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Fatty acid metabolism and the Randle Cycle. Fatty acid is taken up either via diffusion or via CD36/FATP transporters. Once inside the cytosolic compartment of the cell, fatty acid is esteri fi ed to long chain acyl CoA. The acyl group of long chain acyl CoA is then transferred to carnitine via carnitine palmitoyltransferaase-1 (CPT-1). The acylcarnitine is then shuttled into the mitochondria, and converted back to long chain acyl CoA by CPT 2. Long chain acyl CoA then enters the fatty acid β -oxidation cycle, producing acetyl CoA which enters the TCA cycle to produce reducing equivalents NADH, and FADH 2 . The Randle Cycle describes the reciprocal relationship between fatty acid and glucose metabolism. The increased generation of acetyl CoA, NADH and FADH 2 derived from fatty acid β -oxidation decreases glucose/pyruvate oxidation via the inhibition of PDH. The increased supply of fatty acid β -oxidation-derived acetyl CoA to TCA cycle can also decrease glycolysis due to the inhibitory effects of citrate on phosphofructokinase. Acetyl CoA derived from glucose oxidation is exported to the cytosol, where it can act as a substrate for acetyl CoA carboxylase (ACC), which can increase the generation of malonyl CoA, and endogenous inhibitor of CPT-1, and therefore decreases fatty acid β -oxidation when glucose (pyruvate) oxidation is increased.
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Fatty acids are a major fuel source used to sustain contractile function in heart and oxidative skeletal muscle. To meet the energy demands of these muscles, the uptake and β-oxidation of fatty acids must be coordinately regulated in order to ensure an adequate, but not excessive, supply for mitochondrial β-oxidation. However, imbalance between fat...
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... both the heart and skeletal muscle the two main sources of fatty acid in the blood are free fatty acid (FFA) bound to albumin derived from the lipolysis of adipose tissue, and FFA released from TG contained in chylomicrons and very low-density lipoprotein (VLDL) by lipoprotein lipase (LPL) (Fig. 2) [105,106]. LPL is highly expressed in the heart [107]. Fatty acids derived from the hydrolysis of TG by LPL have been suggested to be the principal source of fat for cardiac utilization [108]. Alteration of LPL can significantly impact myocardial fatty acid metabolism. Although data are variable, diabetes and insulin resistance are ...
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... depends on both fatty acid concentration in the blood and the regulation of the transporters [114,115]. A number of fatty acid transporters have been identified, including fatty acid translocase (FAT)/CD36, plasma membrane-bound fatty acid binding protein (FABPpm), and the tissue-specific fatty acid transport protein (FATP) family (FATP 1-6) ( Fig. 2) [36,116,117]. The exact proportion each of these transporters contributes to fatty acid uptake is not clear, but FAT/CD36 is thought to be a predominant transporter, and is the one most studied. By either FAT/CD36 inhibition or CD36 deletion, it has been shown that 68% of the fatty acids taken up and oxidized by the heart occurs via ...
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... transported into the cytosol, non-esterified fatty acid is esterified to long chain acyl CoA by fatty acyl CoA synthase (FACS) (Fig. 2). While the majority of the acyl groups on long chain acyl CoAs are destined for mitochondria for β-oxidation, a small portion of long chain acyl CoAs can be converted into intracellular lipid intermedi- ates, such as TG, phospholipids, DAG, and ceramide. Theoretically, a decrease in fatty acid β-oxidation can lead to lipid ...
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... undergoing β-oxidation, the acyl groups from long chain acyl-CoA must first be transported across the mitochondrial outer and inner membranes. This process is facilitated by a carnitine-dependent transport system, which includes carnitine palmitoyl transferase-1 (CPT-1), carnitine translocase (CAT), and carnitine palmitoyl trans- ferase-2 (CPT-2) (Fig. 2). CPT-1, located on the outer membrane of mitochondria, is the key and rate-limiting enzyme involved in mitochondrial fatty acid uptake. CPT-1 catalyzes the reaction where long chain acyl CoA and carnitine react to form acylcarnitine. Acylcarnitine is then transported across the inner mitochondrial membrane by CAT. Once in the ...
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... malonyl CoA concentration can alter mitochondrial uptake of fatty acid and consequently the rate of fatty acid oxidation in the mitochondria [127,128]. The concentration of malonyl CoA is controlled by its turnover, in which acetyl CoA carboxylase (ACC) catalyzes the synthesis pathway, and malonyl CoA decarboxylase (MCD) controls its degradation (Fig. 2). It is generally accepted that CPT-1 is the rate- limiting enzyme of mitochondrial fatty acid uptake [126,129,130]. However, recent studies suggest that this may not be the case as changes in long chain acyl CoA uptake and oxidation have been found to be independent of CPT-1 activity ...
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... (PFK-1), in which 1 molecule of glucose forms 2 molecules of pyruvate and 2 NADH [167]. In the heart and oxidative skeletal muscle, pyruvate and NADH are shuttled into the mitochondria, where pyruvate is converted into acetyl CoA by the pyruvate dehydrogenase (PDH) complex, and then acetyl CoA enters the TCA cycle and electron transport chain (Fig. 2). Acetyl CoA is also the end product of β- oxidation of fatty acids. As a result, oxidation of fatty acid in muscle causes an increase in the mitochondrial ratio of [acetyl-CoA]/ [CoA], which inhibits PDH. High rates of fatty acid β-oxidation can also lead to inhibition of phosphofructokinase-1 by citrate and of hexokinase by glucose ...
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... inhibits insulin action via the inhibition of Akt phosphorylation [77,78]. This concept is supported by a study which shows that blocking ceramide synthesis restores phosphorylation of Akt in previously insulin-resistant myotubes [77]. However, the role of ceramide in the development of insulin resistance in skeletal muscle has been challenged [79]. In one study, no difference in the level of ceramide between type II diabetics, glucose intolerant and healthy individuals has been found [80]. Given these contradictions, the role of ceramide as a metabolite accounting for the development of insulin resistance needs clari fi cation. The role of ceramide in inducing cardiac insulin resistance has also not been explored. DAG is a lipid metabolite that can act as a secondary messenger in intracellular signaling. This metabolite has also been proposed to attribute to the initiation of insulin resistance. Intracellular DAG has been found to be greatly increased in skeletal muscle from insulin- resistant rodents and humans [8,81,82] and in skeletal muscle after lipid infusion [9]. In human studies, accumulation of DAG in skeletal muscle of obese, and diabetic individuals was found to be positively correlated with the increased activity of PKC- θ [83,84], which is known to impair insulin signaling via serine phosphorylation of IRS-1 [9,84]. It has been postulated that accelerated oxidation of fatty acid may reduce the levels of lipid intermediates, and protect from insulin resistance. In support of this hypothesis, overexpression of carnitine palmitotyltransferase-1 (CPT-1) in L6 cells (which increases mitochondrial fatty acid uptake) protects the cell from fatty acid-induced insulin resistance [85], an effect associated with a decrease in DAG. The role of lipid intermediates in mediating insulin resistance in the heart has received less extensive research attention. The increased concentration of TG in association with insulin resistance has been observed in heart from the high fat fed rodents, obese humans and genetically obese and type 2 diabetic rodent models [53,86-89]. Cardiac dysfunction in Zucker obese rats is positively correlated with the accumulation of intra-myocardial TG and ceramide [89,90]. Accumulation of ceramide in the rat heart following a high-fat diet consisting of saturated fatty acids has also been shown [91]. Cardiac overexpression of PPAR α in mice on a high fat diet can also augment intramyocardial content of ceramide [92]. The conversion and accumulation of these lipid intermediates has been implicated in the development of insulin resistance, cardiac dysfunction and heart failure [93-95]. However, it remains controversial whether the accumulation of lipid intermediates might cause an impairment of insulin action in the heart and cardiac dysfunction. High fat feeding of rats simultaneously treated with an inhibitor of CPT-1 results in the accumulation of intramyocardial TG without any features of cardiac hypertrophy or dysfunction [96]. Numerous studies in animal models and humans show that inhibition of mitochondrial fatty acid uptake and β -oxidation either prevents or reverses heart failure [97-102]. It is worth mentioning that in the majority of studies the link between accumulation of intramyocardial lipid intermediates and impaired insulin sensitivity (not heart dysfunction) of the heart is missing. In addition, studies examining the mechanisms of heart insulin resistance associated with the accumulation of lipid metabolites have been faced with numerous discrepancies. Although excessive uptake of fatty acid by the heart and skeletal muscle has been implicated as a major cause of insulin resistance, it should be recognized that fatty acids are also an important source of fuel for oxidative muscles. As a result, a highly regulated process exists to deliver, take up, esterify, and oxidize fatty acids in oxidative muscles. It should be noted that the heart and skeletal muscle can have very different rates of fatty acid oxidation. Heart muscle is highly oxidative, while skeletal muscle consists of different fi ber types. There are two main types of skeletal muscles: red/slow-twitch fi bers (type 1) which have a high oxidative, low glycolytic capacity that favors aerobic energy production, and white/fast-twitch fi bers (type 2) that have a low oxidative, high glycolytic capacity that favors anaerobic energy production [103,104]. The control of fatty acid β -oxidation that is discussed in this review may not apply to type 2 skeletal muscle, although most studies examining the role of fatty acid uptake and oxidation contribution to insulin resistance do not distinguish between these two fi ber types. For both the heart and skeletal muscle the two main sources of fatty acid in the blood are free fatty acid (FFA) bound to albumin derived from the lipolysis of adipose tissue, and FFA released from TG contained in chylomicrons and very low-density lipoprotein (VLDL) by lipoprotein lipase (LPL) (Fig. 2) [105,106]. LPL is highly expressed in the heart [107]. Fatty acids derived from the hydrolysis of TG by LPL have been suggested to be the principal source of fat for cardiac utilization [108]. Alteration of LPL can signi fi cantly impact myocardial fatty acid metabolism. Although data are variable, diabetes and insulin resistance are associated with increased LPL secretion [109]. Lipolysis of adipose tissue, which liberates FFA from adipocytes, plays another important regulatory role, especially in the skeletal muscle when chylomicron and VLDL levels decrease in post-absorptive state. Hormone-sensitive lipase (HSL), whose activity is dependent on the concentration of hormones, is the rate-limiting enzyme for adipose tissue lipolysis. Epinephrine can stimulate HSL by phosphorylation through the activation of cAMP dependent protein kinase [110], whereas insulin can inhibit HSL by dephosphorylating this enzyme [111]. Therefore, the amount of FFA release from lipolysis can vary largely depending on the balance between epinephrine stimulation and insulin inhibition. As will be discussed, it is our contention that alterations in fatty acid supply to heart and skeletal muscle are likely to be the major contributor to insulin resistance in muscle. The uptake of fatty acid into the heart and skeletal muscle is not yet fully understood. Passive diffusion was initially thought to be the main manner of fatty acid uptake into the heart and skeletal muscle, since the hydrophobic fatty acid can readily pass through the lipid bilayer of the sarcolemma [112]. However, many studies have demonstrated that a protein-mediated transport mechanism is involved, and this is the major pathway by which fatty acids traverse the sarcolemma [113]; thus uptake of fatty acids into the heart and skeletal muscle depends on both fatty acid concentration in the blood and the regulation of the transporters [114,115]. A number of fatty acid transporters have been identi fi ed, including fatty acid translocase (FAT)/CD36, plasma membrane-bound fatty acid binding protein (FABPpm), and the tissue-speci fi c fatty acid transport protein (FATP) family (FATP 1-6) (Fig. 2) [36,116,117]. The exact proportion each of these transporters contributes to fatty acid uptake is not clear, but FAT/CD36 is thought to be a predominant transporter, and is the one most studied. By either FAT/CD36 inhibition or CD36 deletion, it has been shown that 68% of the fatty acids taken up and oxidized by the heart occurs via this transporter [118-120]. In addition, these transporters may interact with each other to facilitate fatty acid uptake, as interactions between FAT/CD36 and FABPpm, and between FAT/CD36 and FATP have been identi fi ed in controlling fatty acid uptake [36,113,117,121]. It should also be noted that the sarcolemmal content of these transporters can rapidly change. Muscle contraction leads to the translocation of FAT/CD36 from intracellular depots to the sarcolemmal membrane and the subsequent up-regulation of fatty acid transport [122]. Insulin, leptin and AMP-activated protein kinase (AMPK) activation can also rapidly induce translocation of FAT/CD36 from intracellular depots to the sarcolemma and increase fatty acid uptake [120]. Translocation of FAT/CD36 is also changed in a number of chronic pathological states. For instance, Luiken et al. [123] and Bonen et al. [124] demonstrated that in obese rats, as well as obese humans and type 2 diabetic patients, the rate of fatty acid transport is up-regulated, which is associated with increased translocation of FAT/ CD36 to the sarcolemmal membrane. Once transported into the cytosol, non-esteri fi ed fatty acid is esteri fi ed to long chain acyl CoA by fatty acyl CoA synthase (FACS) (Fig. 2). While the majority of the acyl groups on long chain acyl CoAs are destined for mitochondria for β -oxidation, a small portion of long chain acyl CoAs can be converted into intracellular lipid intermediates, such as TG, phospholipids, DAG, and ceramide. Theoretically, a decrease in fatty acid β -oxidation can lead to lipid accumulation. The acceleration of fatty acid β -oxidation may lessen the potential for insulin resistance. However, evidence on the role of fatty acid β oxidation in contributing to insulin-resistance is controversial [88, 125], as will be discussed later. Before undergoing β -oxidation, the acyl groups from long chain acyl-CoA must fi rst be transported across the mitochondrial outer and inner membranes. This process is facilitated by a carnitine-dependent transport system, which includes carnitine palmitoyl transferase-1 (CPT-1), carnitine translocase (CAT), and carnitine palmitoyl trans- ferase-2 (CPT-2) (Fig. 2). CPT-1, located on the outer membrane of mitochondria, is the key and rate-limiting enzyme involved in mitochondrial fatty acid uptake. CPT-1 catalyzes the reaction where long chain acyl CoA and carnitine react to form acylcarnitine. Acylcarnitine is then transported across the ...
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... of fuel for oxidative muscles. As a result, a highly regulated process exists to deliver, take up, esterify, and oxidize fatty acids in oxidative muscles. It should be noted that the heart and skeletal muscle can have very different rates of fatty acid oxidation. Heart muscle is highly oxidative, while skeletal muscle consists of different fi ber types. There are two main types of skeletal muscles: red/slow-twitch fi bers (type 1) which have a high oxidative, low glycolytic capacity that favors aerobic energy production, and white/fast-twitch fi bers (type 2) that have a low oxidative, high glycolytic capacity that favors anaerobic energy production [103,104]. The control of fatty acid β -oxidation that is discussed in this review may not apply to type 2 skeletal muscle, although most studies examining the role of fatty acid uptake and oxidation contribution to insulin resistance do not distinguish between these two fi ber types. For both the heart and skeletal muscle the two main sources of fatty acid in the blood are free fatty acid (FFA) bound to albumin derived from the lipolysis of adipose tissue, and FFA released from TG contained in chylomicrons and very low-density lipoprotein (VLDL) by lipoprotein lipase (LPL) (Fig. 2) [105,106]. LPL is highly expressed in the heart [107]. Fatty acids derived from the hydrolysis of TG by LPL have been suggested to be the principal source of fat for cardiac utilization [108]. Alteration of LPL can signi fi cantly impact myocardial fatty acid metabolism. Although data are variable, diabetes and insulin resistance are associated with increased LPL secretion [109]. Lipolysis of adipose tissue, which liberates FFA from adipocytes, plays another important regulatory role, especially in the skeletal muscle when chylomicron and VLDL levels decrease in post-absorptive state. Hormone-sensitive lipase (HSL), whose activity is dependent on the concentration of hormones, is the rate-limiting enzyme for adipose tissue lipolysis. Epinephrine can stimulate HSL by phosphorylation through the activation of cAMP dependent protein kinase [110], whereas insulin can inhibit HSL by dephosphorylating this enzyme [111]. Therefore, the amount of FFA release from lipolysis can vary largely depending on the balance between epinephrine stimulation and insulin inhibition. As will be discussed, it is our contention that alterations in fatty acid supply to heart and skeletal muscle are likely to be the major contributor to insulin resistance in muscle. The uptake of fatty acid into the heart and skeletal muscle is not yet fully understood. Passive diffusion was initially thought to be the main manner of fatty acid uptake into the heart and skeletal muscle, since the hydrophobic fatty acid can readily pass through the lipid bilayer of the sarcolemma [112]. However, many studies have demonstrated that a protein-mediated transport mechanism is involved, and this is the major pathway by which fatty acids traverse the sarcolemma [113]; thus uptake of fatty acids into the heart and skeletal muscle depends on both fatty acid concentration in the blood and the regulation of the transporters [114,115]. A number of fatty acid transporters have been identi fi ed, including fatty acid translocase (FAT)/CD36, plasma membrane-bound fatty acid binding protein (FABPpm), and the tissue-speci fi c fatty acid transport protein (FATP) family (FATP 1-6) (Fig. 2) [36,116,117]. The exact proportion each of these transporters contributes to fatty acid uptake is not clear, but FAT/CD36 is thought to be a predominant transporter, and is the one most studied. By either FAT/CD36 inhibition or CD36 deletion, it has been shown that 68% of the fatty acids taken up and oxidized by the heart occurs via this transporter [118-120]. In addition, these transporters may interact with each other to facilitate fatty acid uptake, as interactions between FAT/CD36 and FABPpm, and between FAT/CD36 and FATP have been identi fi ed in controlling fatty acid uptake [36,113,117,121]. It should also be noted that the sarcolemmal content of these transporters can rapidly change. Muscle contraction leads to the translocation of FAT/CD36 from intracellular depots to the sarcolemmal membrane and the subsequent up-regulation of fatty acid transport [122]. Insulin, leptin and AMP-activated protein kinase (AMPK) activation can also rapidly induce translocation of FAT/CD36 from intracellular depots to the sarcolemma and increase fatty acid uptake [120]. Translocation of FAT/CD36 is also changed in a number of chronic pathological states. For instance, Luiken et al. [123] and Bonen et al. [124] demonstrated that in obese rats, as well as obese humans and type 2 diabetic patients, the rate of fatty acid transport is up-regulated, which is associated with increased translocation of FAT/ CD36 to the sarcolemmal membrane. Once transported into the cytosol, non-esteri fi ed fatty acid is esteri fi ed to long chain acyl CoA by fatty acyl CoA synthase (FACS) (Fig. 2). While the majority of the acyl groups on long chain acyl CoAs are destined for mitochondria for β -oxidation, a small portion of long chain acyl CoAs can be converted into intracellular lipid intermediates, such as TG, phospholipids, DAG, and ceramide. Theoretically, a decrease in fatty acid β -oxidation can lead to lipid accumulation. The acceleration of fatty acid β -oxidation may lessen the potential for insulin resistance. However, evidence on the role of fatty acid β oxidation in contributing to insulin-resistance is controversial [88, 125], as will be discussed later. Before undergoing β -oxidation, the acyl groups from long chain acyl-CoA must fi rst be transported across the mitochondrial outer and inner membranes. This process is facilitated by a carnitine-dependent transport system, which includes carnitine palmitoyl transferase-1 (CPT-1), carnitine translocase (CAT), and carnitine palmitoyl trans- ferase-2 (CPT-2) (Fig. 2). CPT-1, located on the outer membrane of mitochondria, is the key and rate-limiting enzyme involved in mitochondrial fatty acid uptake. CPT-1 catalyzes the reaction where long chain acyl CoA and carnitine react to form acylcarnitine. Acylcarnitine is then transported across the inner mitochondrial membrane by CAT. Once in the mitochondrial matrix, acylcarnitine is re-converted back to long chain acyl CoA and carnitine by CPT-2. Long chain acyl CoA then enters the β -oxidation pathway. As the enzyme of mitochondrial fatty acid uptake, CPT-1 is highly regulated. In both the heart and skeletal muscle, malonyl CoA is a key molecule responsible for regulation of CPT-1, since it is a potent allosteric inhibitor of CPT-1 [126]. As CPT-1 governs the entrance of long chain acyl CoA into the mitochondria, any changes in malonyl CoA concentration can alter mitochondrial uptake of fatty acid and consequently the rate of fatty acid oxidation in the mitochondria [127,128]. The concentration of malonyl CoA is controlled by its turnover, in which acetyl CoA carboxylase (ACC) catalyzes the synthesis pathway, and malonyl CoA decarboxylase (MCD) controls its degradation (Fig. 2). It is generally accepted that CPT-1 is the rate- limiting enzyme of mitochondrial fatty acid uptake [126,129,130]. However, recent studies suggest that this may not be the case as changes in long chain acyl CoA uptake and oxidation have been found to be independent of CPT-1 activity [131-134]. Two isoforms of ACC have been identi fi ed in the heart and skeletal muscle, ACC 1 (265 kDa) and ACC 2 (280 KDa), with ACC 2 predominating in both heart and skeletal muscle [135,136]. In ACC 2 de fi cient mice, marked increases in muscle fatty acid oxidation rates have been observed, indicating that ACC 2 is a key regulator of fatty acid oxidation in muscle [137]. A key determinant of ACC activity is the activity of AMP-activated protein kinase (AMPK). AMPK, also called the “ fuel sensor, ” is a serine/threonine kinase that responds to metabolic stresses with increased AMP/ATP and Cr/PCr ratios [138,139]. Insulin can also inhibit AMPK in the heart under conditions where the AMP/ATP and Cr/PCr ratios do not change [140]. AMPK is a heterotrimeric protein, consisting of an α catalytic subunit and β and γ regulatory subunits. AMPK is activated by phosphorylation of Thr172 on the catalytic α -subunit [138]. To date, AMPK kinases (AMPKKs) known to phosphorylate Thr172 in mammalian cells include LKB1, the calmodulin-dependent protein kinase kinases (CaMKK), and TAK1 [138,141]. Recently, we identi fi ed the myosin light chain kinase (MLCK) as another potential AMPKK responsible for the activation of AMPK during cardiac ischemia (Jaswal et al., manuscript submitted). AMPK plays an important role in regulating fatty acid β -oxidation, as well as glucose uptake and glycolysis [142- 144]. In both the heart [145,146] and skeletal muscle [71,147], AMPK can phosphorylate and inactivate ACC, which relieves CPT-1 from malonyl CoA's inhibitory effect, resulting in a stimulation of fatty acid β -oxidation. In the rat heart we showed that AMPK is able to phosphorylate both ACC 1 and ACC 2, resulting in an almost complete loss of ACC activity [136,145]. Others also have shown that in both the heart and skeletal muscle, as a consequence of decreased ACC activity, malonyl CoA levels decrease and fatty acid β -oxidation rates increase [148-150]. AMPK and ACC phosphorylation are increased concurrently with a decline in malonyl CoA concentration and an increase in fatty acid β oxidation in rodents and humans [147,150-153]. In skeletal muscle, it has also been suggested that AMPK can directly activate MCD [154]. A number of studies have shown that in both the heart and skeletal muscle, conditions with increased fatty acid β -oxidation are associated with high MCD activity [155,156]. In contrast, MCD inhibition can decrease the contribution of fatty acid β -oxidation from 90% to 50% of total ATP production, with a concomitant increase in ...
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... (Jaswal et al., manuscript submitted). AMPK plays an important role in regulating fatty acid β -oxidation, as well as glucose uptake and glycolysis [142- 144]. In both the heart [145,146] and skeletal muscle [71,147], AMPK can phosphorylate and inactivate ACC, which relieves CPT-1 from malonyl CoA's inhibitory effect, resulting in a stimulation of fatty acid β -oxidation. In the rat heart we showed that AMPK is able to phosphorylate both ACC 1 and ACC 2, resulting in an almost complete loss of ACC activity [136,145]. Others also have shown that in both the heart and skeletal muscle, as a consequence of decreased ACC activity, malonyl CoA levels decrease and fatty acid β -oxidation rates increase [148-150]. AMPK and ACC phosphorylation are increased concurrently with a decline in malonyl CoA concentration and an increase in fatty acid β oxidation in rodents and humans [147,150-153]. In skeletal muscle, it has also been suggested that AMPK can directly activate MCD [154]. A number of studies have shown that in both the heart and skeletal muscle, conditions with increased fatty acid β -oxidation are associated with high MCD activity [155,156]. In contrast, MCD inhibition can decrease the contribution of fatty acid β -oxidation from 90% to 50% of total ATP production, with a concomitant increase in glucose oxidation. Using MCD inhibitors we have shown that in isolated working hearts perfused with high levels of fatty acid, pharmacological inhibition of MCD increases malonyl CoA levels, decreases fatty acid β -oxidation, and increases glucose oxidation up to 10 fold [157]. As will be discussed, this is actually associated with an increase in insulin sensitivity. AMPK is activated in skeletal muscle during exercise [158,159]. During moderate intensity exercise, skeletal muscle fatty acid oxidation increases. In rats, this increase is thought to be due to the activation of MCD by AMPK and a consequent decrease in malonyl CoA levels in the muscle during exercise [154]. However, during exercise of increasing intensity, fatty acid β -oxidation rates decrease or remain at a plateau in humans [160,161]. Although the mechanism has not yet been elucidated, AMPK plays an important role in regulating fatty acid β -oxidation during exercise. In addition to the regulation of substrate oxidation, available data also suggest that alteration of malonyl CoA concentration may regulate muscle insulin action [5,127,162]. A proposed mechanism for this action is that chronic increases in muscle malonyl CoA lead to accumulation of DAG concomitant with the activation of PKC's, thereby reducing insulin signal transduction [163,164]. However, increasing malonyl CoA concentration under acute conditions has been shown to have no effect on altering insulin signaling [127]. Although one recent study demonstrated that acutely reduced malonyl CoA in human muscle by exercise may contribute to improved insulin action on glucose uptake [128], the role of malonyl CoA in mediating insulin sensitivity remains unclear [34,35,165]. β -oxidation of long chain acyl CoA in the mitochondria involves a number of enzymes, including acyl CoA dehydrogenase, enoyl-CoA hydratase, L -3-hydroxyacyl-CoA dehydrogenase, and 3-ketoacyl-CoA thiolase [166]. Each cycle of fatty acid β -oxidation results in the shortening of the fatty acid by two carbons, as well as the production of acetyl CoA, FADH 2 and NADH. Each of these enzymes is sensitive to feedback inhibition by the products of its enzymatic reaction. Acetyl CoA derived from β -oxidation can then enter the TCA cycle, which produces NADH and FADH 2 . NADH and FADH 2 are subsequently used in the electron transport chain to produce ATP. Accelerating fatty acid β -oxidation has been proposed as an approach to decrease muscle insulin resistance, thereby increasing glucose uptake. However, it is important to recognize that a complex interaction between muscle glucose and fatty acid metabolism exists. When fatty acid β -oxidation is increased, glucose oxidation is consequently decreased, a phenomenon that is termed the “ Randle Cycle ” [1]. The inter-regulation between fatty acid and glucose metabolism implicates that substrate preference may contribute to the development of insulin resistance. Once glucose is taken up via facilitated transport by two types of glucose transporters: GLUT1 and predominantly GLUT4 [126] into the myocyte, it is phosphorylated to glucose-6-phosphate by hexokinase. In the non-oxygen dependent glycolysis pathway, glucose-6-phosphate is converted to fructose-6-phosphate and then irreversibly into fructose 1, 6-bisphosphate via phosphofructokinase-1 (PFK-1), in which 1 molecule of glucose forms 2 molecules of pyruvate and 2 NADH [167]. In the heart and oxidative skeletal muscle, pyruvate and NADH are shuttled into the mitochondria, where pyruvate is converted into acetyl CoA by the pyruvate dehydrogenase (PDH) complex, and then acetyl CoA enters the TCA cycle and electron transport chain (Fig. 2). Acetyl CoA is also the end product of β oxidation of fatty acids. As a result, oxidation of fatty acid in muscle causes an increase in the mitochondrial ratio of [acetyl-CoA]/[CoA], which inhibits PDH. High rates of fatty acid β -oxidation can also lead to inhibition of phosphofructokinase-1 by citrate and of hexokinase by glucose 6-phosphate. Randle and colleagues proposed that this inhibition of glucose oxidation by the β -oxidation of fatty acid would inhibit the effect of physiological concentrations of insulin to accelerate glucose or sugar clearance [1,168]. As a result, any strategy to stimulate fatty acid β -oxidation needs to consider the possible direct inhibitory effects of fatty acid on glucose metabolism. The existence of the Randle Cycle in heart has been clearly demonstrated. Cardiac substrate selection during the early neonatal development is achieved by changes in several regulatory enzymes controlling glucose and fatty acid utilization, among which, increased expression of pyruvate dehydrogenase kinase 4 (PDK4) exhibits a unique pattern [146]. In experimental diabetes and starvation, which are both associated with decreased glucose utilization and increased fatty acid β -oxidation, speci fi c upregulation of cardiac PDK4 is well documented [169]. In addition, cardiac speci fi c overexpression of PDK4 is suf fi cient to cause a loss of metabolic fl exibility [165]. Furthermore, activation of PPAR α , known to enhance fatty acid oxidation, led to the enhanced cardiac PDK4 mRNA expression [155]. In contrast, some questions persist as to whether the Randle Cycle exists in skeletal muscle. Several studies have challenged the existence of Randle Cycle, which proposes that increased fatty acid β -oxidation contributes to insulin resistance. Studies using a combination of lipid and heparin infusion with carbon nuclear magnetic resonance ( 13 C-NMR) spectroscopy and phosphorus NMR ( 31 P-NMR) spectroscopy, demonstrated that maintaining high levels of plasma FFA decreases intracellular content of glucose and glucose 6-phosphate [93,156]. It was concluded that if the Randle cycle is operative, increased glucose 6-phosphate level should be expected. However, this argument assumes that glucose uptake is not impaired to the same extent as glycolysis, and does not consider the role of fatty acid inhibition of glucose oxidation. Based on these observations, it has been suggested that in contrast to the prediction by the Randle cycle, defective insulin-stimulated glucose transport activity is the major factor in skeletal muscle responsible for insulin resistance in obese patients and patients with type 2 diabetes. Another study using TG and heparin infusion showed that an increase in FFA availability decreased glucose uptake, and this is not due to the increase in fatty acid oxidation, but rather a main defect in glucose uptake resulting in a secondary defect in glucose oxidation [162]. These authors suggested that the rate of glycolysis, determined by the intracellular availability of glucose-6-phosphate, is the predominant factor determining the rate of glucose oxidation. These notions lead to the opposite perspective to certain aspects of the traditional view of the Randle Cycle. A study from Boden et al. [5] demonstrated that the inhibitory effect of increased plasma FFA on whole body glucose uptake and glucose storage was only apparent after 2 – 4 h, whereas effects on glucose oxidation were evident in the fi rst hour [156,163]. These authors concluded that, during hyperinsulinemia, lipid rapidly replaced carbohydrate as fuel for oxidation in muscle and inhibit glucose uptake. Studies from Curi et al. also provided evidence to support the Randle Cycle and the inhibition of insulin signaling pathway in skeletal muscle in the presence of FFA [164,170]. They found that acute exposure of rat soleus muscle to fatty acid leads to an increase in intracellular content of glucose 6-phosphate in the presence of insulin. They postulated that fatty acid acutely potentiates insulin-stimulated glycogen synthesis by a mechanism that requires its metabolism (i.e. the Randle Cycle). Koves et al. [35] reported that respiratory exchange ratio (RER) decreases with high fat feeding in mice, suggesting a greater reliance on fatty acid as a source of fuel. This is accompanied by an impairment of whole body glucose clearance as demonstrated by glucose tolerance test and insulin sensitivity test. In mice de fi cient in MCD, however, there is no decrease in RER and no impairment in glucose tolerance, suggesting that a decrease in fatty acid β -oxidation, particularly in the muscle, which is the predominant tissue for glucose disposal, can improve glucose clearance and insulin sensitivity [35]. In human skeletal muscle cells, siRNA-mediated knockdown of MCD, which decreases mitochondrial fatty acid uptake and β -oxidation, results in an increased glucose oxidation as well as an increase in insulin-stimulated ...
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... HSL by dephosphorylating this enzyme [111]. Therefore, the amount of FFA release from lipolysis can vary largely depending on the balance between epinephrine stimulation and insulin inhibition. As will be discussed, it is our contention that alterations in fatty acid supply to heart and skeletal muscle are likely to be the major contributor to insulin resistance in muscle. The uptake of fatty acid into the heart and skeletal muscle is not yet fully understood. Passive diffusion was initially thought to be the main manner of fatty acid uptake into the heart and skeletal muscle, since the hydrophobic fatty acid can readily pass through the lipid bilayer of the sarcolemma [112]. However, many studies have demonstrated that a protein-mediated transport mechanism is involved, and this is the major pathway by which fatty acids traverse the sarcolemma [113]; thus uptake of fatty acids into the heart and skeletal muscle depends on both fatty acid concentration in the blood and the regulation of the transporters [114,115]. A number of fatty acid transporters have been identi fi ed, including fatty acid translocase (FAT)/CD36, plasma membrane-bound fatty acid binding protein (FABPpm), and the tissue-speci fi c fatty acid transport protein (FATP) family (FATP 1-6) (Fig. 2) [36,116,117]. The exact proportion each of these transporters contributes to fatty acid uptake is not clear, but FAT/CD36 is thought to be a predominant transporter, and is the one most studied. By either FAT/CD36 inhibition or CD36 deletion, it has been shown that 68% of the fatty acids taken up and oxidized by the heart occurs via this transporter [118-120]. In addition, these transporters may interact with each other to facilitate fatty acid uptake, as interactions between FAT/CD36 and FABPpm, and between FAT/CD36 and FATP have been identi fi ed in controlling fatty acid uptake [36,113,117,121]. It should also be noted that the sarcolemmal content of these transporters can rapidly change. Muscle contraction leads to the translocation of FAT/CD36 from intracellular depots to the sarcolemmal membrane and the subsequent up-regulation of fatty acid transport [122]. Insulin, leptin and AMP-activated protein kinase (AMPK) activation can also rapidly induce translocation of FAT/CD36 from intracellular depots to the sarcolemma and increase fatty acid uptake [120]. Translocation of FAT/CD36 is also changed in a number of chronic pathological states. For instance, Luiken et al. [123] and Bonen et al. [124] demonstrated that in obese rats, as well as obese humans and type 2 diabetic patients, the rate of fatty acid transport is up-regulated, which is associated with increased translocation of FAT/ CD36 to the sarcolemmal membrane. Once transported into the cytosol, non-esteri fi ed fatty acid is esteri fi ed to long chain acyl CoA by fatty acyl CoA synthase (FACS) (Fig. 2). While the majority of the acyl groups on long chain acyl CoAs are destined for mitochondria for β -oxidation, a small portion of long chain acyl CoAs can be converted into intracellular lipid intermediates, such as TG, phospholipids, DAG, and ceramide. Theoretically, a decrease in fatty acid β -oxidation can lead to lipid accumulation. The acceleration of fatty acid β -oxidation may lessen the potential for insulin resistance. However, evidence on the role of fatty acid β oxidation in contributing to insulin-resistance is controversial [88, 125], as will be discussed later. Before undergoing β -oxidation, the acyl groups from long chain acyl-CoA must fi rst be transported across the mitochondrial outer and inner membranes. This process is facilitated by a carnitine-dependent transport system, which includes carnitine palmitoyl transferase-1 (CPT-1), carnitine translocase (CAT), and carnitine palmitoyl trans- ferase-2 (CPT-2) (Fig. 2). CPT-1, located on the outer membrane of mitochondria, is the key and rate-limiting enzyme involved in mitochondrial fatty acid uptake. CPT-1 catalyzes the reaction where long chain acyl CoA and carnitine react to form acylcarnitine. Acylcarnitine is then transported across the inner mitochondrial membrane by CAT. Once in the mitochondrial matrix, acylcarnitine is re-converted back to long chain acyl CoA and carnitine by CPT-2. Long chain acyl CoA then enters the β -oxidation pathway. As the enzyme of mitochondrial fatty acid uptake, CPT-1 is highly regulated. In both the heart and skeletal muscle, malonyl CoA is a key molecule responsible for regulation of CPT-1, since it is a potent allosteric inhibitor of CPT-1 [126]. As CPT-1 governs the entrance of long chain acyl CoA into the mitochondria, any changes in malonyl CoA concentration can alter mitochondrial uptake of fatty acid and consequently the rate of fatty acid oxidation in the mitochondria [127,128]. The concentration of malonyl CoA is controlled by its turnover, in which acetyl CoA carboxylase (ACC) catalyzes the synthesis pathway, and malonyl CoA decarboxylase (MCD) controls its degradation (Fig. 2). It is generally accepted that CPT-1 is the rate- limiting enzyme of mitochondrial fatty acid uptake [126,129,130]. However, recent studies suggest that this may not be the case as changes in long chain acyl CoA uptake and oxidation have been found to be independent of CPT-1 activity [131-134]. Two isoforms of ACC have been identi fi ed in the heart and skeletal muscle, ACC 1 (265 kDa) and ACC 2 (280 KDa), with ACC 2 predominating in both heart and skeletal muscle [135,136]. In ACC 2 de fi cient mice, marked increases in muscle fatty acid oxidation rates have been observed, indicating that ACC 2 is a key regulator of fatty acid oxidation in muscle [137]. A key determinant of ACC activity is the activity of AMP-activated protein kinase (AMPK). AMPK, also called the “ fuel sensor, ” is a serine/threonine kinase that responds to metabolic stresses with increased AMP/ATP and Cr/PCr ratios [138,139]. Insulin can also inhibit AMPK in the heart under conditions where the AMP/ATP and Cr/PCr ratios do not change [140]. AMPK is a heterotrimeric protein, consisting of an α catalytic subunit and β and γ regulatory subunits. AMPK is activated by phosphorylation of Thr172 on the catalytic α -subunit [138]. To date, AMPK kinases (AMPKKs) known to phosphorylate Thr172 in mammalian cells include LKB1, the calmodulin-dependent protein kinase kinases (CaMKK), and TAK1 [138,141]. Recently, we identi fi ed the myosin light chain kinase (MLCK) as another potential AMPKK responsible for the activation of AMPK during cardiac ischemia (Jaswal et al., manuscript submitted). AMPK plays an important role in regulating fatty acid β -oxidation, as well as glucose uptake and glycolysis [142- 144]. In both the heart [145,146] and skeletal muscle [71,147], AMPK can phosphorylate and inactivate ACC, which relieves CPT-1 from malonyl CoA's inhibitory effect, resulting in a stimulation of fatty acid β -oxidation. In the rat heart we showed that AMPK is able to phosphorylate both ACC 1 and ACC 2, resulting in an almost complete loss of ACC activity [136,145]. Others also have shown that in both the heart and skeletal muscle, as a consequence of decreased ACC activity, malonyl CoA levels decrease and fatty acid β -oxidation rates increase [148-150]. AMPK and ACC phosphorylation are increased concurrently with a decline in malonyl CoA concentration and an increase in fatty acid β oxidation in rodents and humans [147,150-153]. In skeletal muscle, it has also been suggested that AMPK can directly activate MCD [154]. A number of studies have shown that in both the heart and skeletal muscle, conditions with increased fatty acid β -oxidation are associated with high MCD activity [155,156]. In contrast, MCD inhibition can decrease the contribution of fatty acid β -oxidation from 90% to 50% of total ATP production, with a concomitant increase in glucose oxidation. Using MCD inhibitors we have shown that in isolated working hearts perfused with high levels of fatty acid, pharmacological inhibition of MCD increases malonyl CoA levels, decreases fatty acid β -oxidation, and increases glucose oxidation up to 10 fold [157]. As will be discussed, this is actually associated with an increase in insulin sensitivity. AMPK is activated in skeletal muscle during exercise [158,159]. During moderate intensity exercise, skeletal muscle fatty acid oxidation increases. In rats, this increase is thought to be due to the activation of MCD by AMPK and a consequent decrease in malonyl CoA levels in the muscle during exercise [154]. However, during exercise of increasing intensity, fatty acid β -oxidation rates decrease or remain at a plateau in humans [160,161]. Although the mechanism has not yet been elucidated, AMPK plays an important role in regulating fatty acid β -oxidation during exercise. In addition to the regulation of substrate oxidation, available data also suggest that alteration of malonyl CoA concentration may regulate muscle insulin action [5,127,162]. A proposed mechanism for this action is that chronic increases in muscle malonyl CoA lead to accumulation of DAG concomitant with the activation of PKC's, thereby reducing insulin signal transduction [163,164]. However, increasing malonyl CoA concentration under acute conditions has been shown to have no effect on altering insulin signaling [127]. Although one recent study demonstrated that acutely reduced malonyl CoA in human muscle by exercise may contribute to improved insulin action on glucose uptake [128], the role of malonyl CoA in mediating insulin sensitivity remains unclear [34,35,165]. β -oxidation of long chain acyl CoA in the mitochondria involves a number of enzymes, including acyl CoA dehydrogenase, enoyl-CoA hydratase, L -3-hydroxyacyl-CoA dehydrogenase, and 3-ketoacyl-CoA thiolase [166]. Each cycle of fatty acid β -oxidation results in the shortening of the fatty acid by two carbons, as well as the production of acetyl CoA, FADH 2 and NADH. Each of these enzymes is sensitive to ...
Context 11
... with the accumulation of intra-myocardial TG and ceramide [89,90]. Accumulation of ceramide in the rat heart following a high-fat diet consisting of saturated fatty acids has also been shown [91]. Cardiac overexpression of PPAR α in mice on a high fat diet can also augment intramyocardial content of ceramide [92]. The conversion and accumulation of these lipid intermediates has been implicated in the development of insulin resistance, cardiac dysfunction and heart failure [93-95]. However, it remains controversial whether the accumulation of lipid intermediates might cause an impairment of insulin action in the heart and cardiac dysfunction. High fat feeding of rats simultaneously treated with an inhibitor of CPT-1 results in the accumulation of intramyocardial TG without any features of cardiac hypertrophy or dysfunction [96]. Numerous studies in animal models and humans show that inhibition of mitochondrial fatty acid uptake and β -oxidation either prevents or reverses heart failure [97-102]. It is worth mentioning that in the majority of studies the link between accumulation of intramyocardial lipid intermediates and impaired insulin sensitivity (not heart dysfunction) of the heart is missing. In addition, studies examining the mechanisms of heart insulin resistance associated with the accumulation of lipid metabolites have been faced with numerous discrepancies. Although excessive uptake of fatty acid by the heart and skeletal muscle has been implicated as a major cause of insulin resistance, it should be recognized that fatty acids are also an important source of fuel for oxidative muscles. As a result, a highly regulated process exists to deliver, take up, esterify, and oxidize fatty acids in oxidative muscles. It should be noted that the heart and skeletal muscle can have very different rates of fatty acid oxidation. Heart muscle is highly oxidative, while skeletal muscle consists of different fi ber types. There are two main types of skeletal muscles: red/slow-twitch fi bers (type 1) which have a high oxidative, low glycolytic capacity that favors aerobic energy production, and white/fast-twitch fi bers (type 2) that have a low oxidative, high glycolytic capacity that favors anaerobic energy production [103,104]. The control of fatty acid β -oxidation that is discussed in this review may not apply to type 2 skeletal muscle, although most studies examining the role of fatty acid uptake and oxidation contribution to insulin resistance do not distinguish between these two fi ber types. For both the heart and skeletal muscle the two main sources of fatty acid in the blood are free fatty acid (FFA) bound to albumin derived from the lipolysis of adipose tissue, and FFA released from TG contained in chylomicrons and very low-density lipoprotein (VLDL) by lipoprotein lipase (LPL) (Fig. 2) [105,106]. LPL is highly expressed in the heart [107]. Fatty acids derived from the hydrolysis of TG by LPL have been suggested to be the principal source of fat for cardiac utilization [108]. Alteration of LPL can signi fi cantly impact myocardial fatty acid metabolism. Although data are variable, diabetes and insulin resistance are associated with increased LPL secretion [109]. Lipolysis of adipose tissue, which liberates FFA from adipocytes, plays another important regulatory role, especially in the skeletal muscle when chylomicron and VLDL levels decrease in post-absorptive state. Hormone-sensitive lipase (HSL), whose activity is dependent on the concentration of hormones, is the rate-limiting enzyme for adipose tissue lipolysis. Epinephrine can stimulate HSL by phosphorylation through the activation of cAMP dependent protein kinase [110], whereas insulin can inhibit HSL by dephosphorylating this enzyme [111]. Therefore, the amount of FFA release from lipolysis can vary largely depending on the balance between epinephrine stimulation and insulin inhibition. As will be discussed, it is our contention that alterations in fatty acid supply to heart and skeletal muscle are likely to be the major contributor to insulin resistance in muscle. The uptake of fatty acid into the heart and skeletal muscle is not yet fully understood. Passive diffusion was initially thought to be the main manner of fatty acid uptake into the heart and skeletal muscle, since the hydrophobic fatty acid can readily pass through the lipid bilayer of the sarcolemma [112]. However, many studies have demonstrated that a protein-mediated transport mechanism is involved, and this is the major pathway by which fatty acids traverse the sarcolemma [113]; thus uptake of fatty acids into the heart and skeletal muscle depends on both fatty acid concentration in the blood and the regulation of the transporters [114,115]. A number of fatty acid transporters have been identi fi ed, including fatty acid translocase (FAT)/CD36, plasma membrane-bound fatty acid binding protein (FABPpm), and the tissue-speci fi c fatty acid transport protein (FATP) family (FATP 1-6) (Fig. 2) [36,116,117]. The exact proportion each of these transporters contributes to fatty acid uptake is not clear, but FAT/CD36 is thought to be a predominant transporter, and is the one most studied. By either FAT/CD36 inhibition or CD36 deletion, it has been shown that 68% of the fatty acids taken up and oxidized by the heart occurs via this transporter [118-120]. In addition, these transporters may interact with each other to facilitate fatty acid uptake, as interactions between FAT/CD36 and FABPpm, and between FAT/CD36 and FATP have been identi fi ed in controlling fatty acid uptake [36,113,117,121]. It should also be noted that the sarcolemmal content of these transporters can rapidly change. Muscle contraction leads to the translocation of FAT/CD36 from intracellular depots to the sarcolemmal membrane and the subsequent up-regulation of fatty acid transport [122]. Insulin, leptin and AMP-activated protein kinase (AMPK) activation can also rapidly induce translocation of FAT/CD36 from intracellular depots to the sarcolemma and increase fatty acid uptake [120]. Translocation of FAT/CD36 is also changed in a number of chronic pathological states. For instance, Luiken et al. [123] and Bonen et al. [124] demonstrated that in obese rats, as well as obese humans and type 2 diabetic patients, the rate of fatty acid transport is up-regulated, which is associated with increased translocation of FAT/ CD36 to the sarcolemmal membrane. Once transported into the cytosol, non-esteri fi ed fatty acid is esteri fi ed to long chain acyl CoA by fatty acyl CoA synthase (FACS) (Fig. 2). While the majority of the acyl groups on long chain acyl CoAs are destined for mitochondria for β -oxidation, a small portion of long chain acyl CoAs can be converted into intracellular lipid intermediates, such as TG, phospholipids, DAG, and ceramide. Theoretically, a decrease in fatty acid β -oxidation can lead to lipid accumulation. The acceleration of fatty acid β -oxidation may lessen the potential for insulin resistance. However, evidence on the role of fatty acid β oxidation in contributing to insulin-resistance is controversial [88, 125], as will be discussed later. Before undergoing β -oxidation, the acyl groups from long chain acyl-CoA must fi rst be transported across the mitochondrial outer and inner membranes. This process is facilitated by a carnitine-dependent transport system, which includes carnitine palmitoyl transferase-1 (CPT-1), carnitine translocase (CAT), and carnitine palmitoyl trans- ferase-2 (CPT-2) (Fig. 2). CPT-1, located on the outer membrane of mitochondria, is the key and rate-limiting enzyme involved in mitochondrial fatty acid uptake. CPT-1 catalyzes the reaction where long chain acyl CoA and carnitine react to form acylcarnitine. Acylcarnitine is then transported across the inner mitochondrial membrane by CAT. Once in the mitochondrial matrix, acylcarnitine is re-converted back to long chain acyl CoA and carnitine by CPT-2. Long chain acyl CoA then enters the β -oxidation pathway. As the enzyme of mitochondrial fatty acid uptake, CPT-1 is highly regulated. In both the heart and skeletal muscle, malonyl CoA is a key molecule responsible for regulation of CPT-1, since it is a potent allosteric inhibitor of CPT-1 [126]. As CPT-1 governs the entrance of long chain acyl CoA into the mitochondria, any changes in malonyl CoA concentration can alter mitochondrial uptake of fatty acid and consequently the rate of fatty acid oxidation in the mitochondria [127,128]. The concentration of malonyl CoA is controlled by its turnover, in which acetyl CoA carboxylase (ACC) catalyzes the synthesis pathway, and malonyl CoA decarboxylase (MCD) controls its degradation (Fig. 2). It is generally accepted that CPT-1 is the rate- limiting enzyme of mitochondrial fatty acid uptake [126,129,130]. However, recent studies suggest that this may not be the case as changes in long chain acyl CoA uptake and oxidation have been found to be independent of CPT-1 activity [131-134]. Two isoforms of ACC have been identi fi ed in the heart and skeletal muscle, ACC 1 (265 kDa) and ACC 2 (280 KDa), with ACC 2 predominating in both heart and skeletal muscle [135,136]. In ACC 2 de fi cient mice, marked increases in muscle fatty acid oxidation rates have been observed, indicating that ACC 2 is a key regulator of fatty acid oxidation in muscle [137]. A key determinant of ACC activity is the activity of AMP-activated protein kinase (AMPK). AMPK, also called the “ fuel sensor, ” is a serine/threonine kinase that responds to metabolic stresses with increased AMP/ATP and Cr/PCr ratios [138,139]. Insulin can also inhibit AMPK in the heart under conditions where the AMP/ATP and Cr/PCr ratios do not change [140]. AMPK is a heterotrimeric protein, consisting of an α catalytic subunit and β and γ regulatory subunits. AMPK is activated by phosphorylation of Thr172 on the catalytic α -subunit [138]. To date, AMPK kinases (AMPKKs) known to phosphorylate ...
Context 12
... the heart and skeletal muscle the two main sources of fatty acid in the blood are free fatty acid (FFA) bound to albumin derived from the lipolysis of adipose tissue, and FFA released from TG contained in chylomicrons and very low-density lipoprotein (VLDL) by lipoprotein lipase (LPL) (Fig. 2) [105,106]. LPL is highly expressed in the heart [107]. Fatty acids derived from the hydrolysis of TG by LPL have been suggested to be the principal source of fat for cardiac utilization [108]. Alteration of LPL can signi fi cantly impact myocardial fatty acid metabolism. Although data are variable, diabetes and insulin resistance are associated with increased LPL secretion [109]. Lipolysis of adipose tissue, which liberates FFA from adipocytes, plays another important regulatory role, especially in the skeletal muscle when chylomicron and VLDL levels decrease in post-absorptive state. Hormone-sensitive lipase (HSL), whose activity is dependent on the concentration of hormones, is the rate-limiting enzyme for adipose tissue lipolysis. Epinephrine can stimulate HSL by phosphorylation through the activation of cAMP dependent protein kinase [110], whereas insulin can inhibit HSL by dephosphorylating this enzyme [111]. Therefore, the amount of FFA release from lipolysis can vary largely depending on the balance between epinephrine stimulation and insulin inhibition. As will be discussed, it is our contention that alterations in fatty acid supply to heart and skeletal muscle are likely to be the major contributor to insulin resistance in muscle. The uptake of fatty acid into the heart and skeletal muscle is not yet fully understood. Passive diffusion was initially thought to be the main manner of fatty acid uptake into the heart and skeletal muscle, since the hydrophobic fatty acid can readily pass through the lipid bilayer of the sarcolemma [112]. However, many studies have demonstrated that a protein-mediated transport mechanism is involved, and this is the major pathway by which fatty acids traverse the sarcolemma [113]; thus uptake of fatty acids into the heart and skeletal muscle depends on both fatty acid concentration in the blood and the regulation of the transporters [114,115]. A number of fatty acid transporters have been identi fi ed, including fatty acid translocase (FAT)/CD36, plasma membrane-bound fatty acid binding protein (FABPpm), and the tissue-speci fi c fatty acid transport protein (FATP) family (FATP 1-6) (Fig. 2) [36,116,117]. The exact proportion each of these transporters contributes to fatty acid uptake is not clear, but FAT/CD36 is thought to be a predominant transporter, and is the one most studied. By either FAT/CD36 inhibition or CD36 deletion, it has been shown that 68% of the fatty acids taken up and oxidized by the heart occurs via this transporter [118-120]. In addition, these transporters may interact with each other to facilitate fatty acid uptake, as interactions between FAT/CD36 and FABPpm, and between FAT/CD36 and FATP have been identi fi ed in controlling fatty acid uptake [36,113,117,121]. It should also be noted that the sarcolemmal content of these transporters can rapidly change. Muscle contraction leads to the translocation of FAT/CD36 from intracellular depots to the sarcolemmal membrane and the subsequent up-regulation of fatty acid transport [122]. Insulin, leptin and AMP-activated protein kinase (AMPK) activation can also rapidly induce translocation of FAT/CD36 from intracellular depots to the sarcolemma and increase fatty acid uptake [120]. Translocation of FAT/CD36 is also changed in a number of chronic pathological states. For instance, Luiken et al. [123] and Bonen et al. [124] demonstrated that in obese rats, as well as obese humans and type 2 diabetic patients, the rate of fatty acid transport is up-regulated, which is associated with increased translocation of FAT/ CD36 to the sarcolemmal membrane. Once transported into the cytosol, non-esteri fi ed fatty acid is esteri fi ed to long chain acyl CoA by fatty acyl CoA synthase (FACS) (Fig. 2). While the majority of the acyl groups on long chain acyl CoAs are destined for mitochondria for β -oxidation, a small portion of long chain acyl CoAs can be converted into intracellular lipid intermediates, such as TG, phospholipids, DAG, and ceramide. Theoretically, a decrease in fatty acid β -oxidation can lead to lipid accumulation. The acceleration of fatty acid β -oxidation may lessen the potential for insulin resistance. However, evidence on the role of fatty acid β oxidation in contributing to insulin-resistance is controversial [88, 125], as will be discussed later. Before undergoing β -oxidation, the acyl groups from long chain acyl-CoA must fi rst be transported across the mitochondrial outer and inner membranes. This process is facilitated by a carnitine-dependent transport system, which includes carnitine palmitoyl transferase-1 (CPT-1), carnitine translocase (CAT), and carnitine palmitoyl trans- ferase-2 (CPT-2) (Fig. 2). CPT-1, located on the outer membrane of mitochondria, is the key and rate-limiting enzyme involved in mitochondrial fatty acid uptake. CPT-1 catalyzes the reaction where long chain acyl CoA and carnitine react to form acylcarnitine. Acylcarnitine is then transported across the inner mitochondrial membrane by CAT. Once in the mitochondrial matrix, acylcarnitine is re-converted back to long chain acyl CoA and carnitine by CPT-2. Long chain acyl CoA then enters the β -oxidation pathway. As the enzyme of mitochondrial fatty acid uptake, CPT-1 is highly regulated. In both the heart and skeletal muscle, malonyl CoA is a key molecule responsible for regulation of CPT-1, since it is a potent allosteric inhibitor of CPT-1 [126]. As CPT-1 governs the entrance of long chain acyl CoA into the mitochondria, any changes in malonyl CoA concentration can alter mitochondrial uptake of fatty acid and consequently the rate of fatty acid oxidation in the mitochondria [127,128]. The concentration of malonyl CoA is controlled by its turnover, in which acetyl CoA carboxylase (ACC) catalyzes the synthesis pathway, and malonyl CoA decarboxylase (MCD) controls its degradation (Fig. 2). It is generally accepted that CPT-1 is the rate- limiting enzyme of mitochondrial fatty acid uptake [126,129,130]. However, recent studies suggest that this may not be the case as changes in long chain acyl CoA uptake and oxidation have been found to be independent of CPT-1 activity [131-134]. Two isoforms of ACC have been identi fi ed in the heart and skeletal muscle, ACC 1 (265 kDa) and ACC 2 (280 KDa), with ACC 2 predominating in both heart and skeletal muscle [135,136]. In ACC 2 de fi cient mice, marked increases in muscle fatty acid oxidation rates have been observed, indicating that ACC 2 is a key regulator of fatty acid oxidation in muscle [137]. A key determinant of ACC activity is the activity of AMP-activated protein kinase (AMPK). AMPK, also called the “ fuel sensor, ” is a serine/threonine kinase that responds to metabolic stresses with increased AMP/ATP and Cr/PCr ratios [138,139]. Insulin can also inhibit AMPK in the heart under conditions where the AMP/ATP and Cr/PCr ratios do not change [140]. AMPK is a heterotrimeric protein, consisting of an α catalytic subunit and β and γ regulatory subunits. AMPK is activated by phosphorylation of Thr172 on the catalytic α -subunit [138]. To date, AMPK kinases (AMPKKs) known to phosphorylate Thr172 in mammalian cells include LKB1, the calmodulin-dependent protein kinase kinases (CaMKK), and TAK1 [138,141]. Recently, we identi fi ed the myosin light chain kinase (MLCK) as another potential AMPKK responsible for the activation of AMPK during cardiac ischemia (Jaswal et al., manuscript submitted). AMPK plays an important role in regulating fatty acid β -oxidation, as well as glucose uptake and glycolysis [142- 144]. In both the heart [145,146] and skeletal muscle [71,147], AMPK can phosphorylate and inactivate ACC, which relieves CPT-1 from malonyl CoA's inhibitory effect, resulting in a stimulation of fatty acid β -oxidation. In the rat heart we showed that AMPK is able to phosphorylate both ACC 1 and ACC 2, resulting in an almost complete loss of ACC activity [136,145]. Others also have shown that in both the heart and skeletal muscle, as a consequence of decreased ACC activity, malonyl CoA levels decrease and fatty acid β -oxidation rates increase [148-150]. AMPK and ACC phosphorylation are increased concurrently with a decline in malonyl CoA concentration and an increase in fatty acid β oxidation in rodents and humans [147,150-153]. In skeletal muscle, it has also been suggested that AMPK can directly activate MCD [154]. A number of studies have shown that in both the heart and skeletal muscle, conditions with increased fatty acid β -oxidation are associated with high MCD activity [155,156]. In contrast, MCD inhibition can decrease the contribution of fatty acid β -oxidation from 90% to 50% of total ATP production, with a concomitant increase in glucose oxidation. Using MCD inhibitors we have shown that in isolated working hearts perfused with high levels of fatty acid, pharmacological inhibition of MCD increases malonyl CoA levels, decreases fatty acid β -oxidation, and increases glucose oxidation up to 10 fold [157]. As will be discussed, this is actually associated with an increase in insulin sensitivity. AMPK is activated in skeletal muscle during exercise [158,159]. During moderate intensity exercise, skeletal muscle fatty acid oxidation increases. In rats, this increase is thought to be due to the activation of MCD by AMPK and a consequent decrease in malonyl CoA levels in the muscle during exercise [154]. However, during exercise of increasing intensity, fatty acid β -oxidation rates decrease or remain at a plateau in humans [160,161]. Although the mechanism has not yet been elucidated, AMPK plays an important role in regulating fatty acid β -oxidation during exercise. In ...
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Citations
... It is well-established, that obesity is associated with alterations in FAs metabolism, including partitioning between oxidation, storage, and changes in membrane structure, which in turn may affect the metabolic rate and initiate inflammatory processes (Zhang et al., 2010). Not surprisingly, in the present study, we noticed significant alterations in the composition of muscular PLs fraction under the FAs oversupply conditions. ...
Numerous strategies have been proposed to minimize obesity-associated health effects, among which phytocannabinoids appear to be effective and safe compounds. In particular, cannabigerol (CBG) emerges as a potent modulator of the composition of membrane phospholipids (PLs), which plays a critical role in the development of insulin resistance. Therefore, here we consider the role of CBG treatment on the composition of PLs fraction with particular emphasis on phospholipid subclasses (e.g., phosphatidylcholine (PC), phosphatidylethanolamine (PE), phosphatidylserine (PS), and phosphatidylinositol (PI)) in the red gastrocnemius muscle of Wistar rats fed the standard or high-fat, high-sucrose (HFHS) diet. The intramuscular PLs content was determined by gas-liquid chromatography and based on the composition of individual FAs, we assessed the stearoyl-CoA desaturase 1 (SCD1) index as well as the activity of n-3 and n-6 polyunsaturated fatty acids (PUFAs) pathways. Expression of various proteins engaged in the inflammatory pathway, FAs elongation, and desaturation processes was measured using Western blotting. Our research has demonstrated the important association of obesity with alterations in the composition of muscular PLs, which was significantly improved by CBG supplementation, enriching the lipid pools in n-3 PUFAs and decreasing the content of arachidonic acid (AA), which in turn influenced the activity of PUFAs pathways in various PLs subclasses. CBG also inhibited the local inflammation development and profoundly reduced the SCD1 activity. Collectively, restoring the PLs homeostasis of the myocyte membrane by CBG indicates its new potential medical application in the treatment of obesity-related metabolic disorders.
... Reducing cytoplasmic lipid accumulation is a primary function of sirtuin-induced fatty acid oxidation. Despite the promotion of fatty acid oxidation, muscle glucose metabolism may be disrupted [91]. Formononetin, known for its potent apoptotic-inducing properties, is also believed to have such characteristics [65,87]. ...
There are a wide variety of phytochemicals collectively known as polyphenols. Their structural diversity results in a broad range of characteristics and biological effects. Polyphenols can be found in a variety of foods and drinks, including fruits, cereals, tea, and coffee. Studies both in vitro and in vivo, as well as clinical trials, have shown that they possess potent antioxidant activities, numerous therapeutic effects, and health advantages. Dietary polyphenols have demonstrated the potential to prevent many health problems, including obesity, atherosclerosis, high blood sugar, diabetes, hypertension, cancer, and neurological diseases. In this paper, the protective effects of polyphenols and the mechanisms behind them are investigated in detail, citing the most recent available literature. This review aims to provide a comprehensive overview of the current knowledge on the role of polyphenols in preventing and managing chronic diseases. The cited publications are derived from in vitro, in vivo, and human-based studies and clinical trials. A more complete understanding of these naturally occurring metabolites will pave the way for the development of novel polyphenol-rich diet and drug development programs. This, in turn, provides further evidence of their health benefits.
... Two fatty acid metabolism pathways, butanoate metabolism, and mono-unsaturated fatty acid β oxidation were also associated with T2DM among PD patients. Higher levels of fatty acid metabolites can impact the severity of insulin resistance 65,66 . Fatty acid oxidation has been linked to PD onset and mild cognitive impairment in a previous metabolic study of PD patients 67 . ...
Type 2 diabetes mellitus (T2DM) is a common comorbidity among Parkinson’s disease (PD) patients. Yet, little is known about dysregulated pathways that are unique in PD patients with T2DM. We applied high-resolution metabolomic profiling in serum samples of 636 PD and 253 non-PD participants recruited from Central California. We conducted an initial discovery metabolome-wide association and pathway enrichment analysis. After adjusting for multiple testing, in positive (or negative) ion mode, 30 (25) metabolic features were associated with T2DM in both PD and non-PD participants, 162 (108) only in PD participants, and 32 (7) only in non-PD participants. Pathway enrichment analysis identified 17 enriched pathways associated with T2DM in both the PD and non-PD participants, 26 pathways only in PD participants, and 5 pathways only in non-PD participants. Several amino acid, nucleic acids, and fatty acid metabolisms were associated with T2DM only in the PD patient group suggesting a possible link between PD and T2DM.
... L-carnitine, an essential compound, plays vital roles in the body, particularly in energy metabolism [1][2][3]. Carnitine accumulates in skeletal muscle [4], and its primary role is to transport fatty acids (FAs) to the mitochondria, thereby contributing to the skeletal muscle energy supply [5,6]. Also, in cardiac muscle, the primary energy source of the human heart is free FAs, which are broken down by β-oxidation and enter the tricarboxylic acid (TCA) cycle, where they ultimately convert into adenosine triphosphate (ATP). ...
Introduction
L-carnitine exerts protective effects, such as maintaining mitochondrial functions and decreasing reactive oxygen species, while acylcarnitine (AC) is linked to the development of heart failure and atherosclerosis.
Hypothesis
Serum carnitines play important pathophysiological roles in cardiovascular diseases.
Methods
Pre-operative biochemical data were obtained from 117 patients (71 men, average age 69.9 years) who underwent surgery for cardiovascular diseases. Measurements included pre-operative biochemical data including estimated glomerular filtration rate (eGFR), physical functions, skeletal muscle mass index (SMI) measured by bioelectrical impedance analysis, anterior thigh muscle thickness (MTh) measured by ultrasound, and routine echocardiography. Carnitine components were measured with the enzyme cycling method. Muscle wasting was diagnosed based on the Asian Working Group for Sarcopenia criteria.
Results
Plasma brain natriuretic peptide (BNP) level was correlated with serum free carnitine (FC) and AC level, and the acylcarnitine/free carnitine ratio (AC/FC). AC/FC was elevated with stage of chronic kidney disease. In multivariate analysis, log (eGFR) and log (BNP) were extracted as independent factors to define log (serum AC) (eGFR: β = 0.258, p = 0.008; BNP: β = 0.273, p = 0.011), even if corrected for age, sex and body mass index. AC/FC was negatively correlated with hand-grip strength (r = -0.387, p = 0.006), SMI (r = -0.314, p = 0.012), and anterior thigh MTh (r = -0.340, p = 0.014) in men.
Conclusions
A significant association between serum AC level and AC/FC, and chronic kidney disease and heart failure exists in patients with cardiovascular diseases who have undergone cardiovascular surgery. Skeletal muscle loss and muscle wasting are also linked to the elevation of serum AC level and AC/FC.
... Normal cardiac function depends on adequate consumption of oxygen and oxidizable substrates with the ultimate goal of generating sufficient ATP via oxidative phosphorylation to meet the heart's energy demands (4). In the healthy, well-perfused heart, approximately 70%-90% of ATP is produced by the β-oxidation of fatty acids, with most of the remainder coming from glucose and lactate oxidation. ...
Introduction and objectives
Mitochondrial pyruvate carrier (MPC) mediates the entry of pyruvate into mitochondria, determining whether pyruvate is incorporated into the Krebs cycle or metabolized in the cytosol. In heart failure (HF), a large amount of pyruvate is metabolized to lactate in the cytosol rather than being oxidized inside the mitochondria. Thus, MPC activity or expression might play a key role in the fate of pyruvate during HF. The purpose of this work was to study the levels of the two subunits of this carrier, named MPC1 and MPC2, in human hearts with HF of different etiologies.
Methods
Protein and mRNA expression analyses were conducted in cardiac tissues from three donor groups: patients with HF with reduced ejection fraction (HFrEF) with ischemic cardiomyopathy (ICM) or idiopathic dilated cardiomyopathy (IDC), and donors without cardiac pathology (Control). MPC2 plasma levels were determined by ELISA.
Results
Significant reductions in the levels of MPC1, MPC2, and Sirtuin 3 (SIRT3) were observed in ICM patients compared with the levels in the Control group. However, no statistically significant differences were revealed in the analysis of MPC1 and MPC2 gene expression among the groups. Interestingly, Pyruvate dehydrogenase complex (PDH) subunits expression were increased in the ICM patients. In the case of IDC patients, a significant decrease in MPC1 was observed only when compared with the Control group. Notably, plasma MPC2 levels were found to be elevated in both disease groups compared with that in the Control group.
Conclusion
Decreases in MPC1 and/or MPC2 levels were detected in the cardiac tissues of HFrEF patients, with ischemic or idiopatic origen, indicating a potential reduction in mitochondrial pyruvate uptake in the heart, which could be linked to unfavorable clinical features.
... The absorbed metformin activates the phosphorylation of AMPK to improve glycemic control and IS, whereas the gut microenvironment-modulatory effect, especially the enrichment of Akkermansia, is attributed to the unabsorbed fraction (Foretz et al., 2023). According to our study, the absorbed baicalein mainly Maintaining the balance between lipogenesis and β-oxidation is essential for IS (Zhang, Keung et al., 2010). De novo lipogenesis, a process regulated by the energy sensor AMPK, increases lipid synthesis and accumulation in the liver, contributing to the development of insulin resistance. ...
Baicalein is a natural flavonoid abundant in various foods and dietary plants, including Tuber aestivum and Oroxylum indicum . In this study, we investigated the role of baicalein in enhancing the insulin‐sensitizing effect of metformin in mice with prediabetes. Baicalein, when combined with 25% of normal‐dose metformin, achieved a diabetes‐reversion rate of 80%, which was 1.86‐fold that of normal‐dose metformin. Mechanistically, baicalein enhanced the insulin‐sensitizing effect of metformin on lipid metabolism by inhibiting de novo lipogenesis through the AMP‐activated protein kinase/SREBP‐1c/FASN pathway and by inducing fatty‐acid β‐oxidation through the upregulation of ACSL1, CPT1A , EHHADH , and acyl‐CoA dehydrogenases (ACADL/ACADM/ACADS). Meanwhile, baicalein enhanced the insulin‐sensitizing effect of metformin via the modulation of the gut microenvironment by enriching probiotics, especially Akkermansia by 53.4‐fold, depleting opportunistic pathogens, and strengthening the intestinal barrier. The improved gut microenvironment led to the alleviation of chronic endotoxemia, as evidenced by decreased levels of lipopolysaccharide and proinflammatory cytokines. Furthermore, baicalein enhanced the effect of metformin on decreasing the circulating level of branched‐chain amino acids (BCAAs), which further improved insulin sensitivity by normalizing the mTORC1/p70S6K/IRS1 signaling pathway and de novo lipogenesis. Moreover, the role of baicalein in enhancing the insulin‐sensitizing effect of metformin was verified by an oleic acid‐induced steatosis model and a BCAA‐induced insulin resistance model in hepatocytes. Our study laid a theoretical foundation for developing baicalein into a dietary supplement for diabetes prevention. The diverse mechanisms of food‐derived flavonoids can be applied in the development of dietary supplements to enhance the efficacy of oral hyperglycemic agents currently used in clinics.
... 21 The mechanism involving JNK1 in MIR is explained by inhibition of insulin signaling mediated by serine-307 phosphorylation of IRS-1. 22 Another key point in triggering MIR by increased JNK1 arising from increased macrophage concentration in myocardial tissue. ...
Background: Low availability of Glut-4 transporters in the sarcolemma of cardiac cells characterizes myocardial insulin resistance (MIR), which is triggered separately from generalized insulin resistance. Insulin receptors are quite evident in the heart muscle and vessels, and mitochondrial activity performs a significant role in MIR preserving cellular homeostasis through cell reproduction, cells livelihoods, and energy generation. Objective: To evaluate the MIR mechanism and its association with hypertension by signaling pathways design. Methods: PubMed database was employed to search for reviews publications with MIR. The referenced data of the signaling pathway was chosen by aggregating references from the Kyoto Encyclopedia of Genes and Genomes (KEGG) database. A signaling pathway was designed based on MIR research manuscripts, where we show several mechanisms included in the MIR. The KEGG server was employed to exploit the interrelationship protein-protein, and elaborate signaling pathway diagram. The signaling pathway mapping was carried out with PathVisio software. Results: We selected 42 articles from a total of 450 articles in the PubMed database that presented a significant association between the terms “insulin resistance myocardial” AND “signaling pathway” AND “systemic arterial hypertension”. Founded on database-validated research papers, we chose well-founded pathways and we succeeded in representative description of these pathways. The reproduction contigs taken from the KEGG database designed the signaling pathway of the bio-molecules that lead to MIR. Thus, the acting among multiple mechanisms releases factors that participate in the development of MIR. Conclusion: The interaction among various mechanisms and molecular interactions are important factors in developing MIR.
... The adult heart obtains 50-70% of its energy through the β-oxidation of fatty acids in the mitochondria of cardiac cells [72]. Depending on nutrient availability, the myocardium can dynamically switch from the preferential use of lipids to glucose as an energy resource to maintain stable ATP production. ...
In the last few years, the use of anesthetic drugs has been related to effects other than those initially related to their fundamental effect, hypnosis. Halogenated anesthetics, mainly sevoflurane, have been used as a therapeutic tool in patients undergoing cardiac surgery, thanks to the beneficial effect of the cardiac protection they generate. This effect has been described in several research studies. The mechanism by which they produce this effect has been associated with the effects generated by anesthetic preconditioning and postconditioning. The mechanisms by which these effects are induced are directly related to the modulation of oxidative stress and the cellular damage generated by the ischemia/reperfusion procedure through the overexpression of different enzymes, most of them included in the Reperfusion Injury Salvage Kinase (RISK) and the Survivor Activating Factor Enhancement (SAFE) pathways. Mitochondria is the final target of the different routes of pre- and post-anesthetic conditioning, and it is preserved from the damage generated in moments of lack of oxygen and after the recovery of the normal oxygen concentration. The final consequence of this effect has been related to better cardiac function in this type of patient, with less myocardial damage, less need for inotropic drugs to achieve normal myocardial function, and a shorter hospital stay in intensive care units. The mechanisms through which mitochondrial homeostasis is maintained and its relationship with the clinical effect are the basis of our review. From a translational perspective, we provide information regarding mitochondrial physiology and physiopathology in cardiac failure and the role of halogenated anesthetics in modulating oxidative stress and inducing myocardial conditioning.
... Sirtuin-induced fatty acid oxidation is important, because it lowers cytoplasmic lipid accumulation. However, elevated fatty acid oxidation could interfere with glucose metabolism in the muscle [202]. In addition, formononetin is considered as a strong apoptotic inducer [198]. ...
The clinical relationship between diabetes and inflammation is well-established. Various branches of science independently have confirmed that disrupting oxidant-antioxidant equilibrium and elevated lipid peroxidation could be a potential mechanism for chronic kidney disease associated with Type 2 diabetes mellitus (T2DM). Under diabetic condition, hyperglycemia, especially inflammation, and increased reactive oxygen species generation are bidirectionally associated. Inflammation, oxidative stress and tissue damage are believed to have a role in the development of diabetes. Although the exact mechanism underlying the oxidative stress and its impact on diabetes progression remains uncertain, the hyperglycemia-inflammation-oxidative stress interaction clearly plays a significant role in onset and progression of vascular disease, kidney disease, hepatic injury, pancreas damage and, therefore holds promise as a therapeutic target. Evidence strongly indicates that the use of multiple antidiabetic medications therapy fails to achieve the normal range for glycated hemoglobin target, signifying treatment resistant diabetes. Antioxidants with polyphenols are considered useful as adjuvant therapy for their potential anti-inflammatory effect and antioxidant activity. We aimed to analyze the current major points reported in preclinical in vivo and clinical studies of antioxidants in the prevention or treatment of inflammation in T2DM. Then, we will share our speculative vision of the future diabetes clinical trials.
... Within the cycling events of this positive feedback system are sustained systemic pro-oxidative/pro-inflammatory activities that potentiate cardiovascular disease. References for Figure 5: a [94,188,[367][368][369][370][371][372][373]; b [186,187,[293][294][295]349,[374][375][376][377][378][379]; c [141,142,149,155,179,380,381]; d [312,313,340,[382][383][384][385][386][387][388][389][390][391][392], e [305,[393][394][395][396][397][398], f [394,395]; g [305,399,400]; h [401][402][403]; i [403,404]; j [141,142,381]; k [405]; l [188,[406][407][408][409][410][411][412]; m [94,185,188,189,297,[344][345][346]375,[413][414][415][416][417][418][419]; n [420][421][422][423][424][425]; o [426,427]; p [179,392,[428][429][430][431][432][433][434][435][436][437][438][439][440][441][442]. ...
Despite enormous global efforts within clinical research and medical practice to reduce cardiovascular disease(s) (CVD), it still remains the leading cause of death worldwide. While genetic factors clearly contribute to CVD etiology, the preponderance of epidemiological data indicate that a major common denominator among diverse ethnic populations from around the world contributing to CVD is the composite of Western lifestyle cofactors, particularly Western diets (high saturated fat/simple sugar [particularly high fructose and sucrose and to a lesser extent glucose] diets), psychosocial stress, depression, and altered sleep/wake architecture. Such Western lifestyle cofactors are potent drivers for the increased risk of metabolic syndrome and its attendant downstream CVD. The central nervous system (CNS) evolved to respond to and anticipate changes in the external (and internal) environment to adapt survival mechanisms to perceived stresses (challenges to normal biological function), including the aforementioned Western lifestyle cofactors. Within the CNS of vertebrates in the wild, the biological clock circuitry surveils the environment and has evolved mechanisms for the induction of the obese, insulin-resistant state as a survival mechanism against an anticipated ensuing season of low/no food availability. The peripheral tissues utilize fat as an energy source under muscle insulin resistance, while increased hepatic insulin resistance more readily supplies glucose to the brain. This neural clock function also orchestrates the reversal of the obese, insulin-resistant condition when the low food availability season ends. The circadian neural network that produces these seasonal shifts in metabolism is also responsive to Western lifestyle stressors that drive the CNS clock into survival mode. A major component of this natural or Western lifestyle stressor-induced CNS clock neurophysiological shift potentiating the obese, insulin-resistant state is a diminution of the circadian peak of dopaminergic input activity to the pacemaker clock center, suprachiasmatic nucleus. Pharmacologically preventing this loss of circadian peak dopaminergic activity both prevents and reverses existing metabolic syndrome in a wide variety of animal models of the disorder, including high fat-fed animals. Clinically, across a variety of different study designs, circadian-timed bromocriptine-QR (quick release) (a unique formulation of micronized bromocriptine—a dopamine D2 receptor agonist) therapy of type 2 diabetes subjects improved hyperglycemia, hyperlipidemia, hypertension, immune sterile inflammation, and/or adverse cardiovascular event rate. The present review details the seminal circadian science investigations delineating important roles for CNS circadian peak dopaminergic activity in the regulation of peripheral fuel metabolism and cardiovascular biology and also summarizes the clinical study findings of bromocriptine-QR therapy on cardiometabolic outcomes in type 2 diabetes subjects.
