Energy sensing by the AMP-activated protein kinase and its effects on muscle metabolism

The AMP-activated protein kinase (AMPK) is a sensor of cellular energy status, and a regulator of energy balance at both the cellular and whole body levels. Although ubiquitously expressed, its function is best understood in skeletal muscle. AMPK contains sites that reversibly bind AMP or ATP, with an increase in cellular AMP:ATP ratio (signalling a fall in cellular energy status) switching on the kinase. In muscle, AMPK activation is therefore triggered by sustained contraction, and appears to be particularly important in the metabolic changes that occur in the transition from resistance to endurance exercise. Once activated, AMPK switches on catabolic processes that generate ATP, while switching off energy-requiring processes not essential in the short term. Thus, it acutely activates glucose uptake (by promoting translocation of the transporter GLUT4 to the membrane) and fatty acid oxidation, while switching off glycogen synthesis and protein synthesis (the later via inactivation of the mammalian target-of-rapamycin pathway). Prolonged AMPK activation also causes some of the chronic adaptations to endurance exercise, such as increased GLUT4 expression and mitochondrial biogenesis. AMPK contains a glycogen-binding domain that causes a sub-fraction to bind to the surface of the glycogen particle, and it can inhibit glycogen synthesis by phosphorylating glycogen synthase. We have shown that AMPK is inhibited by exposed non-reducing ends in glycogen. We are working on the hypothesis that this ensures that glycogen synthesis is rapidly activated when glycogen becomes depleted after exercise, but is switched off again as soon as glycogen stores are replenished.     

Novel metabolic roles of L-arginine in body energy metabolism and possible clinical applications

Although the body can synthesize L-arginine, exogenous supplementation may be sometimes necessary, especially in particular conditions which results in depleted endogenous source. Among diseases and states when exogenous supplementation may be necessary are: burns, severe wounds, infections, insufficient circulation, intensive physical activity or sterility. In recent time, the attention was paid to the use of L-arginine supplementation by athletes during intensive sport activity, to enhance tissue growth and general performance, to potentiate the ergogenic potential and muscle tolerance to high intensive work and gas exchange threshold, to decrease ammonia liberation and recovery performance period and to improve wound healing. High-intensity exercise produces transient hyperammoniemia, presumably due to AMP catabolism. Catabolic pathways of AMP may involve its deamination or dephosphorylation, mainly in order to compensate fall in adenylate enrgy charge (AEC), due to AMP rise. The enzymes of purine metabolism have been documented to be particularly sensitive to the effect of dietary L-arginine supplementation. L-arginine supplementation leads to redirection of AMP deamination on account of increased AMP dephosphorylation and subsequent adenosine production and may increase ATP regeneration via activation of AMP kinase (AMPK) pathway. The central role of AMPK in regulating cellular ATP regeneration, makes this enzyme as a central control point in energy homeostasis. The effects of L-arginine supplementation on energy expenditure were successful independently of age or previous disease, in young sport active, elderly, older population and patients with angina pectoris.     

Role of hypothalamic AMP-kinase in food intake regulation

Adenosine monophosphate-activated protein kinase (AMPK) functions as a cellular fuel gauge that regulates metabolic pathways in nutrient metabolism. Recent studies have strongly implicated that AMPK in the hypothalamus regulates energy metabolism by integrating inputs from multiple hormones, peptides, neurotransmitters, and nutrients. Leptin is an adipocyte hormone that regulates food intake and energy expenditure in peripheral tissues. Leptin inhibits AMPK activity in the arcuate and paraventricular hypothalamus, and its inhibition is necessary for the anorexic effect of leptin. Alteration of hypothalamic AMPK activity is sufficient to change food intake and body weight. Furthermore, fasting/refeeding, glucose, and melanocortin receptor alter AMPK activity in the hypothalamus. Adiponectin has also been shown to increase food intake by activating AMPK in the arcuate hypothalamus. Recent data have shown that acetyl-coenzyme A carboxylase/malonyl-coenzyme A/carnitine palmitoyltransferase-1/fatty acid oxidation and mammalian target of rapamycin signalings are putative downstream pathways for food intake regulation in response to hypothalamic AMPK. Thus, these results suggest that food intake and nutrient metabolism are coordinately regulated by the common signaling pathway of AMPK in the hypothalamus.     

Isoleucine, a blood glucose-lowering amino acid, increases glucose uptake in rat skeletal muscle in the absence of increases in AMP-activated protein kinase activity

Leucine and isoleucine were shown to stimulate insulin-independent glucose uptake in skeletal muscle cells in vitro. In this study, we examined the effects of leucine and isoleucine on blood glucose in food-deprived rats and on glucose metabolism in skeletal muscle in vivo. Furthermore, we investigated the possible involvement of the energy sensor, 5'-AMP-activated protein kinase (AMPK), in the modulation of glucose uptake in skeletal muscle, which is independent of insulin, and also in leucine- or isoleucine-stimulated glucose uptake. Oral administration of isoleucine, but not leucine, significantly decreased the plasma glucose concentration. An i.v. bolus of 2-[1,2-3H]-deoxyglucose (2-[3H]DG) was administered to calculate glucose uptake. Glucose uptake in the skeletal muscle did not differ after leucine administration, but glucose uptake in the muscles of rats administered isoleucine was 73% greater than in controls, suggesting that isoleucine increases skeletal muscle glucose uptake in vivo. On the contrary, in the skeletal muscles, administration of leucine but not isoleucine significantly increased [U-14C]-glucose incorporation into glycogen compared with controls. AMPK alpha1 activity in skeletal muscle was not affected by leucine or isoleucine administration. However, isoleucine, but not leucine, significantly decreased AMPK alpha2 activity. The decrease in AMPK alpha2 activity was thought to be due to decreases in AMP content and the AMP:ATP ratio, which were related to the isoleucine administration. This is the first report of isoleucine stimulating glucose uptake in rat skeletal muscle in vivo, and these results indicate that there might be a relation between the reduction in blood glucose and the increase in skeletal muscle glucose uptake that occur with isoleucine administration in rats. The alterations in glucose metabolism caused by isoleucine may result in an improvement of the availability of ATP in the absence of increases in AMP-activated protein kinase activity in skeletal muscle.     

Respiration uncoupling and metabolism in the control of energy expenditure

Metabolic energy expenditure negatively regulates energy balance. Metabolic and catabolic pathways contribute to energy expenditure. Catabolic pathways split C-containing molecules into small molecules and generate reduced coenzymes and ATP. For a given amount of substrate, any increase in energy expenditure requires either increased ATP hydrolysis or decreased ATP synthesis. In skeletal muscles substrate utilisation is coupled to ATP production, whereas ATP hydrolysis is activated during physical exercise and increases energy expenditure. In brown adipose tissue activation of cells during exposure to cold increases substrate utilisation in such a way that glucose and fatty acid oxidation detach from the orthodox coupling to ATP synthesis and result in thermogenesis. The unique mechanism of uncoupling respiration that occurs in brown adipocyte mitochondria represents an attractive strategy for promoting energy expenditure and decreasing the fat content of the body. Moreover, ectopic expression of brown fat uncoupling protein (UCP) 1 in mouse skeletal muscle and induction of UCP1 in mouse or human white adipocytes promote fatty acid oxidation and resistance to obesity. In normal conditions UCP2 and UCP3 do not seem to contribute substantially to energy expenditure. Whether the induction of UCP1, the induction of other UCP or chemical mild uncoupling represent promising strategies for attenuating nutrient efficiency and counteracting obesity should be considered.     

Antidiabetic potentials of Momordica charantia: multiple mechanisms behind the effects

Momordica charantia fruits are used as a vegetable in many countries. From time immemorial, it has also been used for management of diabetes in the Ayurvedic and Chinese systems of medicine. Information regarding the standardization of this vegetable for its usage as an antidiabetic drug is scanty. There are many reports on its effects on glucose and lipid levels in diabetic animals and some in clinical trials. Reports regarding its mechanism of action are limited. So in the present review all the information is considered to produce some concrete findings on the mechanism behind its hypoglycemic and hypolipidemic effects. Studies have shown that M. charantia repairs damaged β-cells, increases insulin levels, and also enhance the sensitivity of insulin. It inhibits the absorption of glucose by inhibiting glucosidase and also suppresses the activity of disaccharidases in the intestine. It stimulates the synthesis and release of thyroid hormones and adiponectin and enhances the activity of AMP-activated protein kinase (AMPK). Effects of M. charantia like transport of glucose in the cells, transport of fatty acids in the mitochondria, modulation of insulin secretion, and elevation of levels of uncoupling proteins in adipose and skeletal muscles are similar to those of AMPK and thyroxine. Therefore it is proposed that effects of M. charantia on carbohydrate and fat metabolism are through thyroxine and AMPK.     

兔热暴露时脑能量代谢的变化

用高效液相色谱法（ＨＰＬＣ）测定热应激条件下脑能量物质的变化，并以ＡＴＰ、ＡＤＰ、ＡＭＰ、ＥＣ、ＡＴＰ／ＡＤＰ和ＡＴＰ／ＡＭＰ为指标，探讨不同热应激强度下能量物质的变化情况及其发生变化的可能机理。结果表明，热病组动物的病ＡＴＰ、ＡＤＰ含量与对照组比较，有显著性差异，ＡＭＰ明显升高，ＥＣ及ＡＴＰ／ＡＤＰ、ＡＴＰ／ＡＭＰ的幽会显著下降，提示，当动物发生射病时，脑组织能量物质严重不足，能量贮存重度匮乏     

Effects of α-ketoglutarate on energy status in the intestinal mucosa of weaned piglets chronically challenged with lipopolysaccharide

The present study determined whether α-ketoglutarate (AKG) might affect the expression of AMP-activated protein kinase (AMPK) and energy status in the intestinal mucosa of piglets challenged with Escherichia coli lipopolysaccharide (LPS). A total of eighteen piglets (weaned at 21?d of age) were allocated to one of three treatments: (1) non-challenged (control); (2) LPS-challenged (LPS); (3) LPS+1?% AKG (LPS+AKG). Piglets in the control and LPS groups were fed a maize- and soyabean meal-based diet, and the LPS+AKG group was fed the basal diet supplemented with 1?% AKG. On days 10, 12, 14 and 16 of the trial, piglets in the LPS and LPS+AKG groups were challenged with LPS (80?μg/kg body weight), whereas piglets in the control group received the same volume of sterile saline. Pigs were euthanised 24?h after the last administration of LPS or saline to obtain intestinal mucosae for biochemical analysis. Compared with the control group, LPS administration decreased (P?相似文献   

Cellular energy metabolism in rats receiving diets contaminated with lindane]

Young male rats, Wistar CF strain, about 70 g body weight, were fed a well-balanced diet containing 0 (control), 60 or 240 ppm lindane. The day before the experiment, all the animals were fasted, and some of them placed in a restraint wheel forcing them to walk on during 18 hrs; another group was given an i.p. injection of 2.6 g/kg glucose 30 minutes before their sacrifice. The redox and energy potentials of liver and muscle tissues were estimated after the determination of the following compounds: lactate, pyruvate, beta-hydroxybutyrate, acetoacetate, ATP, ADP, AMP, inorganic phosphate, NADP and NADPH. No effect of lindane was observed on muscle metabolism and the 60 ppm dose was without significant effect on liver metabolism. At the 240 ppm dosage: a. Lindane ingestion increased the liver betaHOB/AcAc ratio and decreased the Lac/pyr ratio. The ATP/ADP ratio was not significantly lowered, although the ATP concentration was diminished and, conversely, the AMP and inorganic P ones were elevated; b. Whereas lindane lowered the glucose effect on the mitochondrial redox potential, it had no influence on the increasing of the ATP/ADP ratio by glucose, or on the antiketogenic effect of this sugar; c. In the animals fed the lindane-contaminated diet, muscular exercise increased the liver betaHOB/AcAc and NADPH/NADP ratios, while the lac/pyr and ATP/ADP ratios were unaltered. But blood pyruvate was increased. The following interpretation has been given. Lindane ingestion inhibits liver mitochondrial activity and increases ketogenesis. The glucose treatment results in a poor glucose utilization for energy needs in the contaminated animals and the forced muscular exercise shows that gluconeogenesis proceeds at a slower rate than in the controls. It is suggested that an increased demand in NADPH, as resulting from the induction of the microsomal enzymes by lindane, is one of the mechanisms by which the pesticide inhibits the activity of the tricarboxylic acid cycle.     

Simulation of the metabolism of absorbed energy-yielding nutrients in young sheep: efficiency of utilization of acetate

A previously described mathematical model that simulates the metabolism of absorbed nutrients was used to examine factors influencing the efficiency of utilization of acetate in a sheep weighing 25 kg. A significant component of the model was a function representing substrate cycles that degraded ATP when its concentration reached twice initial levels. Acetate utilization was simulated when up to 2 g mol/d were added to four diets (representing forages and concentrates) that supplied varying proportions of absorbed volatile fatty acids, glucose and protein. The basal diets provided either 4.375 (near energy balance) or 8.75 MJ/d absorbed energy. The predicted net efficiency of utilization (kf) of the energy in added acetate was high (0.58-0.70) for all combinations of absorbed nutrients at the low level of energy absorption, whereas at the higher level, it ranged from 0.16 (forage) to 0.49 (high protein concentrate). Low kf values were always associated with a considerable flux of ATP through the degradation pathway. The increase in ATP concentration that caused this pathway to operate was linked to an inhibition in the utilization of acetyl-CoA for fatty acid synthesis and an increase in its oxidation. The simulated addition of exogenous NADPH or its precursors (particularly glucose and propionate) to these diets repartitioned acetyl-CoA flux towards fatty acid synthesis instead of oxidation, decreased the flux of ATP through the degradation pathway and increased the kf of added acetate. Although a negative relationship was predicted between kf of added acetate and NADPH production for diets with increasing protein content, kf still depended on ATP flux through the degradation pathway. Addition of glucose to the high protein diets decreased this flux by decreasing acetyl-CoA oxidation and increasing fatty acid synthesis. The predictions suggest that the efficiency of acetate utilization in ruminants may be influenced by NADPH availability when a considerable amount of absorbed energy is derived from acetate. Increased absorption of glucose or propionate enhanced NADPH production, but the major effect on acetate utilization of increasing dietary protein was not through NADPH production.     

Biosynthesis of aflatoxins

The role of zinc on the primary metabolism of Aspergillus parasiticus in relation to aflatoxin biosynthesis was studied. Zinc deficiency impaired growth and metabolism of nucleic acid and protein while stimulating that of lipid. The activities of enzymes of glycolytic cycle were affected indicating that these are zinc dependent enzymes. Impaired glycolytic cycle tends to reduce the level of primary metabolites like pyruvate, citrate and oxaloacetate which trigger aflatoxin formation. During stationary phase these precursors accumulate as these are not used up for the synthesis of secondary metabolites (aflatoxins) due to zinc deficiency. ATP and energy-charge (E.C.) which are important for various physiological processes like growth are reduced in zinc deficiency. Also zinc deficiency results in low levels of AMP which favour synthesis of lipid. Inorganic phosphate accumulated due to zinc deficiency and this may be unfavourable for aflatoxin synthesis.     

Hypothesis: energy wastage in alcoholism and drug abuse: possible role of hepatic microsomal enzymes.

Hepatic microsomal drug oxidation appears to be an energy-wasteful process because it has no known link with energy-conserving mechanisms such as the synthesis of ATP, and in addition it requires the uncoupled oxidation of NADPH. It is postulated that this can appreciably alter the energy balance of the whole body under certain conditions. Such an imbalance would be favored by the repeated intake of drugs that induce hepatic microsomal enzymes and by the provision of ethanol as a major source of calories. The hypothesis is consistent with the changes in body weight in humans and animals after chronic ethanol intake. It is supported by observations of an increased oxygen consumption in rats given ethanol or barbiturates in doses that induce hepatic microsomal enzymes.     

Metformin: its emerging role in oncology

Metformin is considered, in conjunction with lifestyle modification, as a first-line treatment modality for type 2 diabetes mellitus (DM). Recently, several clinical studies have reported reduced incidence of neoplastic diseases in DM type 2 patients treated with metformin, as compared to diet or other antidiabetic agents. Moreover, in vitro studies have disclosed significant antiproliferative and proapoptotic effects of metformin on different types of cancer. Metformin acts by activating AMP-activated protein kinase (AMPK), a key player in the regulation of energy homeostasis. Moreover, by activating AMPK, metformin inhibits the mammalian target of rapamycin complex 1 (mTORC1) resulting in decreased cancer cell proliferation. Concomitantly, metformin induces activation of LKB1 (serine/threonine kinase 11), a tumor suppressor gene, which is required for the phosphorylation and activation of AMPK. These new encouraging experimental data supporting the anti-cancer effects of metformin urgently require further clinical studies in order to establish its use as a synergistic therapy targeting the AMPK/mTOR signaling pathway.     

Energy metabolism in the liver of rats fed a diet contaminated with dithiocarbamates]

Young male rats, Wistar CF strain, weighing about 100 g, were fed during 14 days with a well-balanced diet, but containing either 275 p.p.m. nabame, either 600 p.p.m. thirame or 3 600 p.p.m. zinebe. The animals given the non-contaminated diet were the controls. On the evening before the experiment, they were all fasted and some of them, forced to walk during 18 hours in a restraint wheel. On the morning of the experiment, some of the rats which have not been working were placed in a cold room at + 4 degrees C, and some others were given an i.p. injection of 2,6 g glucose per kg body weight. The animals were then killed, those that received the glucose treatment 30 mn after the injection, the cold-exposed rats 90 mn after the beginning of their exposure. The redox and energy potentials of the liver tissue were determined after the enzymatic assay of the following liver metabolites : lactate, pyruvate, beta-hydroxybutyrate, acetoacetate, ATP, ADP, AMP, inorganic phosphate. The thirame group rats had the smallest body weight and the lowest food intake. All the pesticides-exposed animals has a higher liver weight than predicted by their body weight. The pesticides-containing diets decreased liver lactate concentration and the lac/pyr ratio. Thirame was the more efficient and it partly impaired the glucose induced increase of the cytoplasmic redox potential, as estimated from the variation of the lac/pyr ratio. The pesticide-containing diets also lowered the liver concentrations of beta-hydroxybutyrate, acetoacetate, and their ratio. Last the pesticides, which but slightly modified the liver contents in adenine nucleotides and inorganic phosphate in the fasting state, increased the ATP fall following cold exposure and decreased the net ATP synthesis produced by glucose administration. The thirame diet was the more efficient in our experimental conditions, the zinebe diet the least one. It was concluded in our discussion that dietary dithiocarbamates either induced a hyperthyroidic status in the animal, or acted themselves as thyroxin-like compounds, because the liver metabolism was more directed towards heat production than towards that of chemical energy available for syntheses.     

Undernutrition during the preweaning period changes calcium ATPase and ADPase activities of synaptosomal fractions of weanling rats

The presence of activities that hydrolyse externally added ATP to adenosine in synaptosomal preparations from various sources is well demonstrated. The hydrolysis of ATP to AMP can be mediated either by the concerted action of enzymes or by an ATP-diphosphohydrolase (EC 3.6.1.5; apyrase). Undernutrition during the preweaning period can delay the development of several enzymes involved in the metabolism of neurotransmitters or neuronal function. In young rats, the presence of an apyrase in synaptosomal preparations from cerebral cortex was investigated. The results suggested that the hydrolysis of externally added ATP and ADP can be mediated by a single enzyme. The effects of preweaning undernutrition on the hydrolysis of ATP and ADP were also investigated. In weanling rats, previous undernutrition caused a decrease of about 20% in the hydrolysis of both substrates in synaptosomal fractions.     

Quercetin attenuates domoic acid-induced cognitive deficits in mice

Domoic acid (DA) is one of the best known marine toxins, causative of important neurotoxic alterations. DA effects are documented both in wildlife and experimental assays, showing that this toxin causes severe injuries principally in the hippocampal area. Accumulating evidence indicates that mitochondrial dysfunction and oxidative stress are involved in DA-induced cognitive functional impairment. Therefore, therapeutics targeted to improve mitochondrial function and increase oxidative stress defence could be bene?cial. Quercetin, a bio?avanoid, has been reported to have potent neuroprotective effects and anti-oxidative ability, but its preventive effects on DA-induced mitochondrial dysfunction and cognitive impairment have not been well characterised. In this study, we evaluated the effects of quercetin on DA-induced cognitive deficits in mice and explored its potential mechanism. Our results showed that the oral administration of quercetin to DA-treated mice significantly improved their behavioural performance in a novel objective recognition task and a Morris water maze task. These improvements were mediated, at least in part, by a stimulation of PPARγ coactivator 1α-mediated mitochondrial biogenesis signalling and an amelioration of mitochondrial dysfunction. Moreover, quercetin activated nuclear factorerythroid-2-related factor-2 (Nrf2)-mediated phase II enzymes and decreased reactive oxygen species and protein carbonylation. Furthermore, the AMP-activated protein kinase (AMPK) activity significantly increased in the quercetin-treated group. Taken together, these findings suggest that a reduction in mitochondrial dysfunction through the increase of AMPK activity, coupled with an increase in Nrf2 pathway mediated oxidative defence, may be one of the mechanisms by which quercetin improves cognitive impairment induced by DA in mice.