Diabetes Unit, Section of Endocrinology, and Departments of Medicine and Physiology, Boston University Medical School, Boston, Massachusetts 02118
![]() |
ABSTRACT |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
Previous studies have shown that
5-aminoimidazole-4-carboxamide ribonucleoside (AICAR), a cell-permeable
activator of AMP-activated protein kinase, increases the rate of fatty
acid oxidation in skeletal muscle of fed rats. The present study
investigated the mechanism by which this occurs and, in particular,
whether changes in the activity of malonyl-CoA decarboxylase (MCD) and
the -isoform of acetyl-CoA carboxylase (ACC
) are involved. In
addition, the relationship between changes in fatty acid oxidation
induced by AICAR and its effects on glucose uptake and metabolism was
examined. In incubated soleus muscles isolated from fed rats, AICAR (2 mM) increased fatty acid oxidation (90%) and decreased ACC
activity (40%) and malonyl-CoA concentration (50%); however, MCD activity was
not significantly altered. In soleus muscles from overnight-fasted rats, AICAR decreased ACC
activity (40%), as it did in fed rats; however, it had no effect on the already high rate of fatty acid oxidation or the low malonyl-CoA concentration. In keeping with its
effect on fatty acid oxidation, AICAR decreased glucose oxidation by
44% in fed rats but did not decrease glucose oxidation in fasted rats.
It had no effect on glucose oxidation when fatty acid oxidation was
inhibited by 2-bromopalmitate. Surprisingly, AICAR did not significantly increase glucose uptake or assayable AMP-activated protein kinase activity in incubated soleus muscles from fed or fasted
rats. These results indicate that, in incubated rat soleus muscle,
1) AICAR does not activate MCD or stimulate glucose uptake as it does in extensor digitorum longus and epitrochlearis muscles, 2) the ability of AICAR to increase fatty acid oxidation and
diminish glucose oxidation and malonyl-CoA concentration is dependent
on the nutritional status of the rat, and 3) the ability of
AICAR to diminish assayable ACC activity is independent of nutritional state.
malonyl-coenzyme A; malonyl-coenzyme A decarboxylase; acetyl-coenzyme A carboxylase; AMP-activated protein kinase; nutritional state
![]() |
INTRODUCTION |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
MALONYL-CoA is an intermediate in the de novo synthesis of fatty acids and an allosteric inhibitor of carnitine palmitoyltransferase I (CPT-I), the enzyme that regulates the rate at which long-chain fatty acyl CoAs (LCFA-CoAs) enter the mitochondria, where they are oxidized (30, 41). In tissues such as skeletal and cardiac muscle, in which fatty acid synthesis is minimal (3), the primary role of malonyl-CoA is presumably the regulation of CPT-I. Malonyl-CoA levels in these muscles and possibly in other tissues may be regulated by acetyl-CoA carboxylase (ACC), the rate-limiting enzyme in its synthesis (35, 44), and malonyl-CoA decarboxylase (MCD), which may control its degradation (2, 14, 17, 40).
ACC, the major isoform expressed in skeletal muscle (1, 6, 18,
28), is thought to be regulated via two mechanisms: 1) allosteric activation by cytosolic citrate and inhibition
by LCFA-CoAs, which appear to regulate alterations in its
activity in response to changes in nutritional state and plasma insulin and glucose (9, 32, 35, 39, 45), and 2)
covalent modification due to phosphorylation by AMP-activated protein
kinase (AMPK). AMPK-mediated changes in assayable ACC
activity have
been demonstrated in response to "stressful" stimuli such as
ischemia/hypoxia, inhibition of oxidative phosphorylation and
glucose metabolism, and exercise (13, 20, 24-26, 29).
Less is known about MCD regulation in skeletal muscle, although recent
studies have shown that activation of AMPK during muscle contraction
phosphorylates and activates MCD, suggesting that it also participates
in the control of malonyl-CoA concentration (40).
In addition to exercise, AMPK in muscle and other tissues can be
activated by perfusion or incubation with
5-aminoimidazole-4-carboxamide ribonucleoside (AICAR). When taken up
into cells, AICAR is phosphorylated to form ZMP, an AMP analog that
activates AMPK. In perfused rat hindquarter (31) and
isolated epitrochlearis muscle preparations from fed animals
(21), AICAR mimics many acute effects of exercise and
electrically induced contractions, including increased fatty acid
oxidation and decreased ACC activity and malonyl-CoA concentration (2, 31). In addition, in an incubated extensor digitorum longus (EDL) muscle preparation, it increases MCD activity
(40). Yet another effect of AICAR is to increase glucose
uptake by enhancing glucose transporter translocation, which it does in
cardiac myocytes (36) and perfused gastrocnemius muscle
(27). Finally, chronic AICAR administration in vivo has
been shown to mimic a number of effects of physical training, including
increases in GLUT-4 protein, hexokinase activity, and muscle glycogen
(23).
Although the effects of AICAR on fatty acid oxidation and its link to
changes in malonyl-CoA concentration are well documented, the relative
roles of ACC and MCD are unclear. In addition, it is not known how
such factors as nutritional status and the type of muscle studied
affect its action. To examine these questions, the effects of AICAR
were compared in soleus muscle strips isolated from fed and
overnight-fasted rats. The present report describes its effects on
glucose and fatty acid oxidation, glucose uptake, and the activities of
ACC
, MCD, and AMPK.
![]() |
METHODS |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
Animals. Male Sprague-Dawley rats (140-151 g; Charles River Breeding Laboratories, Wilmington, MA) were kept in the departmental animal house with a 12:12-h light-dark cycle (lights on from 0600 to 1800) at room temperature. They were fed standard Purina rat chow ad libitum, or food was removed at 1600 during the day before they were killed.
In vitro muscle incubation. On the experimental day, rats were anesthetized with pentobarbital sodium (60 mg/kg ip), and soleus muscle strips were prepared and tied to stainless steel clips as described previously (38). Muscles were preincubated for 20 min at 37°C in open 12 × 75 mm test tubes containing 3.0 ml of Krebs-Henseleit buffer [10 mM glucose, 10 mU/ml insulin (67 µM), 2% fatty acid-free bovine serum albumin, and 2 mM AICAR; Sigma]. The media were gassed continuously with 95% O2-5% CO2. Muscle strips were then transferred to a new set of identical test tubes and incubated with fresh medium containing 0.2 mM palmitate complexed to 2% bovine serum albumin and AICAR or 2 mM 2-bromopalmitate (2-BPA). The muscles were incubated for 60 min. Gassing was terminated after the initial 10 min, and the test tubes were covered. At the end of the incubation, muscles were removed, blotted on gauze pads, and frozen in liquid nitrogen.
Glucose and fatty acid oxidation. For oxidation studies, incubation media contained 0.2 µCi/ml [U-14C]glucose or 0.2 µCi/ml [1-14C]palmitate (New England Nuclear). At the end of 60 min, the medium was transferred to a 25-ml Erlenmeyer flask fitted with a center well containing filter paper saturated with 0.3 ml of phenylethylamine. After medium acidification with 0.3 ml of 5 N HCl, the flasks were shaken at 37°C for 60 min, and the center wells were removed and transferred to vials for liquid scintillation counting.
[14C]lactate release, net lactate release, and glycogen synthesis. The release of [14C]lactate from muscle incubated with media containing [U-14C]glucose was determined as previously described using Dowex ion-exchange chromatography (19). Net lactate release was assessed spectrophotometrically (15). Glycogen synthesis was determined by measuring the rate of [U-14C]glucose incorporated into glycogen (11).
AMPK, ACC, MCD, and malonyl-CoA.
AMPK and ACC
tissue extracts were prepared as previously described
(43), with two simple modifications that did not alter activity: 1) buffers A and B did not
contain diisopropyl fluorophosphate, and 2) the high-speed
spin was eliminated, and homogenates were spun only at 13,500 g for 12 min. AMPK homogenates were immunoprecipitated with
nonimmune sera or with specific antisera directed against the
2-catalytic subunit of the AMPK heterotrimer
(42). Immunoprecipitates were collected on protein A/G
beads and washed extensively, and the immobilized enzyme was assayed as
previously described (46), with the following
modifications: 50 µl of reaction mixture were added to the
immunoprecipitates, and 25 µl of the resultant mixture were spotted
on p81 filter paper. Also, 5% trichloroacetic acid-1% sodium
pyrophosphate was used to wash the filter papers. ACC
was assayed as
previously described (43). The ACC
antibody was kindly
provided by Lee A. Witters, Darmouth Medical School, Hanover, NH. The
initial muscle homogenate was diluted 1:1 with buffer B and
incubated for 2.5 h with 5.0 µl of 7AD3 monoclonal antibody and
25 µl of agarose-protein A/G plus beads. The beads were washed twice
with buffer B and once with Tris-acetate buffer (pH 7.4).
Beads were then assayed for ACC activity at 0.2 mM citrate by the
14CO2 fixation assay (47).
Protein content. Protein amounts were determined spectrophotometrically using the Bio-Rad DC protein assay system and a Hewlett-Packard model 8450A diode array spectrophotometer.
Statistics. Values are means ± SE for the indicated number of muscles. Statistical significance was assessed by group comparison with the use of Student's t-test or by one-way analysis of variance followed by Student-Newman-Keuls post hoc analysis.
![]() |
RESULTS |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
Effects of AICAR on fatty acid oxidation by soleus muscles of fed
rats.
In soleus muscles isolated from fed rats, incubation with AICAR
resulted in a 90% increase in fatty acid oxidation (Fig.
1A), which was accompanied by 50%
decreases in malonyl-CoA concentration (Fig. 1B) and ACC
activity (Fig. 1C). AICAR tended to increase MCD activity
(Fig. 1D); however, the effect was not statistically significant.
|
Effects of AICAR on fatty acid oxidation by soleus muscles in
overnight-fasted rats.
In muscle from overnight-fasted rats, the rate of fatty acid oxidation
was already high, and incubation with AICAR did not increase it further
(Fig. 2A), nor did it decrease the
concentration of malonyl-CoA (Fig. 2B). As in muscles from
fed rats, AICAR decreased the activity of ACC (40%) and had no
effect on MCD activity (Fig. 2, C and
D).
|
Effects of AICAR on glucose uptake and metabolism.
Incubation with AICAR decreased glucose oxidation (44%) in soleus
muscles isolated from fed rats but had no effect on muscles from fasted
rats (Table 1). In neither group did it
affect glucose uptake, as estimated by [14C]lactate
release from muscles incubated with [U-14C]glucose
(7), nor did it affect glycogenolysis, as assessed from
net lactate release minus [14C]lactate release
(48), or glycogen synthesis (Table 1).
|
Effect of 2-BPA on AICAR-induced changes in fatty acid and glucose
oxidation.
A recent report suggests that AICAR may increase glucose oxidation in
human umbilical vein endothelial cells independent of its effects on
fatty acid oxidation (12). In contrast, its different effects on incubated soleus muscle preparations from fed and fasted rats suggest that AICAR inhibits glucose oxidation only when it concurrently increases fatty acid oxidation. To examine this question further, muscles were incubated with 2-BPA, an inhibitor of CPT-I and
other enzymes involved in fatty acid metabolism (10). As shown in Table 2, 2-BPA completely
suppressed the AICAR-induced increase in fatty acid oxidation, and no
decrease in glucose oxidation was observed.
|
Effects of AICAR on AMPK activity in soleus muscle from fed and
fasted rats.
Data showing the effect of AICAR on assayable AMPK activity are
presented in Table 3. Surprisingly,
incubation with AICAR had no effect on assayable activity of the
2-isoform of AMPK in soleus muscles from fed or fasted
rats.
|
![]() |
DISCUSSION |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
Effects of AICAR on fatty acid oxidation and ACC and MCD
activities.
Previous studies have shown that AICAR increases fatty acid oxidation
in skeletal muscle (2, 31, 33). This effect has been
attributed to the activation of AMPK, which phosphorylates and inhibits
ACC, leading to a decrease in the concentration of malonyl-CoA
(31). Recent work has shown that, in an incubated EDL
muscle preparation, AICAR also phosphorylates and activates MCD, an
enzyme that degrades malonyl-CoA (40), suggesting that its
concentration, and thus fatty acid oxidation, may be dually regulated
by ACC and MCD via AMPK.
Glucose disposition and uptake. The results also indicate that AICAR does not enhance glucose oxidation, as it has been reported to do in cultured endothelium (12). Rather, incubation with AICAR leads to inhibition of glucose oxidation. This appeared secondary to its ability to activate fatty acid oxidation, since it was observed in incubated soleus muscles from fed but not fasted rats. Furthermore, the inhibition of glucose oxidation did not occur in soleus muscles from fed rats when 2-BPA was used to suppress the increase in fatty acid oxidation caused by AICAR.
One could assume, on the basis of these data, that glucose is the major fuel in the incubated rat soleus. In fact, the major fuel appears to be endogenous lipid. As shown previously in the incubated soleus (34) and perfused hindquarter (4), glucose oxidation accounts for at most 20-30% of the ATP generated in these muscle preparations. It has also been shown that the major fuel of these muscle preparations is endogenous lipid and that measurement of 14CO2 generated from medium 14C-labeled fatty acids underestimates the true rate of fatty acid oxidation by 60-90% (4, 34). This is probably attributable to the need for exogenous fatty acids to equilibrate with an intracellular pool(s) before their use for oxidation. That glucose oxidation is decreased in the fed state after incubation with AICAR, in one respect, was surprising, since it has been proposed that the AMPK cascade acts as a "fuel gauge" that signals the cell to increase the oxidation of fatty acids and the uptake of glucose (in muscle) when there is a paucity of fuel (20). Instead, AICAR activated one oxidative pathway while inhibiting another. If the AMPK cascade responded solely to a perceived fuel deficit, one would hypothesize that an increase in AMPK activity would signal a more generalized oxidization of fuels. This, together with the observation that AICAR does not increase oxygen consumption as does muscle contraction in a perfused hindquarter preparation (31), raises the possibility that the role of AMPK in the muscle cell may extend beyond the maintenance of its ATP and creatine phosphate content.Different effects of AICAR in the soleus and other muscles.
The lack of an effect of AICAR on glucose uptake and AMPK
activation is at variance with previous studies in which it was shown
to activate AMPK and stimulate glucose uptake, in the presence and
absence of insulin, in rat epitrochlearis (22) and EDL
(unpublished observations) muscles and the perfused rat hindquarter
(31). This could be related to differences in muscle fiber
type, since these preparations are much richer in white fibers, in
which the AMPK 2-catalytic subunit associates with the
1- and
2-subunits, than in the soleus, in
which the AMPK
2-catalytic subunit only associates with
the
1-subunit (8). Arguing against this
notion, two recent studies found that AMPK activity and glucose
transport in the soleus were increased in response to AICAR in vivo
(5) and in vitro (16). The former study
(5) showed increased glucose uptake in soleus muscles of
100- to 130-g rats infused with AICAR. The latter study
(16) used isolated split soleus muscles from younger,
starved (24 h) rats and different incubation media and conditions. The
reason for the differences between these studies and the present study
remains to be determined.
![]() |
ACKNOWLEDGEMENTS |
---|
This study was supported in part by National Institutes of Health (NIH) Grants DK-19514 and DK-49147 and a grant from the Juvenile Diabetes Foundation (to N. B. Ruderman and A. K. Saha). D. J. Dean was a recipient of an NIH Traineeship (T32-DK-07201) and a fellowship from the Juvenile Diabetes Foundation.
![]() |
FOOTNOTES |
---|
Address for reprint requests and other correspondence: A. K. Saha, Diabetes and Metabolism Unit, Boston University Medical Center, 650 Albany St., EBRC-827, Boston, MA 02118 (E-mail: aksaha{at}bu.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.
Received 10 October 2000; accepted in final form 29 March 2001.
![]() |
REFERENCES |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
1.
Abu-Elheiga, L,
Almarza-Ortega DB,
Baldini A,
and
Wakil SJ.
Human acetyl-CoA carboxylase 2. Molecular cloning, characterization, chromosomal mapping, and evidence for two isoforms.
J Biol Chem
272:
10669-10677,
1997
2.
Alam, N,
and
Saggerson ED.
Malonyl-CoA and the regulation of fatty acid oxidation in soleus muscle.
Biochem J
334:
233-241,
1998[ISI][Medline].
3.
Awan, MM,
and
Saggerson ED.
Malonyl-CoA metabolism in cardiac myocytes and its relevance to the control of fatty acid oxidation.
Biochem J
295:
61-66,
1993[ISI][Medline].
4.
Berger, M,
Hagg SA,
Goodman MN,
and
Ruderman NB.
Glucose metabolism in perfused skeletal muscle. Effects of starvation, diabetes, fatty acids, acetoacetate, insulin and exercise on glucose uptake and disposition.
Biochem J
158:
191-202,
1976[ISI][Medline].
5.
Bergeron, R,
Russell RR, III,
Young LH,
Ren JM,
Marcucci M,
Lee A,
and
Shulman GI.
Effect of AMPK activation on muscle glucose metabolism in conscious rats.
Am J Physiol Endocrinol Metab
276:
E938-E944,
1999
6.
Bianchi, A,
Evans JL,
Iverson AJ,
Nordlund AC,
Watts TD,
and
Witters LA.
Identification of an isozymic form of acetyl-CoA carboxylase.
J Biol Chem
265:
1502-1509,
1990
7.
Challiss, RA,
Lozeman FJ,
Leighton B,
and
Newsholme EA.
Effects of the -adrenoceptor agonist isoprenaline on insulin sensitivity in soleus muscle of the rat.
Biochem J
233:
377-381,
1986[ISI][Medline].
8.
Chen, Z,
Heierhorst J,
Mann RJ,
Mitchelhill KI,
Michell BJ,
Witters LA,
Lynch GS,
Kemp BE,
and
Stapleton D.
Expression of the AMP-activated protein kinase 1 and
2 subunits in skeletal muscle.
FEBS Lett
460:
343-348,
1999[ISI][Medline].
9.
Chien, D,
Dean D,
Saha AK,
Flatt JP,
and
Ruderman NB.
Malonyl-CoA content and fatty acid oxidation in rat muscle and liver in vivo.
Am J Physiol Endocrinol Metab
279:
E259-E265,
2000
10.
Coleman, RA,
Rao P,
Fogelsong RJ,
and
Bardes ES.
2-Bromopalmitoyl-CoA and 2-bromopalmitate: promiscuous inhibitors of membrane-bound enzymes.
Biochim Biophys Acta
1125:
203-209,
1992[ISI][Medline].
11.
Cuendet, GS,
Loten EG,
Jeanrenaud B,
and
Renold AE.
Decreased basal, non-insulin-stimulated glucose uptake and metabolism by skeletal soleus muscle isolated from obese-hyperglycemic (ob/ob) mice.
J Clin Invest
58:
1078-1088,
1976[ISI][Medline].
12.
Dagher, Z,
Ruderman N,
Tornheim K,
and
Ido Y.
The effect of AMP-activated protein kinase and its activator AICAR on the metabolism of human umbilical vein endothelial cells.
Biochem Biophys Res Commun
265:
112-115,
1999[ISI][Medline].
13.
Davies, SP,
Carling D,
Munday MR,
and
Hardie DG.
Diurnal rhythm of phosphorylation of rat liver acetyl-CoA carboxylase by the AMP-activated protein kinase, demonstrated using freeze-clamping. Effects of high fat diets.
Eur J Biochem
203:
615-623,
1992[Abstract].
14.
Dyck, JR,
Berthiaume LG,
Thomas PD,
Kantor PF,
Barr AJ,
Barr R,
Singh D,
Hopkins TA,
Voilley N,
Prentki M,
and
Lopaschuk GD.
Characterization of rat liver malonyl-CoA decarboxylase and the study of its role in regulating fatty acid metabolism.
Biochem J
350:
599-608,
2000[ISI][Medline].
15.
Engel, PC,
and
Jones JB.
Causes and elimination of erratic blanks in enzymatic metabolite assays involving the use of NAD+ in alkaline hydrazine buffers: improved conditions for the assay of L-glutamate, L-lactate, and other metabolites.
Anal Biochem
88:
475-484,
1978[ISI][Medline].
16.
Fryer, LG,
Hajduch E,
Rencurel F,
Salt IP,
Hundal HS,
Hardie DG,
and
Carling D.
Activation of glucose transport by AMP-activated protein kinase via stimulation of nitric oxide synthase.
Diabetes
49:
1978-1985,
2000[Abstract].
17.
Goodwin, GW,
and
Taegtmeyer H.
Regulation of fatty acid oxidation of the heart by MCD and ACC during contractile stimulation.
Am J Physiol Endocrinol Metab
277:
E772-E777,
1999
18.
Ha, J,
Lee JK,
Kim KS,
Witters LA,
and
Kim KH.
Cloning of human acetyl-CoA carboxylase- and its unique features.
Proc Natl Acad Sci USA
93:
11466-11470,
1996
19.
Hammerstedt, RH.
A rapid method for isolating glucose metabolites involved in substrate cycling.
Anal Biochem
109:
443-448,
1980[ISI][Medline].
20.
Hardie, DG,
and
Carling D.
The AMP-activated protein kinasefuel gauge of the mammalian cell?
Eur J Biochem
246:
259-273,
1997[Abstract].
21.
Hayashi, T,
Hirshman MF,
Fujii N,
Habinowski SA,
Witters LA,
and
Goodyear LJ.
Metabolic stress and altered glucose transport: activation of AMP-activated protein kinase as a unifying coupling mechanism.
Diabetes
49:
527-531,
2000[Abstract].
22.
Hayashi, T,
Hirshman MF,
Kurth EJ,
Winder WW,
and
Goodyear LJ.
Evidence for 5'-AMP-activated protein kinase mediation of the effect of muscle contraction on glucose transport.
Diabetes
47:
1369-1373,
1998[Abstract].
23.
Holmes, BF,
Kurth-Kraczek EJ,
and
Winder WW.
Chronic activation of 5'-AMP-activated protein kinase increases GLUT-4, hexokinase, and glycogen in muscle.
J Appl Physiol
87:
1990-1995,
1999
24.
Kim, KH.
Regulation of mammalian acetyl-coenzyme A carboxylase.
Annu Rev Nutr
17:
77-99,
1997[ISI][Medline].
25.
Kim, KH,
Lopez-Casillas F,
Bai DH,
Luo X,
and
Pape ME.
Role of reversible phosphorylation of acetyl-CoA carboxylase in long-chain fatty acid synthesis.
FASEB J
3:
2250-2256,
1989
26.
Kudo, N,
Barr AJ,
Barr RL,
Desai S,
and
Lopaschuk GD.
High rates of fatty acid oxidation during reperfusion of ischemic hearts are associated with a decrease in malonyl-CoA levels due to an increase in 5'-AMP-activated protein kinase inhibition of acetyl-CoA carboxylase.
J Biol Chem
270:
17513-17520,
1995
27.
Kurth-Kraczek, EJ,
Hirshman MF,
Goodyear LJ,
and
Winder WW.
5'-AMP-activated protein kinase activation causes GLUT4 translocation in skeletal muscle.
Diabetes
48:
1667-1671,
1999[Abstract].
28.
Lopaschuk, GD,
Witters LA,
Itoi T,
Barr R,
and
Barr A.
Acetyl-CoA carboxylase involvement in the rapid maturation of fatty acid oxidation in the newborn rabbit heart.
J Biol Chem
269:
25871-25878,
1994
29.
Louis, NA,
and
Witters LA.
Glucose regulation of acetyl-CoA carboxylase in hepatoma and islet cells.
J Biol Chem
267:
2287-2293,
1992
30.
McGarry, JD.
The mitochondrial carnitine palmitoyltransferase system: its broadening role in fuel homoeostasis and new insights into its molecular features.
Biochem Soc Trans
23:
321-324,
1995[ISI][Medline].
31.
Merrill, GF,
Kurth EJ,
Hardie DG,
and
Winder WW.
AICA riboside increases AMP-activated protein kinase, fatty acid oxidation, and glucose uptake in rat muscle.
Am J Physiol Endocrinol Metab
273:
E1107-E1112,
1997[ISI][Medline].
32.
Munday, MR,
Milic MR,
Takhar S,
Holness MJ,
and
Sugden MC.
The short-term regulation of hepatic acetyl-CoA carboxylase during starvation and refeeding in the rat.
Biochem J
280:
733-737,
1991[ISI][Medline].
33.
Muoio, DM,
Seefeld K,
Witters LA,
and
Coleman RA.
AMP-activated kinase reciprocally regulates triacylglycerol synthesis and fatty acid oxidation in liver and muscle: evidence that sn-glycerol-3-phosphate acyltransferase is a novel target.
Biochem J
338:
783-791,
1999[ISI][Medline].
34.
Pearce, FJ,
and
Connett RJ.
Effect of lactate and palmitate on substrate utilization of isolated rat soleus.
Am J Physiol Cell Physiol
238:
C149-C159,
1980[Abstract].
35.
Ruderman, NB,
Saha AK,
Vavvas D,
and
Witters LA.
Malonyl-CoA, fuel sensing, and insulin resistance.
Am J Physiol Endocrinol Metab
276:
E1-E18,
1999
36.
Russell, RR, III,
Bergeron R,
Shulman GI,
and
Young LH.
Translocation of myocardial GLUT-4 and increased glucose uptake through activation of AMPK by AICAR.
Am J Physiol Heart Circ Physiol
277:
H643-H649,
1999
37.
Sacksteder, KA,
Morrell JC,
Wanders RJ,
Matalon R,
and
Gould SJ.
MCD encodes peroxisomal and cytoplasmic forms of malonyl-CoA decarboxylase and is mutated in malonyl-CoA decarboxylase deficiency.
J Biol Chem
274:
24461-24468,
1999
38.
Saha, AK,
Kurowski TG,
and
Ruderman NB.
A malonyl-CoA fuel-sensing mechanism in muscle: effects of insulin, glucose, and denervation.
Am J Physiol Endocrinol Metab
269:
E283-E289,
1995
39.
Saha, AK,
Laybutt DR,
Dean D,
Vavvas D,
Sebokova E,
Ellis B,
Klimes I,
Kraegen EW,
Shafrir E,
and
Ruderman NB.
Cytosolic citrate and malonyl-CoA regulation in rat muscle in vivo.
Am J Physiol Endocrinol Metab
276:
E1030-E1037,
1999
40.
Saha, AK,
Schwarsin AJ,
Roduit R,
Masse F,
Kaushik V,
Tornheim K,
Prentki M,
and
Ruderman NB.
Activation of malonyl CoA decarboxylase in rat skeletal muscle by contraction and the AMP-activated protein kinase activator AICAR.
J Biol Chem
275:
24279-24283,
2000
41.
Saha, AK,
Vavvas D,
Kurowski TG,
Apazidis A,
Witters LA,
Shafrir E,
and
Ruderman NB.
Malonyl-CoA regulation in skeletal muscle: its link to cell citrate and the glucose-fatty acid cycle.
Am J Physiol Endocrinol Metab
272:
E641-E648,
1997
42.
Stapleton, D,
Mitchelhill KI,
Gao G,
Widmer J,
Michell BJ,
Teh T,
House CM,
Fernandez CS,
Cox T,
Witters LA,
and
Kemp BE.
Mammalian AMP-activated protein kinase subfamily.
J Biol Chem
271:
611-614,
1996
43.
Vavvas, D,
Apazidis A,
Saha AK,
Gamble J,
Patel A,
Kemp BE,
Witters LA,
and
Ruderman NB.
Contraction-induced changes in acetyl-CoA carboxylase and 5'-AMP-activated kinase in skeletal muscle.
J Biol Chem
272:
13255-13261,
1997
44.
Winder, WW,
and
Hardie DG.
AMP-activated protein kinase, a metabolic master switch: possible roles in type 2 diabetes.
Am J Physiol Endocrinol Metab
277:
E1-E10,
1999
45.
Winder, WW,
MacLean PS,
Lucas JC,
Fernley JE,
and
Trumble GE.
Effect of fasting and refeeding on acetyl-CoA carboxylase in rat hindlimb muscle.
J Appl Physiol
78:
578-582,
1995
46.
Witters, LA,
and
Kemp BE.
Insulin activation of acetyl-CoA carboxylase accompanied by inhibition of the 5'-AMP-activated protein kinase.
J Biol Chem
267:
2864-2867,
1992
47.
Witters, LA,
Watts TD,
Daniels DL,
and
Evans JL.
Insulin stimulates the dephosphorylation and activation of acetyl-CoA carboxylase.
Proc Natl Acad Sci USA
85:
5473-5477,
1988[Abstract].
48.
Young, ME,
Radda GK,
and
Leighton B.
Activation of glycogen phosphorylase and glycogenolysis in rat skeletal muscle by AICARan activator of AMP-activated protein kinase.
FEBS Lett
382:
43-47,
1996[ISI][Medline].