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Rangueil Hospital, 31403 Toulouse, France
Address all correspondence and requests for reprints to: Dr. Rémy Burcelin, Unité Mixte de Recherche 5018, Centre National de la Recherche Scientifique-Paul Sabatier University and Institut Federatif de Recherche 31, Rangueil Hospital, L1 Building, 31403 Toulouse, France. E-mail: burcelin{at}toulouse.inserm.fr.
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Abstract |
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Introduction |
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MSH (7). In addition to the hormones and neuropeptides, variations in concentrations of nutrients, such as lipids and glucose, are also detected by the brain (8, 9, 10). As a consequence to these stimuli, a new cerebral efferent signal is generated toward peripheral organs that control glucose homeostasis within a regulatory reflex loop. To date, the major physiological functions described to be controlled by the brain are food intake, hepatic glucose metabolism, and the secretion of insulin and counterregulatory hormones. In addition, we (1) and others (2, 11, 12, 13, 14) showed that muscle glucose transport could be increased in response to cerebral infusion, but little is known about the role of the brain in the control of muscle glycogen synthesis. In addition, the molecular regulatory mechanisms responsible for cerebral nutrient and hormonal sensing remain to be determined.
The AMP-activated kinase is a heterotrimeric complex made of several isoforms of -, ß-, and 
-subunits (15) that are regulated allosterically by AMP and covalently by threonine phosphorylation via an upstream kinase (15). Recently, it has become generally accepted that the AMP-activated kinase could act as an intracellular energy sensor controlling energy balance in the cells. In liver and muscle, the enzyme controls glucose and lipid oxidation through a mechanism involving the translocation of GLUT4 and acetyl-coenzyme A carboxylase (ACC), respectively (4, 16, 17, 18). In brain, the AMP-activated kinase controls food intake (19, 20) through a mechanism that could also be associated with the regulation of the malonyl-coenzyme A (malonyl-CoA) concentration (21). In addition, the enzyme could be involved in neuron survival during glucose deprivation (22). The above data suggest an important role of AMP-activated kinase as a fuel sensor in the brain. This hypothesis also gained support from recent observations by our team. Mice deleted for the 2 AMP-activated kinase isoform are insulin resistant and have a dramatically reduced insulin-stimulated muscle glycogen synthesis activity (23). The important observation is that insulin resistance was not dependent upon the lack of expression of AMP-activated kinase in the muscle, because mice expressing a dominant negative form of AMP-activated kinase specifically in the muscles (18) had a normal insulin-stimulated glycogen synthesis activity and were not insulin resistant (23). Furthermore, the mutant mice were characterized by excessive catecholamine excretion, indicating impaired autonomic nervous system activity. Together the data suggest that the impaired glucose metabolism could be due to the lack of AMP-activated kinase in the brain, which could be a sensor for insulin to trigger muscle glycogen synthesis and hence insulin sensitivity.
In the present study we determined the muscle glycogen synthesis rate in vivo in mice infused in the brain with the pharmacological AMP-activated kinase activator AICAR, insulin, or glucose under physiological hyperinsulinemia and in basal conditions. Our data show that the cerebral AICAR infusion increased insulin-sensitive glycogen synthesis in muscles. The effect of insulin was antagonized by a cerebral glucose infusion. In addition, within minutes, cerebral insulin, AICAR, or glucose injection regulates the AMP-activated kinase phosphorylation state in the hypothalamus, suggesting an important role for this enzyme as an intracellular fuel sensor.
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Materials and Methods |
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Surgical procedures
To perform intracerebroventricular (icv) infusions, the mice were fitted with an indwelling cannula (Lupertino, Alzet, Cupertino, CA) in the right lateral ventricle 1 wk before implantation of the iv catheter. Briefly, the mice were anesthetized with ketamine/xylazine. A 1-cm midline incision was made across the top of the skull, the animal was placed on a stereotaxic apparatus, and the periosteum was cleaned. A hole, 1 mm in diameter, was made 0.1 mm lateral, 0.22 mm anteroposterior from the bregma and 1.5 mm deep. Two supporting screws, 1.2 mm in diameter and 3.2 mm in height, were placed bilaterally, one in the posterior quadrant of the skull and the other in the anterior part of the skull, and secured in place with acrylic dental cement (Magasin Général Dentaire, Paris, France). The cannula was filled with ACF and connected to a Tygon (Charny, France) catheter blocked by a nail. The mice were allowed to recover for 7 d. At completion of the recovery period, the mice that did not reach the presurgical weight were discarded.
To infuse the iv solutions, a catheter was implanted into the femoral vein under anesthesia, sealed under the back skin, and externalized on the back of the neck as previously described (24, 25). The mice were allowed to recover for 4 d before the infusions.
Infusions
The mice were fasted for 6 h before the infusions. The mice were connected to the infusion apparatus 2 h before the start of the infusions with free access to water. Intracerbroventricular infusions were then performed for 3 h with ACF or insulin at a rate of 0.2 or 1 mU/kg·min, AICAR at a rate of 0.2 or 2 µg/kg·min or glucose at a rate of approximately 0.3 mg/kg·min. Simultaneously, the whole body glucose utilization rate was determined under basal and hyperinsulinemic euglycemic conditions. In the basal state, D-[3H]3-glucose was continuously infused through the femoral vein at a rate of 10 µCi/kg·min for 3 h. Under physiological hyperinsulinemic conditions, insulin was infused at a rate of 4 mU/kg·min for 3 h, but D-[3H]3-glucose was infused at a rate of 30 µCi/kg·min, higher than in the basal condition, to ensure a detectable plasma D-[3H]3-glucose enrichment. Throughout the infusion, blood glucose was assessed from blood samples (3.5 µl) collected from the tip of the tail vein when needed using a blood glucose meter. Euglycemia was maintained by periodically adjusting a variable infusion of 10% or 16.5% glucose. Plasma glucose concentrations and D-[3H]3-glucose-specific activity were determined in 5 µl blood sampled from the tip of the tail vein every 10 min during the last hour of the infusion.
Intracerebroventricular injections
Mice bearing an icv catheter were fasted overnight and injected with ACF, glucose (5 mg), insulin (25 µU), or AICAR (150 µg) over 5 sec. The mice were decapitated 10 min later, and the brain was quickly removed from the skull within 15 sec and cooled in a frozen brain frame (World Precision Instruments, Stevenage, UK) to immediately prevent any endogenous enzymatic reaction. A 3-mm coronal section corresponding to the hypothalamus was sliced out and snap-frozen in liquid nitrogen.
Biochemical analyses
Plasma glucose was determined extemporaneously during the infusion procedures using a glucose meter (Roche Diagnostic, Rotkreuze, Switzerland). Plasma insulin was determined using a specific RIA (Linco Research, Inc., St. Louis, MO).
Muscle glycogen synthesis rate was determined by extracting total glycogen, which includes unlabeled and 3H-labeled glycogen, with perchloric acid (6%, wt/vol) and precipitating glycogen with ethanol as described previously (20). Briefly, 100 mg hindlimb muscles were ground up in 10 vol perchloric acid and spun down to eliminate the unground particles. The supernatant was precipitated with 15 vol ice-cold absolute ethanol overnight. The glycogen was precipitated by overnight exposure at –20 C and recovered by centrifugation. The precipitating procedure was performed twice to ensure the elimination of [3H]glucose. The precipitated radioactive glycogen was then dissolved in distilled water, and the radioactivity was counted in the presence of scintillation buffer. The radioactivity was divided by the D-[3H]3-glucose specific activity to determine the rate of synthesis.
Western blotting of hypothalamic AMP-activated kinase
Western blots were prepared from hypothalami dissected out as follows briefly. From a frozen coronal slice of 3 mm corresponding to the hypothalamic region, a triangle with sides of 2 mm corresponding to the hypothalamus and including all the arcuate nucleus was then dissected out and immediately ground in 6 vol 50 mM Tris buffer (pH 7.5) containing 1 mM EDTA, 1 mM EGTA, 1 mM dithiothreitol, 50 mM NaF, 5 mM Na3PO4, 1% Triton, and a mixture of proteases inhibitors. The tissue extract was centrifuged, the supernatant was isolated, and the protein concentration was determined using a Bio-Rad Laboratory (Hercules, CA) protein assay. Sixty micrograms of the proteins were resolved by 12% acrylamide SDS-PAGE and transferred to a polyvinylidene difluoride membrane. Primary antibodies against the phosphorylated and the total forms (2) of the AMP-activated kinase were gifts from Dr. Grahame Hardie (University of Dundee, Dundee, Scotland, UK). They were diluted 1:2000 in 10 ml, then incubated overnight at 4 C. The polyclonal sheep antiserum against AMP-activated kinase was directed against the peptide KFLRT(phospho)SCGSPNYA of rat 2. It recognized the human, rat, and mouse AMP-activated kinases. The polyclonal sheep antiserum against the total 2 AMP-activated kinase was directed against the peptide CMMDDSAMHIPPGLKPH of rat 2. It recognized the corresponding rat, human, and mouse AMP-activated kinases.
Secondary antibodies were obtained from DakoCytomation (Glostrup, Denmark) and used according to the manufacturer’s instructions. Visualization of bound antibodies was performed by incubation with horseradish peroxidase-conjugated secondary antibodies and then enhanced chemiluminescence and exposure to x-ray film, and were quantified using the ImageQuant system (Amersham Biosciences, Lyon, France).
Calculations
Calculations of glucose turnover were made from parameters obtained during the last 60 min of the infusions under steady state conditions as described previously (24, 25). Briefly, the D-[3H]3-glucose specific activity was calculated by dividing the D-[3H]3-glucose enrichment by the plasma glucose concentration. The whole body glucose turnover rate was calculated by dividing the rate of D-[3H]3-glucose by the D-[3H]3-glucose plasma specific activity. The whole body glycolytic flux was calculated from the 3H2O accumulated in the plasma during the last hour of the infusions. The whole body glycogen synthesis rate was calculated by subtracting the glycolytic flux from the glucose turnover rate. For each mouse, the mean values were calculated and averaged with values from mice of the same group. The muscle glycogen synthesis rate was calculated by dividing the D-[3H]glycogen content by the duration of the infusion and the D-[3H]3-glucose specific activity in the blood. Hence, the value should be considered an index of the glycogen synthesis rate. Mice showing variations in the steady state D-[3H]3-glucose specific activity larger than 15% during this period were excluded from the study.
Statistical analysis
Results are presented as the mean ± SE. Statistical significance of differences was analyzed by t test for unpaired bilaterally distributed values of unequal variance. Values were considered different at P < 0.05.
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Results |
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). The infusions started on d 0 after 6 h of fasting. The icv and all iv infusions started simultaneously. After a 2-h equilibration period, blood was sampled every 10 min for 1 h for glucose turnover rate analysis.
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). This effect was associated with 20% increased whole body glucose turnover, glycolytic, and glycogen synthesis rates (Fig. 2B), suggesting that AICAR increased muscle insulin sensitivity. AICAR-stimulated muscle glycogen synthesis was specific to muscle, because no differences were noted in liver (1039 ± 328 vs. 1324 ± 239 pg/mg·min in the presence or absence, respectively, of AICAR infusion during clamps). No reproducible effect was observed when AICAR was infused at the rate of 0.2 µg/kg·min.
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Cerebral infusion of AICAR stimulated muscle glycogen synthesis and glucose turnover rates in the basal fasting state
Our first result shows that insulin sensitivity can be increased by cerebral AICAR infusion during hyperinsulinemic conditions. To determine whether this effect is independent of the action of insulin, we then infused AICAR into the lateral ventricle of fasted mice, i.e. when the plasma insulin concentration is low. Indeed, plasma insulin levels were low and were not significantly different in ACF and AICAR-infused mice (10.7 ± 1.1 vs. 16.3 ± 3.8 µU/ml, respectively). In these conditions, muscle and whole body glycogen synthesis were still increased by 153% and 27%, respectively, when AICAR was infused into the brain of fasted mice (Fig. 3).
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(309 pg/mg·min in the presence of insulin during clamp) vs. Fig. 3A (32 pg/mg·min in the absence of insulin, i.e. basal)], whereas there was a 4-fold increase in the whole body glycogen synthesis rate [compare Fig. 2B (49 mg/kg·min in the presence of insulin during clamp) vs. Fig. 3B (12 pg/mg·mi in absence of insulin, i.e. basal)]. Consequently, our data show that the muscles account for at least 40% of the total de novo glycogen synthesis. Studies with cerebral AICAR infusion showed that insulin-stimulated muscle glycogen synthesis is AICAR sensitive, because AICAR induced a 4-fold increase in glycogen synthesis in muscles (Fig. 2A). AICAR sensitivity was specific to muscle and represented a small fraction of the glucose disposal, because whole body glycogen synthesis was increased by only 20% (Fig. 2B). Indeed, we assessed liver glycogen synthesis during clamps in the presence or absence of cerebral AICAR infusion. The data show that liver glycogen synthesis, although increased over basal studies, was not further increased by AICAR infusion during the clamps.
The glycemic profiles were similar between groups. However, glycemia was slightly reduced by 1 mM during less than 2 h of the AICAR infusion compared with that in ACF-infused mice (Fig. 3C).
Cerebral glucose and insulin are regulators of muscle glycogen synthesis and whole body glucose turnover rates
We then studied the role of glucose and insulin as cerebral regulatory factors that could be involved in the activation of muscle glycogen synthesis through an AMP-activated, kinase-dependent mechanism. First, we infused insulin into the cerebral ventricle and assessed glucose metabolism in the basal fasting state. The cerebral infusion of insulin increased muscle glycogen synthesis (Fig. 4A) to a similar extent as when AICAR alone was infused. Consequently, glycogen synthesis and the whole body glucose turnover rates were increased in the presence of cerebral insulin compared with mice infused with ACF alone (Fig. 4B). Similar results were obtained with cerebral rates of insulin infusion as low as 0.2 µU/kg·min (not shown). Plasma insulin levels remained similar between groups (10.7 ± 1.1 and 11.9 ± 1.3 µU/ml in controls and insulin-infused mice, respectively). The blood glucose profiles were slightly increased by 0.5 mM during the first hour of infusion with insulin or AICAR plus insulin, but returned to the levels in ACF-infused mice 1 h before completion of the infusion period (not shown).
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). However, the insulin and/or AICAR stimulatory effects on the parameters measured were blunted by coinfusion with glucose (Fig. 4). Plasma insulin concentrations were unaffected by any of the treatments (12.2 ± 1.3, 11.9 ± 1.2, and 10.7 ± 0.5 µU/ml in glucose, glucose plus insulin, and glucose, insulin, and AICAR treatments, respectively).
Cerebral infusion of glucose inhibits hyperinsulinemia-stimulated muscle glycogen synthesis
Our data show that glucose prevented the stimulatory effects of insulin and AICAR on muscle glycogen synthesis. To further study the effect of cerebral glucose infusion, we performed a euglycemic hyperinsulinemic clamp at physiological insulin levels and simultaneously infused a low rate of glucose or ACF into the cerebral ventricle. Our data showed that cerebral glucose dramatically reduced the effect of peripheral insulin on the stimulation of muscle glycogen synthesis (Fig. 5A). In addition, this was associated with a reduced whole body glycogen synthesis rate and an increased glycolysis rate (Fig. 5B). Consequently, no differences were noted in the whole body glucose turnover rate.
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). Conversely, glucose injection reduced the concentration of phosphorylated AMP-activated kinase by 50% and inhibited the stimulatory effect of insulin.
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Discussion |
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Recently, Viollet et al. (23) demonstrated that 2 AMP-activated kinase has a role in the control of glucose tolerance and insulin sensitivity in knockout mice. The mice were characterized by excessive urinary excretion of catecholamines and were glucose intolerant, but this was reversed by a pharmacological blocker (23). Together these observations suggest that AMP-activated kinase in the central nervous system controls peripheral glucose metabolism through a mechanism involving the autonomic nervous system. However, AMP-activated kinase is a ubiquitous enzyme, and in this report the cellular origin of insulin resistance in the knockout mice was not determined. The present findings indicate that when the AMP-activated kinase activator AICAR was infused into the brain of mice, whole body insulin sensitivity and, more specifically, insulin-stimulated muscle glycogen synthesis were increased. This was assessed in vivo in awake, free-moving mice by the euglycemic hyperinsulinemic clamp at physiological insulin concentration. Our data suggest that insulin resistance of 2 AMP-activated kinase could be due to the lack of the enzyme in the brain. Muscle glycogen synthesis was also activated, but to a lesser extent, by cerebral AICAR infusion when low concentrations of plasma insulin were present, such as during fasting.
The role of cerebral AMP-activated kinase as an intracellular energy sensor for the control of nutritional metabolism has also been suggested previously (20, 27, 28). Recently, the in vivo administration of leptin reduced the activity of AMP-activated kinase (27, 29). The enzyme then phosphorylates ACC and inhibits its activity, subsequently reducing the malonyl-CoA produced. The accumulation of this metabolite was associated with the inhibition of food intake (21). Consequently, the researchers suggest that the inhibitory effect of leptin on food intake is due to the reduced AMP-activated kinase activity, leading to the activation of ACC and the production of malonyl-CoA in the brain. However, our data show that the cerebral infusion of insulin increased AMP-activated kinase phosphorylation. Hypothalamic colocalization of leptin and insulin receptors has been shown in the arcuate nucleus (30, 31) and could be important for the regulation of food intake (32, 33). Consequently, insulin and leptin have opposite effects on AMP-activated kinase; however, both hormones inhibit food intake (32, 33). Our data suggest that the diminution of AMP-activated kinase is not necessary for the inhibition of food intake. It has also been shown that leptin binds neurons from different locations (34, 35, 36, 37), such as the arcuate nucleus, the paraventricular nucleus, the supraoptical nucleus, the lateral hypothalamic nucleus, and the brainstem. Hence, the respective role of each neuron on food intake and its relationship with AMP-activated kinase in the regulatory process remain to be clearly defined. Insulin might have opposite effects on AMP-activated kinase in different neuronal populations. Indeed, it has been shown for leptin that the hormone activates proopiomelanocortin neurons while inhibiting neuropeptide Y-containing neurons in the arcuate nucleus of the hypothalamus (38, 39). Consequently, if AMP-activated kinase is an insulin sensor in each type of neuron, studies of the whole hypothalamic extract may dilute out any differential effect.
With regard to peripheral energy metabolism, leptin is considered a catabolic hormone favoring energy expenditure (40), whereas insulin has the opposite effect. Indeed, we (1) and others (2, 11) previously showed that the intracerebral infusion of leptin increased whole body glucose oxidation and muscle 2-deoxyglucose utilization. Importantly, the fate of glucose was to be oxidized rather than stored. This effect was abolished by sympathetic denervation (12), indicating that glucose uptake was mediated by sympathetic nerves. The present data show that insulin has the effect opposite of leptin by stimulating glucose storage as glycogen. This suggests that the regulation of the glucose storage or oxidation balance depends upon the cerebral regulation of AMP-activated kinase. More observations support this hypothesis. Indeed, it has recently been shown that cerebral insulin signaling is required for the reduction of hepatic gluconeogenesis (41, 42), whereas leptin has the opposite effect, increasing the gluconeogenic flux (3). These observations further demonstrate that peripheral glucose metabolism is clearly dependent upon the roles of nutrients and hormones. Similarly, icv lipid infusion controlled peripheral glucose metabolism by impairing the activity of the autonomic nervous system through a mechanism that could involve carnitine palmitoyltransferase-1 (43, 44, 45).
The activation of muscle glycogen synthesis is mainly under the control of insulin and insulin-like factors, whereas glycogen mobilization occurs mostly under stress conditions through a mechanism involving activation of glycogen synthase kinase 3 (46). Therefore, our data cannot be attributed to a nonspecific stress-induced effect due to the orthosympathetic adrenergic stimulus, because the icv injection of carbachol, a muscarinic receptor agonist, mimicking parasympathetic activation, increased glycogen biosynthesis in the liver (47). Our findings and data from the literature together support the hypothesis that insulin also activates glycogen synthesis by the muscle through a mechanism involving AMP-activated kinase in the brain. However, our data remain pharmacological, because a full dose-response study with insulin has not been performed, and the amount of exogenous insulin required remains elevated.
We also addressed the question of whether insulin activates AMP-activated kinase by studying the phosphorylation state of the enzyme in the hypothalamus of insulin-injected mice. The data showed that the enzyme was indeed phosphorylated 10 min after the injection of insulin. However, this observation does not represent a demonstration, because no phosphorylation of the enzyme was observed after the 3 h of insulin infusion. In addition, the effects on the magnitude of phosphorylation are rather limited compared with the effect on muscle glycogen synthesis. Hence, we cannot rule out that AICAR triggers a mediator other than AMP-activated kinase.
In a second set of experiments we analyzed the cerebral effect of glucose on the control of muscle glycogen synthesis. Our data show that the insulin-stimulated activation of muscle glycogen synthesis during a hyperinsulinemic clamp was inhibited when glucose was infused into the brain of mice. Because the cerebral injection of glucose has been shown to reduce cerebral AMP-activated kinase activity (20, 28), we suggest that the inhibitory effect of cerebral glucose on muscle glycogen synthesis depends upon down-regulation of AMP-activated kinase activity. This hypothesis is supported by data from the pancreatic ß-cell, where the AMP-activated kinase is reduced by high glucose (26, 48). Because ß-cells and glucose-sensitive brain cells are characterized by common molecular mechanisms for glucose sensitivity (10), we suggest that the AMP-activated kinase is a cerebral glucose sensor. In agreement with this hypothesis, cerebral glucose infusion blunted the stimulatory effect of AICAR on muscle glycogen synthesis as well as during a euglycemic hyperinsulinemic clamp. Glucose is also detected by cerebral cells and could generate signals of neural origin toward peripheral tissues, such as the pancreatic ß-cells, to stimulate insulin secretion (49).
It should be noted that our studies are essentially pharmacological in nature. Indeed, we do not know the concentration of insulin or glucose in the brain during the infusions, and a dose-response study has not been fully performed. Similarly, even if AICAR is considered an activator of AMP-activated kinase, side-effects could have occurred.
In conclusion, our data show, for the first time, that muscle glycogen synthesis can be increased by the cerebral action of a hormone, i.e. insulin, and reduced by glucose. Our data suggest that such a mechanism involves AMP-activated kinase. However, this hypothesis remains to be demonstrated in knockout animals.
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Acknowledgments |
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Footnotes |
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Abbreviations: ACC, Acetyl-coenzyme A carboxylase; ACF, artificial cerebrospinal fluid; AICAR, 5-aminoimidazole-4-carboxamide-1-ß-D-ribofuranoside; CoA, coenzyme A; icv, intracerebroventricular.
Received March 3, 2004.
Accepted for publication June 2, 2004.
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2 catalytic subunit controls whole-body insulin sensitivity. J Clin Invest 111:91–98[CrossRef][Medline]
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) or ACF (diluent; 
) in the brain lateral ventricle. Data are the mean ± SEM for 10–12 mice/group. *, Significantly different from the ACF-infused mice (P < 0.05).
