaldelli A, Wolfe RR. A new correction factor for use in tracer estimations of plasma fatty acid oxidation. Am J Physiol Endocrinol Metab. 1995;269:E649-E656.[Abstract/Free Full Text]
18. Turcotte LP, Swenberger JR, Tucker MZ, Yee AJ. Training-induced elevation in FABP_PM is associated with increased palmitate use in contracting muscle. J Appl Physiol. 1999;87:285-293.[Abstract/Free Full Text]
19. Dubois M, Gilles KA, Hamilton JK, Rebers PA, Smith F. Colorimetric method for determination of sugars and related substances. Anal Chem. 1956;28:350-356.
20. Good CA, Kramer H, Somogyi M. The determination of glycogen. J Biol Chem. 1933;100:485-491.[Free Full Text]
21. Ivy JL, Brozinick JT, Torgan CE, Kastello GM. Skeletal muscle glucose transport in obese Zucker rats after exercise training. J Appl Physiol. 1989;66:2635-2641.[Abstract/Free Full Text]
22. Peters SJ, Dyck DJ, Bonen A, Spriet LL. Effects of epinephrine on lipid metabolism in resting skeletal muscle. Am J Physiol Endocrinol Metab. 1998;275:E300-E309.[Abstract/Free Full Text]
23. Armstrong RB, Phelps RO. Muscle fiber type composition of the rat hindlimb. Am J Anat. 1984;171:259-272.[Medline]
24. Abumrad NA, Harmon C, Ibrahimi A. Membrane transport of long-chain fatty acids: evidence for a facilitated process. J Lipid Res. 1998;39:2309-2318.[Abstract/Free Full Text]
25. Berk PD, Stump DD. Mechanisms of cellular uptake of long chain free fatty acids. Mol Cell Biochem. 1999;192:17-31.[Medline]
26. Desai VG, Weindruch R, Hart RW, Feuers RJ. Influences of age and dietary restriction on gastrocnemius electron transport system activities in mice. Arch Biochem Biophys. 1996;333:145-151.[Medline]
27. Aspnes LE, Lee CM, Weindruch R, Chung SS, Roecker EB, Aiken JM. Caloric restriction reduces fiber loss and mitochondrial abnormalities in aged rat muscle. FASEB J. 1997;11:573-581.[Abstract]
28. Luhtala TA, Roecker EB, Pugh T, Feuers RJ, Weindruch R. Dietary restriction attenuates age-related increases in rat skeletal muscle antioxidant enzyme activities. J Gerontol. 1994;49:B231-B238.
29. Unger RH, Orci L. Diseases of liporegulation: new perspective on obesity and related disorders. FASEB J. 2001;15:312-321.[Abstract/Free Full Text]
30. Lee CK, Klopp RG, Weindruch R, Prolla TA. Gene expression profile of aging and its retardation by caloric restriction. Science. 1999;285:1390-1393.[Abstract/Free Full Text]
31. Ruderman NB, Dean D. Malonyl CoA, long chain fatty acyl CoA and insulin resistance in skeletal muscle. J Bas Clin Physiol Pharmacol. 1998;9:295-308.[Medline]
32. Wolfe RR. Metabolic interactions between glucose and fatty acids in humans. J Clin Nutr. 1998;67S:519S-526S.

This Article Abstract Full Text (PDF) Services Download to citation manager PubMed PubMed Citation