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Cardiovascular Research 2007 73(2):278-287; doi:10.1016/j.cardiores.2006.10.008
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Copyright © 2006, European Society of Cardiology

Role of malonyl-CoA in heart disease and the hypothalamic control of obesity

Clifford D.L. Folmes and Gary D. Lopaschuk*

Cardiovascular Research Group, University of Alberta, Edmonton, Alberta, Canada

* Corresponding author. 423 Heritage Medical Research Centre, University of Alberta, Edmonton, Alberta, Canada T6G 2S2. Tel.: +1 780 492 2170; fax: +1 780 492 9753. Email address: gary.lopaschuk{at}ualberta.ca

Received 7 July 2006; revised 13 October 2006; accepted 16 October 2006


   Abstract
Top
 Abstract
1. Introduction
 2. Regulation of cardiac...
 3. Regulation of food...
 4. Conclusions
 References
 
Obesity is an important contributor to the risk of developing insulin resistance, diabetes, and heart disease. Alterations in tissue levels of malonyl-CoA have the potential to impact on the severity of a number of these disorders. This review will focus on the emerging role of malonyl-CoA as a key "metabolic effector" of both obesity and cardiac fatty acid oxidation. In addition to being a substrate for fatty acid biosynthesis, malonyl-CoA is a potent inhibitor of mitochondrial carnitine palmitoyltransferase (CPT) 1, a key enzyme involved in mitochondrial fatty acid uptake. A decrease in myocardial malonyl-CoA levels and an increase in CPT1 activity contribute to an increase in cardiac fatty acid oxidation. An increase in malonyl-CoA degradation due to increased malonyl-CoA decarboxylase (MCD) activity may be one mechanism responsible for this decrease in malonyl-CoA. Another mechanism involves the inhibition of acetyl-CoA carboxylase (ACC) synthesis of malonyl-CoA, due to AMP-activated protein kinase (AMPK) phosphorylation of ACC. Recent studies have demonstrated a role of malonyl-CoA in the hypothalamus as a regulator of food intake. Increases in hypothalamic malonyl-CoA and inhibition of CPT1 are associated with a decrease in food intake in mice and rats, while a decrease in hypothalamic malonyl-CoA increases food intake and weight gain. The exact mechanism(s) responsible for these effects of malonyl-CoA are not clear, but have been proposed to be due to an increase in the levels of long chain acyl CoA, which occurs as a result of malonyl-CoA inhibition of CPT1. Both hypothalamic and cardiac studies have demonstrated that control of malonyl-CoA levels has an important impact on obesity and heart disease. Targeting enzymes that control malonyl-CoA levels may be an important therapeutic approach to treating heart disease and obesity.

KEYWORDS Malonyl-CoA; Fatty acid oxidation; Carnitine palmitoyltransferase 1; Malonyl-CoA decarboxylase; AMP-activated protein kinase; Acetyl-CoA carboxylase


   1. Introduction
Top
 Abstract
 1. Introduction
2. Regulation of cardiac...
 3. Regulation of food...
 4. Conclusions
 References
 
Diabetes mellitus is a major health concern, with the incidence growing at a rate of 6% annually [1]. A dramatic rise in the incidence and severity of obesity is a major reason for this rise in diabetes prevalence [1]. This increase in obesity and diabetes is disconcerting, since these conditions are associated with a high incidence of morbidity and mortality, with heart diseases being a major cause of death in diabetics [2–4]. The high risk for heart disease is due both to a high incidence of coronary artery disease and hypertension in the diabetic, as well as the development of cardiomyopathies that occur independent of these risk factors [5,6]. The prevalence of diastolic dysfunction even in young normotensive diabetic patients is also alarming high [7,8]. The exact cause for cardiac dysfunction during disease is not completely understood. One contributing factor is alteration in cardiac fatty acid metabolism, which contributes to abnormal cardiac function in the diabetic, as well as to the degree of muscle injury during and following myocardial ischemia.

Despite that fact that there are numerous contributing factors to the severity of obesity and abnormal cardiac fatty acid metabolism, of interest for this review is that alterations in the control of tissue levels of malonyl-CoA has emerged as an important contributor to both obesity and heart disease. Malonyl-CoA has long been recognized as an important precursor of fatty acid biosynthesis in lipogenic tissues such as the liver and has an important role in regulating fatty acid oxidation in heart and skeletal muscle. Malonyl-CoA has also recently emerged as an important regulator of food intake and energy balance. This review will focus on the role of malonyl-CoA as a regulator of cardiac fatty acid oxidation and its role in regulating food intake and energy balance.


   2. Regulation of cardiac energy metabolism by malonyl-CoA
Top
 Abstract
 1. Introduction
 2. Regulation of cardiac...
3. Regulation of food...
 4. Conclusions
 References
 
Malonyl-CoA is a key regulator of fatty acid oxidation in the heart. It is a potent inhibitor of carnitine palmitoyltransferase (CPT1), a key enzyme involved in the mitochondrial uptake of fatty acids (Fig. 1). As a result, a rise in cardiac malonyl-CoA levels results in a decrease in mitochondrial fatty acid uptake and oxidation, while a decrease in malonyl-CoA results in an increase in fatty acid oxidation [9–16]. Because of these important metabolic effects, malonyl-CoA levels in the heart are highly regulated. Malonyl-CoA is synthesized by the carboxylation of acetyl-CoA by acetyl-CoA carboxylase (ACC) [9–12] and degraded to acetyl-CoA and carbon dioxide by malonyl-CoA decarboxylase (MCD) (Fig. 1) [13–16]. The synthesis and degradation of malonyl-CoA is important in the control of its steady state level, as its half-life is only 1.25 min [17].


Figure 1
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  		Fig. 1 Enzymatic pathways involved in the regulation of malonyl-CoA control of cardiac fatty acid oxidation. ACC, acetyl-CoA carboxylase: ACS, acyl-CoA synthetase: AMPK, AMP-activated protein kinase: AMPKK, AMP-activated protein kinase kinase: CPT-1/2, carnitine palmitoyl transferase: MCD, malonyl-CoA decarboxylase.

 
ACC activity is dependent on the supply of its substrate, acetyl-CoA and its phosphorylation status at ser79 or ser219 for the ACC265 and ACC280 isoforms, respectively. Our laboratory has shown that in isolated working rat hearts, not only does ACC co-purify with the {alpha}2 catalytic subunit of AMP-activated protein kinase (AMPK), but AMPK can phosphorylate and inactivate both isoforms of ACC, resulting in an almost complete loss of activity [18,19]. Thus, an activation of AMPK results in an decrease in cytosolic malonyl-CoA concentrations and an acceleration of fatty acid oxidation (see Ref. [20] for a review).

MCD catalyzes the decarboxylation of malonyl-CoA, and thus has been proposed to play an important role in the regulation of myocardial fatty acid oxidation. Generally in situations where MCD activity is elevated, malonyl-CoA content is low, which results in elevated rates of fatty acid oxidation [9–16]. While MCD is found in many compartments, including mitochondria, peroxisomes and cytosol [21] it appears that MCD plays an important role in the regulation of cytoplasmic malonyl CoA levels, and therefore fatty acid oxidation, and patients with MCD deficiencies have phenotypes consistent with alterations in fatty acid oxidation [22,23].

2.1. Modulation of cardiac energy metabolism by malonyl-CoA
In order to meet the high energy demands of contraction and ionic homeostasis, the heart must produce a constant and abundant supply of ATP by metabolizing a variety of carbon substrates including carbohydrates (glucose, lactate, and pyruvate), fatty acids and ketone bodies [24,25]. Fatty acids are normally the primary energy substrate of the heart, and are supplied to the heart either as free fatty acids bound to albumin or as fatty acids within triacylglycerols (TG) present within chylomicrons or VLDL [26]. The amount of fatty acids utilized by the heart depends on a number of factors, including the supply of fatty acids to the heart and subcellular alterations in the control of fatty acid metabolism. For instance, an increase in plasma fatty acids, such as can occur in diabetes, increases the contribution of fatty acids to overall energy metabolism, with a reciprocal decrease in glycolysis and glucose oxidation in the heart. Malonyl-CoA control of mitochondrial uptake of fatty acids at the level of CPT1 is another key site of regulation [27,28]. The role of malonyl-CoA in controlling fatty acid oxidation in diabetic patients will be discussed later in this review. Also of relevance is the role of malonyl-CoA in controlling fatty acid oxidation during and following myocardial ischemia.

2.2. Regulation of cardiac fatty acid oxidation during ischemia and reperfusion
Inadequate supply of oxygen during myocardial ischemia results in a reduction in the oxidative metabolism of both carbohydrates and fatty acids, and an impairment of ATP production [25]. As glucose oxidation is inhibited, pyruvate normally metabolized in the mitochondria is converted to lactate to preserve enough oxidized NAD+ to sustain flux through glycolysis. This uncoupling of glycolysis from glucose oxidation is associated with an increase in cytosolic protons, resulting in intracellular acidosis [29–31].

When reperfusion of reversibly injured myocardium occurs, a rapid recovery of oxygen consumption and TCA cycle activity leads to a replenishment of the supply of ATP [30,32,33]. During this reperfusion period, fatty acids can provide over 90% of the myocardium's energy requirement [33,34]. This excessive use of fatty acids is due, in part, to an increase in the levels of circulating fatty acids and to a decrease in the cytosolic malonyl-CoA levels. The decrease in malonyl-CoA is associated with an increase in mitochondrial fatty acid uptake and oxidation [11,32,33,35]. The reduction in malonyl-CoA is due to the ischemia-induced activation of AMPK [36]. AMPK can phosphorylate the heart isoform of ACC on Ser227, resulting to an inactivation of the enzyme [19]. As MCD activity is preserved during reperfusion, there is a reduction in malonyl-CoA levels, a stimulation of fatty acid oxidation and impairment in the recovery of glucose oxidation.

The net consequence of ischemic-induced decreases in malonyl-CoA levels is an increase in the contribution of fatty acid oxidation to overall mitochondrial oxidative metabolism, with a resultant decrease in glucose oxidation. The resultant uncoupling of glycolysis from glucose oxidation results in the production of protons that can lead to the accumulation of sodium and calcium [37]. This can lead to a decrease cardiac efficiency, as well as an increase cell injury and death. It should be noted, however, that not all studies have shown that fatty acid oxidation is accelerated during reperfusion following ischemia. Measurements of fatty acid oxidation in both regionally ischemic hearts [38], in isolated hearts [39,40] and patients [41] have shown that rates can either be unchanged or actually decreased. However, whether this occurred secondary to a decrease in contractile function is not clear. A study by Van de Velde et al. demonstrated in chronically instrumented dogs raising plasma fatty acid levels following LAD coronary artery occlusion could actually improve systolic wall thickening fraction compared to baseline and that this effect was blocked with oxfenicine, a partial fatty acid oxidation blocker however direct measurement of fatty acid oxidation was not performed in this study. This observation is at odds with a large literature which suggests that inhibiting fatty acid oxidation, and hence stimulating glucose oxidation (by the Randle Cycle) is beneficial to the recovery of mechanical function following an ischemic bout (see Ref. [42] for review). This discrepancy may be accounted for by the time frame which the fatty acid levels are modified, as it is typically considered that the most critical time for reperfusion is the first few minutes, thus supplying the heart with more fatty acid 15 min following reperfusion would supply the heart with additional substrate.

Because of the negative consequences of a decrease in cardiac malonyl-CoA levels and increases in fatty acid oxidation during and following ischemia as well as the literature that suggests that partial inhibition of fatty acid oxidation is beneficial, a potential therapeutic approach to treating ischemia is to increase cardiac malonyl-CoA levels. One approach to doing this is to inhibit malonyl-CoA degradation at the level of MCD. Recently, potent MCD inhibitors (CBM-300864 and CBM-301940) have been developed and used to directly determine the role of malonyl-CoA in the metabolic modifications that occur during ischemia and reperfusion [13]. Addition of these inhibitors to aerobically perfused rat hearts resulted in a 7-fold increase in malonyl-CoA levels, which is associated with a partial inhibition of fatty acid oxidation, acceleration of glucose oxidation and maintained glycolytic rates [13]. As predicted based upon the above discussion, MCD inhibition was shown to be beneficial in a number of ischemia/reperfusion models. In isolated working rat hearts subjected to 30 min of global no-flow ischemia and 60 min of reperfusion, MCD inhibition significantly improved cardiac function, associated with a significant increase in glucose oxidation during reperfusion [13]. Post-ischemic cardiac function was improved whether the inhibitors were added prior to ischemia or at the beginning of reperfusion, suggesting that the majority of the benefit of MCD inhibition occurred during reperfusion. Inhibition of MCD also plays an important role during ischemia as observed in an in vivo porcine model of demand-induced ischemia.[13] In this model left anterior descending flow was decreased by 20% followed by a dobutamine stimulation of heart rate and contractility without a change in myocardial oxygen consumption. Inhibition of MCD resulted in a significant increase in malonyl-CoA levels, a doubling of glucose oxidation rates and a significant decrease in lactate production. As a result, cardiac function was improved in treated hearts. These observations were similar in an isolated working rat heart model of mild ischemia, where coronary flow was reduced by 35% of aerobic values for 30 min. Inhibition of MCD shifts residual oxidative metabolism from fatty acid oxidation to glucose oxidation, implying the importance of malonyl-CoA in substrate selection (unpublished data). This shift in oxidative metabolism improves the coupling of glucose metabolism and hence reduced the proton production in the inhibitor treated hearts.

Studies showing ischemic cardioprotection using MCD inhibitors have been confirmed using MCD null mice. If isolated working hearts from mice in which MCD is deleted are subjected to ischemia, a marked cardioprotection is observed [43]. Taken together, these studies suggest that MCD is an important regulator of cardiac fatty acid oxidation in the heart and that pharmacological inhibition of MCD may be beneficial in the treatment of ischemic heart disease. Despite the many studies looking at malonyl-CoA in acute ischemic heart disease; there is little knowledge about the role of malonyl-CoA in chronic ischemic heart disease, and the transition to heart failure.

2.3. Modulation of cardiac fatty acid metabolism in diabetes and obesity
In uncontrolled diabetics, myocardial glucose use is reduced and fatty acid oxidation accounts for most of the catabolic myocardial oxygen consumption.[44–48] This is due in part to a decrease in the number and transport of GLUT 4 to the sarcolemmal membrane. However, a major reason for the decrease in glucose metabolism is the elevated levels of plasma fatty acids seen in the diabetic [45]. Use of fatty acids for mitochondrial oxidative metabolism decreases the activity of pyruvate dehydrogenase and phosphofructokinase 1, key enzymes in glucose oxidation and glycolysis, respectively [45,49,50].

While high circulating levels of fatty acids in the diabetic decrease glucose metabolism, it is clear that other metabolic changes in the heart are also responsible for low rates of glucose metabolism [45,50]. This is supported by the observation that glucose oxidation rates are significantly lower in diabetic rat hearts compared to control hearts, even if hearts are exposed to similar concentrations of fatty acids [46,47,51]. Therefore, it is the combination of high levels of circulating fatty acids and direct alterations in insulin control of fatty acid and glucose oxidation that result in the diabetic rat heart becoming almost entirely dependent on fatty acid oxidation for its energy requirements [44,46,50–52]. We have shown that AMPK activation in streptozotocin diabetic rat hearts is an important mechanism responsible for the increase in fatty acid oxidation rates [53,54]. In addition during diabetes, an increased activity and expression of MCD contributes to the high rates of fatty acid oxidation [47].

Exposure of the heart to high levels of fatty acids also have the potential to result in the accumulation of fatty acids within the myocardium. This accumulation of lipids, has been termed "cardiac lipotoxicity" [55–57]. Excessive accumulation of lipids within non-adipose tissue increases the intracellular pool of long chain fatty acyl CoA, thereby providing fatty acid substrate for non-oxidative processes, including triacylglycerol and diacylglycerol synthesis [55,58–60]. This can lead to cell dysfunction, insulin-resistance and potentially cell death through apoptosis. The potential for lipotoxicity in obesity and insulin-resistance has also recently been described [55,60,61]. A marked accumulation of triacylglycerol occurs within the myocardium of obese and insulin-resistant rats, which is associated with the development of contractile dysfunction [62,63]. We have also shown that insulin-resistant rat hearts have elevated levels of triacylglycerol, which is associated with a decrease in glucose uptake and glycolysis [64,65]. However, presently there is a confusion as to the relative importance of an increase in fatty acid supply versus a decrease in fatty acid oxidative capacity as the major contributor to lipotoxicity. Several studies have implicated a suppression of fatty oxidation as the contributing factor for the accumulation of triacylglycerol and overall lipotoxicity in obesity, insulin resistance and diabetes. In obesity, Roger Unger's group has implicated a downregulation of PPAR{alpha} and an underexpression of fatty acid oxidative enzymes as contributing to lipotoxic heart disease [55]. Young et al. have also suggested that an impairment of myocardial fatty acid oxidation during obesity, insulin-resistance and diabetes may also accelerate contractile dysfunction, due in part to a decrease in PPAR{alpha} responsiveness [66,67]. In support of this Oakes et al. showed using in vivo tracers methods that the average level of cardiac fatty acid oxidation is comparable in ob/ob mice and normal animals [68]. Using 123I-heptadecanoic acid Turpeinen et al. observed that patients with non-insulin dependent diabetes had lowered fatty acid uptake and oxidation, while patients with insulin-dependent diabetes has similar fatty acid kinetics to normal subjects [69]. However recent experimental [51,70–73] and clinical studies [74] have shown that fatty acid oxidation is increased in obesity and insulin-resistance. Using positron emission tomography (PET) and 11C-palmitate imaging, elegant studies by Linda Peterson [74] and Robert Gropler have shown that obese women and type 2 diabetics have an increased uptake and oxidation of fatty acids. Studies using isolated working hearts from obese insulin resistant ob/ob and db/db mice have shown that fatty acid oxidation rates are also elevated [51,70–72]. This increase in fatty acid oxidation is paralleled by a decrease in glucose oxidation and glycolysis, as well as a decrease in cardiac efficiency. These recent studies in mice, parallel studies we performed in obese insulin-resistant JCR/LA rats, in which an increase in fatty acid oxidation contribution to energy production was observed [73]. We have also shown that in mice fed a high fat diet, fatty acid oxidation rates increase in the heart. This is associated with a decrease in insulin-sensitive glucose oxidation. In these high fat fed mice, a significant decrease in cardiac malonyl-CoA levels is observed, which appears to be related to an increase in MCD expression (unpublished data).

Combined, studies to date suggest that there is controversy over whether cardiac fatty acid oxidation rates are increased, or decreased, in obesity, insulin-resistance and type 2 diabetes. Data does suggest, however, that a decrease in malonyl-CoA control of fatty acid oxidation contributes to the observed high fatty acid oxidation rates.

2.4. Ischemic tolerance of the diabetic heart
Epidemiological data and clinical studies have convincingly demonstrated that diabetic patients have increased susceptibility to ischemic injury, as diabetics have increased incidence of atherosclerosis but there are additional important nonvascular components [2,3]. For example, complications of acute myocardial infarction are greater in the diabetic despite having the same size or even smaller infarcts [75,76]. Despite this evidence there has been less consensus in experimental studies as to whether changes in the diabetic heart can modify the severity of ischemic damage. In vitro studies in diabetic rat hearts have shown that when subjected to anoxia or low flow ischemia, these hearts are more sensitive to ischemic injury when compared to control hearts [77–79]. In contrast, a number of studies have shown that diabetic rat hearts will recover to the same degree or even better when subjected to a severe degree of ischemia (no-flow or very low flow) [80,81]. Other studies have shown that diabetic rat hearts can have suppressed function following severe ischemia [82]. It appears that the increased sensitivity of the diabetic heart during hypoxia or mild ischemia is due to a decrease in glucose uptake and metabolism, while the diabetic heart is less sensitive to severe ischemia due to a decrease in the accumulation of glycolytic byproducts and changes in the control of intracellular pH (see Refs. [82,83] for reviews).


   3. Regulation of food intake and obesity by hypothalamic malonyl-CoA
Top
 Abstract
 1. Introduction
 2. Regulation of cardiac...
 3. Regulation of food...
4. Conclusions
 References
 
3.1. Metabolic signaling in the hypothalamic control of energy balance in obesity and insulin-resistance
Hypothalamic control of energy balance plays a central role in the development of obesity [84–86]. This has resulted in a major research effort to understand how hypothalamic neuronal signaling controls both food intake and peripheral energy expenditure (see Refs. [84–86] for reviews). The involvement of anorexigenic and orexigenic signaling pathways in the arcuate nucleus (AN) and paraventricular nucleus (PVN) of the hypothalamus have been well defined. The involvement of several anoxerigenic hormones (leptin, adiponectin, insulin, glucagon-like peptide 1 (GLP-1), glucose, fatty acids, lactate, pyruvate, amino acids, histamine, melanocyte stimulating hormone, and {alpha}-lipoic acid) and oxerigenic hormones on these pathways have also been shown (ghrelin, cannabinoids) [86–91]. These diverse and complex signals converge on neurons in the AN, including neuropeptide Y (NPY)/agouti-related protein (AGRP) neurons and pro-opiomelanocortin (POMC)/cocaine-ampthetamine-related transcript (CART) neurons [86,91].

The hypothalamus not only plays an important role in regulating food intake, but also an important function in central control of peripheral energy expenditure, body fat content, and hepatic glucose production. For example, insulin can act at the level of the hypothalamus to decrease hepatic glucose production [86,92,93]. Glucose sensing neurons in the hypothalamus can also detect hypoglycemia and result in an increase in hepatic glucose production. It is also apparent that a number of anoxerigenic peptides and substances, such as leptin, adiponectin and {alpha}-lipoic acid can increase peripheral energy expenditure [93–95]. This involves CNS sympathetic neuronal control of muscle, liver and adipose tissue function, as well as central mediated alterations in muscle metabolic enzymes (i.e. such as mitochondrial uncoupling proteins in muscle) [93–95].

3.2. Regulation of energy balance by hypothalamic AMPK
Recently, it has become evident that enzymes and metabolites that have important roles in regulating muscle energy metabolism, may also have an important function in controlling hypothalamic function. For instance, the well established anorexic effects of leptin have recently been shown by a number of groups to involve inhibition of hypothalamic AMPK (Fig. 2) [91,94,96–98] Anorexic actions of leptin and {alpha}-lipoic acid have also been shown to inhibit hypothalamic AMPK, while the orexigenic actions of ghrelin are accompanied by activation of hypothalamic AMPK (Fig. 2) [91,94,96–98]. In support of this, icv injection of either AMPK agonists or adenovirus containing constitutively active AMPK in mice promotes food intake [91,97,98]. In addition, the orexigenic actions of endocannabinoids such as {delta}9-tetrahydrocannabinol have recently been shown to be accompanied by an increase in hypothalamic AMPK activity (Fig. 2) [99]. It has been proposed that decreased AMPK activity enhances the suppression of AN NPY/AGRP signaling neurons, resulting in an enhancement of melanocortin receptor (MC4R) inhibition of AMPK in the PVN [91]. The mechanism by which AMPK achieves this is not clear, but one possibility is via inhibition of acetyl-CoA carboxylase (ACC), resulting in a decrease in hypothalamic malonyl-CoA. The role of hypothalamic AMPK in regulating food intake fits with the concept of AMPK being a "fuel gauge", with activation of AMPK in times of metabolic stress promoting food intake.


Figure 2
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  		Fig. 2 Potential role of malonyl-CoA in the pathogenesis of ischemia-reperfusion injury in the heart. LDH, lactate dehydrogenase: NCX, sodium calcium exchanger: NHE, sodium hydrogen exchanger: PDH, pyruvate dehydrogenase.

 
Nutrient sensing in food intake regulation may also involve AMPK. Nutrients such as glucose, amino acids, fatty acids, and pyruvate can signal the hypothalamus to decrease food intake [100,101]. This involves complex signaling pathways involving NPY/AGRP and POMC/CART neurons in the AN. A recent study by Lee et al. [101] showed that inhibition of hypothalamic glucose utilization with 2-deoxyglucose results in an activation of AMPK, while administration of pyruvate decreases AMPK activity. These authors proposed that low neuronal cell ATP levels can trigger a cascade of events via AMPK-mediated events to increase food intake. Low hypothalamic ATP also negatively correlates with the expression of AGRP expression. As a result, hypothalamic neuronal cell energy status may activate AMPK, which then modulates NPY and AGRP expression and subsequent food intake.

AMPK may also be involved in hypothalamic control of peripheral glucose metabolism. The ventromedial hypothalamus (VMH) appears to play a critical role in hypoglycemia sensing [98,100,101]. Specialized glucose-sensing neurons that can be stimulated by glucose have been localized to the VMH. A role of hypothalamic AMPK in hypoglycemia sensing has recently been proposed by McCrimmon et al. [98].

Insulin and insulin-signaling pathways also have a central role in hypothalamic mediated regulation of energy balance [86]. Insulin functions as a "catabolic adiposity negative feedback signal" to provide a central signal to mediate food intake. Insulin administration via the icv route reduces food intake and decreases hepatic glucose production [102]. This involves the insulin signaling pathway that acts through phosphatidylinositol 3-kinase (PI3K) to modify the JAK/STAT signaling pathway, and involves the release of melanocyte-stimulating hormone, increases in POMC expression, and activation of downstream melanocyte "target" neurons [103]. The role of insulin in regulating food intake is supported by studies showing that downregulation of hypothalamic insulin receptors in rats [93] or insulin receptor substrate 2 in mice [92] causes hyperphagia and insulin resistance. Although not previously examined in hypothalamus, we [54,104,105] and other groups [106–109] have shown that insulin inhibits AMPK activity in heart and skeletal muscle. In liver and muscle, it is well known that insulin increases malonyl-CoA levels. This raises the intriguing possibility that insulin inhibits hypothalamic AMPK and increases malonyl-CoA, and that this metabolic signaling may be involved in the effects of insulin on food intake and hepatic glucose production.

3.3. Regulation of energy balance by hypothalamic malonyl-CoA
Alterations in hypothalamic malonyl-CoA have also recently been implicated in the control of food intake. Inhibition of hypothalamic fatty acid synthase (FAS) increases malonyl-CoA levels and decreases food intake in mice [96,110–116]. Fasting also decreases hypothalamic malonyl-CoA, supporting the important role of malonyl-CoA in controlling food intake.

Support for a role of malonyl-CoA in the control of food intake also arises from studies examining the hypothalamic localization of FAS. FAS is expressed in a number of brain regions, including the AN and PVH [111]. Kim et al. also showed that FAS is co-localized with NPY in neurons of the AN [111]. Treatment of mice with the FAS inhibitor, C75, decreased NPY immunoreactivitiy in the axon terminals that innervate the PVH and the lateral hypothalamus. It was concluded that increasing malonyl-CoA levels may alter food intake via interactions within the AN-PVN pathway mediated by NPY.

Recent studies by Luciano Rossetti's group have provided a potential mechanism by which hypothalamic malonyl-CoA may play a central role in nutrient sensing of food intake [117–119]. At the level of the hypothalamus, both glucose and fatty acids decrease food intake, decrease hepatic glucose production, and increase peripheral energy expenditure [117–119]. Glucose, pyruvate, or lactate can increase the supply of acetyl-CoA for ACC malonyl-CoA synthesis, which then results in a malonyl-CoA-induced inhibition of hypothalamic CPT1, thereby increasing long chain acyl CoA (LCAC) levels. Increased fatty levels will also increase hypothalamic LCAC [87,119]. The increase in LCAC then activates KATP channels, resulting in neuronal stimulation that modifies food intake, peripheral energy expenditure and hepatic glucose production (see Ref. [118] for review).

Since alterations in hypothalamic AMPK can modulate energy balance, it is possible that these effects of AMPK may involve alterations in malonyl-CoA. However, this has yet to be established. The study by Minokoshi et al. demonstrating hypothalamic AMPK inhibition by icv injection of leptin proposed that leptin inhibition of AMPK was "consistent with increased hypothalamic malonyl-CoA levels" [91] (Fig. 3). Andersson et al. showed that leptin inhibition of hypothalamic AMPK was accompanied by a decrease in ACC phosphorylation, which normally increases ACC activity [97]. Ghrelin activation of AMPK is accompanied by an increase in ACC phosphorylation.


Figure 3
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  		Fig. 3 Potential hypothalamic AMP-activated protein kinase control of food intake, energy expenditure and hepatic glucose production via modification of malonyl-CoA levels. Leptin, {alpha}-lipoic acid, insulin, and glucose inhibit AMPK (A), while grehlin, fasting, or cannabinoids stimulate AMPK (B). Inhibition of AMPK results in an increase in ACC activity and hypothalamic malonyl-CoA, while activation of AMPK decreases ACC and malonyl-CoA levels. Hypothalamic malonyl-CoA levels can also be increased by inhibition of FAS or MCD (A), while an increase in MCD will decrease malonyl-CoA levels (B). An increase in malonyl-CoA will result in a decrease in food intake, increase in peripheral energy expenditure and a decrease in hepatic glucose production (A), while a decrease in malonyl-CoA will increase food intake, decrease peripheral energy expenditure and increase hepatic glucose production.

 
To date, studies on modulation of hypothalamic malonyl-CoA have concentrated on modifying FAS activity, which uses malonyl-CoA for fatty acid biosynthesis. However, another potential fate of malonyl-CoA is via decarboxylation to acetyl-CoA by MCD. The identification of hypothalamic malonyl-CoA as a mediator of food intake raises the intriguing possibility that the hypothalamus also contains MCD activity that could degrade malonyl-CoA. The hypothalamus does contain MCD activity. In support of this, Kim et al. recently performed RNA in situ hybridziation and localization studies in mice hypothalamus, and showed that MCD in the hypothalamus co-localized with FAS and NPY [111]. ACC was also found to co-localize with FAS and NPY [111]. Colocalization of FAS and NPY also occurs in human hypothalamus [111]. This raises the intriguing possibility that hypothalamic MCD, which regulates malonyl-CoA levels, may also regulate energy balance. In support of this, increasing MCD expression in the arcuate nucleus (using adenoviral delivered MCD) results in an increase food intake and weight gain in mice and rats, and prevented leptin-induced inhibition of food intake [120]. This effect of MCD expression was accompanied by a decrease in hypothalamic long chain acyl CoA in rat hypothalamus, which would be expected if malonyl-CoA inhibition was prevented.

3.4. Mechanisms by which malonyl-CoA regulates food intake
Despite compelling evidence that increases in hypothalamic malonyl-CoA decrease food intake and body weight, the mechanism by which this occurs has not been established. It is likely that malonyl-CoA inhibition of CPT1 is also involved in the malonyl-CoA regulation of food intake in the hypothalamus. Obici and Rossetti have shown that CPT1 inhibition can decrease food intake [121].

Although the mechanism by which hypothalamic malonyl-CoA mediates food intake and peripheral glucose production has not been definitely established, compelling evidence has now been obtained to suggest that malonyl-CoA has an important role in mediating food intake. We also suggest that the actions of AMPK on food intake are also linked to alterations in hypothalamic malonyl-CoA.

3.5. Hypothalamic effects on peripheral energy expenditure
While hormones and metabolites such as leptin, adiponectin, insulin, and glucose have hypothalamic effects on food intake, they can also have central mediated peripheral actions, including central mediated effects on hepatic glucose production [84–86]. These hormones and metabolites also have central actions on peripheral energy metabolism. For instance, the decrease in body weight seen with hypothalamic administration of leptin is due both to a decrease in food intake and an increase in peripheral energy expenditure. While adiponectin and leptin share a number of common hypothalamic signaling pathways (such as the melanocortin pathway), the effect of adiponectin on decreasing body weight appears to be primarily due to an increase in peripheral energy expenditure [91,97], as opposed to a decrease in food intake [95]. The hypothalamic effects of {alpha}-lipoic acid, which inhibits AMPK, also appears to be mediated by an increase in peripheral energy expenditure [94]. A possible explanation for these effects may involve a central mediated effect of malonyl-CoA on peripheral muscle fatty acid oxidation and energy expenditure. Inhibiting hypothalamic fatty acid synthase (with C75) in mice is associated with an increase in skeletal muscle fatty acid oxidation, a decrease in malonyl-CoA, and an increase in UCP3 and PGC-1 [122]. Daniel Lane has proposed a "malonyl-CoA signal" from brain to skeletal muscle that is linked via the sympathetic nervous system.


   4. Conclusions
Top
 Abstract
 1. Introduction
 2. Regulation of cardiac...
 3. Regulation of food...
 4. Conclusions
References
 
Malonyl-CoA is a major regulator of fatty acid oxidation in the myocardium and plays a major role in the cardiovascular pathologies of ischemic heart disease and diabetic cardiomyopathy. Indeed inhibition of fatty acid oxidation using MCD inhibitors has proven to be beneficial during myocardial ischemia and reperfusion. In addition, malonyl-CoA has also recently been implicated in playing a role in the hypothalamus controlling feeding and peripheral energy expenditure, suggesting that it may also play an important role in the development of obesity, insulin resistance and the metabolic syndrome.


   Acknowledgements
 
CDLF is a trainee of the Alberta Heritage Foundation for Medical Research, Canadian Institute of Health Research and Tomorrow's Research Cardiovascular Health Professionals (TORCH). GDL is a Medical Scientist of the Alberta Heritage Foundation for Medical Research.


   Notes
 
Time for primary review 20 days


   References
Top
 Abstract
 1. Introduction
 2. Regulation of cardiac...
 3. Regulation of food...
 4. Conclusions
 References
 

  1. Kopelman P.G., Hitman G.A. Diabetes. Exploding type II. Lancet (1998) 352(Suppl_4):SIV5.[Medline]
  2. Gwilt D.J., Petri M., Lewis P.W., Nattrass M., Pentecost B.L. Myocardial infarct size and mortality in diabetic patients. Br Heart J (1985) 54:466–772.[Abstract/Free Full Text]
  3. Jaffe A.S., Spadaro J.J., Schechtman K., Roberts R., Geltman E.M., Sobel B.E. Increased congestive heart failure after myocardial infarction of modest extent in patients with diabetes mellitus. Am Heart J (1984) 108:31–37.[CrossRef][Web of Science][Medline]
  4. Kannel W.B., McGee D.L. Diabetes and cardiovascular risk factors: the Framingham study. Circulation (1979) 59:8–13.[Abstract/Free Full Text]
  5. Factor S.M., Minase T., Sonnenblick E.H. Clinical and morphological features of human hypertensive-diabetic cardiomyopathy. Am Heart J (1980) 99:446–458.[CrossRef][Web of Science][Medline]
  6. Seneviratne B.I. Diabetic cardiomyopathy: the preclinical phase. Br Med J (1977) 1:1444–1446.[Abstract/Free Full Text]
  7. Poirier P., Bogaty P., Garneau C., Marois L., Dumesnil J.G. Diastolic dysfunction in normotensive men with well-controlled type 2 diabetes: importance of maneuvers in echocardiographic screening for preclinical diabetic cardiomyopathy. Diabetes Care (2001) 24:5–10.[Abstract/Free Full Text]
  8. Redfield M.M., Jacobsen S.J., Burnett J.C. Jr., Mahoney D.W., Bailey K.R., Rodeheffer R.J. Burden of systolic and diastolic ventricular dysfunction in the community: appreciating the scope of the heart failure epidemic. JAMA (2003) 289:194–202.[Abstract/Free Full Text]
  9. Hall J.L., Lopaschuk G.D., Barr A., Bringas J., Pizzurro R.D., Stanley W.C. Increased cardiac fatty acid uptake with dobutamine infusion in swine is accompanied by a decrease in malonyl CoA levels. Cardiovasc Res (1996) 32:879–885.[CrossRef][Web of Science][Medline]
  10. Hall J.L., Stanley W.C., Lopaschuk G.D., Wisneski J.A., Pizzurro R.D., Hamilton C.D., et al. Impaired pyruvate oxidation but normal glucose uptake in diabetic pig heart during dobutamine-induced work. Am J Physiol Heart Circ Physiol (1996) 40:H2320–H2329.
  11. Kudo N., Barr A.J., Barr R.L., Desai S., Lopaschuk G.D. High rates of fatty acid oxidation during reperfusion of ischemic hearts are associated with a decrease in malonyl-CoA levels due to an increase in 5'-AMP-activated protein kinase inhibition of acetyl-CoA carboxylase. J Biol Chem (1995) 270:17513–17520.[Abstract/Free Full Text]
  12. Thampy K.G. Formation of malonyl coenzyme-A in rat-heart – identification and purification of an isozyme of acetyl-coenzyme-A carboxylase from rat-heart. J Biol Chem (1989) 264:17631–17634.[Abstract/Free Full Text]
  13. Dyck J.R., Cheng J.F., Stanley W.C., Barr R., Chandler M.P., Brown S., et al. Malonyl coenzyme a decarboxylase inhibition protects the ischemic heart by inhibiting fatty acid oxidation and stimulating glucose oxidation. Circ Res (2004) 94:78–84.[CrossRef]
  14. Kerner J., Hoppel C.L. Radiochemical malonyl-CoA decarboxylase assay: activity and subcellular distribution in heart and skeletal muscle. Anal Biochem (2002) 306:283–289.[CrossRef][Web of Science][Medline]
  15. Kim Y.S., Kolattukudy P.E. Purification and properties of malonyl-Coa decarboxylase from rat-liver mitochondria and its immunological comparison with enzymes from rat-brain, heart, and mammary-gland. Arch Biochem Biophys (1978) 190:234–246.[CrossRef][Web of Science][Medline]
  16. Saha A.K., Schwarsin A.J., Roduit R., Masse F., Kaushik V., Tornheim K., et al. Activation of malonyl-CoA decarboxylase in rat skeletal muscle by contraction and the AMP-activated protein kinase activator 5-aminoimidazole-4-carboxamide-1-beta-D-ribofuranoside. J Biol Chem (2000) 275:24279–24283.[Abstract/Free Full Text]
  17. Reszko A.E., Kasumov T., Comte B., Pierce B.A., David F., Bederman I.R., et al. Assay of the concentration and 13C-isotopic enrichment of malonyl-coenzyme A by gas chromatography-mass spectrometry. Anal Biochem (2001) 298:69–75.[CrossRef][Web of Science][Medline]
  18. Kudo N., Gillespie J.G., Kung L., Witters L.A., Schulz R., Clanachan A.S., et al. Characterization of 5'AMP-activated protein kinase activity in the heart and its role in inhibiting acetyl-CoA carboxylase during reperfusion following ischemia. Biochim Biophys Acta (1996) 1301:67–75.[Medline]
  19. Dyck J.R., Kudo N., Barr A.J., Davies S.P., Hardie D.G., Lopaschuk G.D. Phosphorylation control of cardiac acetyl-CoA carboxylase by cAMP-dependent protein kinase and 5'-AMP activated protein kinase. Eur J Biochem (1999) 262:184–190.[Web of Science][Medline]
  20. Munday M.R. Regulation of mammalian acetyl-CoA carboxylase. Biochem Soc Trans (2002) 30:1059–1064.[CrossRef][Web of Science][Medline]
  21. Joly E., Bendayan M., Roduit R., Saha A.K., Ruderman N.B., Prentki M. Malonyl-CoA decarboxylase is present in the cytosolic, mitochondrial and peroxisomal compartments of rat hepatocytes. FEBS Lett (2005) 579:6581–6586.[CrossRef][Web of Science][Medline]
  22. Brown G.K., Scholem R.D., Bankier A., Danks D.M. Malonyl coenzyme A decarboxylase deficiency. J Inherit Metab Dis (1984) 7:21–26.[CrossRef][Web of Science][Medline]
  23. Yano S., Sweetman L., Thorburn D.R., Mofidi S., Williams J.C. A new case of malonyl coenzyme A decarboxylase deficiency presenting with cardiomyopathy. Eur J Pediatr (1997) 156:382–383.[CrossRef][Web of Science][Medline]
  24. Opie L.H. The heart: physiology, from cell to circulation. (1998) Philadelphia, Pa: Lippincott-Raven.
  25. Neely J.R., Morgan H.E. Relationship between carbohydrate and lipid metabolism and the energy balance of heart muscle. Annu Rev Physiol (1974) 36:413–459.[CrossRef][Web of Science][Medline]
  26. Stanley W.C., Recchia F.A., Lopaschuk G.D. Myocardial substrate metabolism in the normal and failing heart. Physiol Rev (2005) 85:1093–1129.[Abstract/Free Full Text]
  27. Mcgarry J.D., Foster D.W. Regulation of hepatic fatty acid oxidation and ketone body production. Annu Rev Biochem (1980) 49:395–420.[CrossRef][Web of Science][Medline]
  28. Mcgarry J.D., Woeltje K.F., Kuwajima M., Foster D.W. Regulation of ketogenesis and the renaissance of carnitine palmitoyltransferase. Diabetes Metab Rev (1989) 5:271–284.[Web of Science][Medline]
  29. King L.M., Opie L.H. Glucose and glycogen utilisation in myocardial ischemia-changes in metabolism and consequences for the myocyte. Mol Cell Biochem (1998) 180:3–26.[CrossRef][Web of Science][Medline]
  30. Liu B., Clanachan A.S., Schulz R., Lopaschuk G.D. Cardiac efficiency is improved after ischemia by altering both the source and fate of protons. Circ Res (1996) 79:940–948.[Abstract/Free Full Text]
  31. Liu B., el Alaoui-Talibi Z., Clanachan A.S., Schulz R., Lopaschuk G.D. Uncoupling of contractile function from mitochondrial TCA cycle activity and MVO2 during reperfusion of ischemic hearts. Am J Physiol (1996) 270:H72–H80.[Web of Science][Medline]
  32. Benzi R.H., Lerch R. Dissociation between contractile function and oxidative metabolism in postischemic myocardium. Attenuation by ruthenium red administered during reperfusion. Circ Res (1992) 71:567–576.[Abstract/Free Full Text]
  33. Lopaschuk G.D., Spafford M.A., Davies N.J., Wall S.R. Glucose and palmitate oxidation in isolated working rat hearts reperfused after a period of transient global ischemia. Circ Res (1990) 66:546–553.[Abstract/Free Full Text]
  34. Saddik M., Lopaschuk G.D. Myocardial triglyceride turnover and contribution to energy substrate utilization in isolated working rat hearts. J Biol Chem (1991) 266:8162–8170.[Abstract/Free Full Text]
  35. Oliver M.F., Opie L.H. Effects of glucose and fatty acids on myocardial ischaemia and arrhythmias. Lancet (1994) 343:155–158.[CrossRef][Web of Science][Medline]
  36. Hardie D.G. AMP-activated protein kinase: a master switch in glucose and lipid metabolism. Rev Endocr Metab Disord (2004) 5:119–125.[CrossRef][Web of Science][Medline]
  37. Karmazyn M., Moffat M.P. Na+/H+ exchange and regulation of intracellular Ca2+. Cardiovasc Res (1993) 27:2079–2080.[Web of Science][Medline]
  38. Solomon M.A., Jeffrey F.M., Storey C.J., Sherry A.D., Malloy C.R. Substrate selection early after reperfusion of ischemic regions in the working rabbit heart. Magn Reson Med (1996) 35:820–826.[Web of Science][Medline]
  39. Tamm C., Benzi R., Papageorgiou I., Tardy I., Lerch R. Substrate competition in postischemic myocardium. Effect of substrate availability during reperfusion on metabolic and contractile recovery in isolated rat hearts. Circ Res (1994) 75:1103–1112.[Abstract/Free Full Text]
  40. Sakamoto T., Aoki M., Imai Y., Nemoto S. Carnitine affects fatty acid metabolism after cardioplegic arrest in neonatal rabbit hearts. Ann Thorac Surg (2001) 71:648–653.[Abstract/Free Full Text]
  41. Pietersen H.G., Langenberg C.J., Geskes G., Kester A., de L.S., Van d V., et al. Myocardial substrate uptake and oxidation during and after routine cardiac surgery. J Thorac Cardiovasc Surg (1999) 118:71–80.[Abstract/Free Full Text]
  42. Folmes C.D., Clanachan A.S., Lopaschuk G.D. Fatty acid oxidation inhibitors in the management of chronic complications of atherosclerosis. Curr Atheroscler Rep (2005) 7:63–70.[CrossRef][Medline]
  43. Dyck J.R.B., Barr R., Jishage K., Watanabe M., Kawata Y., Nadzan A.M., et al. Hearts from malonyl CoA decarboxylase null mice are protected from ischemic damage. Circulation (2004) 322. [Abstract].
  44. Goodale W.T., Olson R.E., Hackel D.B. The effects of fasting and diabetes mellitus on myocardial metabolism in man. Am J Med (1959) 27:212–220.[CrossRef][Web of Science][Medline]
  45. Randle P.J., Garland P.B., Newsholme E.A., Hales C.N. Glucose fatty-acid cycle – its role in insulin sensitivity and metabolic disturbances of diabetes mellitus. Lancet (1963) 1:785–789.[Web of Science][Medline]
  46. Wall S.R., Lopaschuk G.D. Glucose oxidation rates in fatty acid-perfused isolated working hearts from diabetic rats. Biochim Biophys Acta (1989) 1006:97–103.[Medline]
  47. Sakamoto J., Barr R.L., Kavanagh K.M., Lopaschuk G.D. Contribution of malonyl-CoA decarboxylase to the high fatty acid oxidation rates seen in the diabetic heart. Am J Physiol Heart Circ Physiol (2000) 278:1196–1204.
  48. Lopaschuk G.D., Tsang H. Metabolism of palmitate in isolated working hearts from spontaneously diabetic "BB" Wistar rats. Circ Res (1987) 61:853–858.[Abstract/Free Full Text]
  49. French T.J., Goode A.W., Holness M.J., MacLennan P.A., Sugden M.C. The relationship between changes in lipid fuel availability and tissue fructose 2,6-bisphosphate concentrations and pyruvate dehydrogenase complex activities in the fed state. Biochem J (1988) 256:935–939.[Web of Science][Medline]
  50. Garland P.B., Randle P.J. Regulation of glucose uptake by muscles. 10. Effects of alloxan-diabetes, starvation, hypophysectomy and adrenalectomy, and of fatty acids, ketone bodies and pyruvate, on the glycerol output and concentrations of free fatty acids, long-chain fatty acyl-coenzyme A, glycerol phosphate and citrate-cycle intermediates in rat heart and diaphragm muscles. Biochem J (1964) 93:678–687.[Web of Science][Medline]
  51. Aasum E., Belke D.D., Severson D.L., Riemersma R.A., Cooper M., Andreassen M., et al. Cardiac function and metabolism in Type 2 diabetic mice after treatment with BM 17.0744, a novel PPAR-alpha activator. Am J Physiol Heart Circ Physiol (2002) 283:949–957.
  52. Ramanathan T., Shirota K., Morita S., Nishimura T., Huang Y., Zheng X., et al. Left ventricular oxygen utilization efficiency is impaired in chronic streptozotocin-diabetic sheep. Cardiovasc Res (2002) 55:749–756.[Abstract/Free Full Text]
  53. Gamble J., Lopaschuk G.D. Glycolysis and glucose oxidation during reperfusion of ischemic hearts from diabetic rats. Biochim Biophys Acta (1994) 1225:191–199.[Medline]
  54. Gamble J., Lopaschuk G.D. Insulin inhibition of 5' adenosine monophosphate-activated protein kinase in the heart results in activation of acetyl coenzyme A carboxylase and inhibition of fatty acid oxidation. Metabolism (1997) 46:1270–1274.[CrossRef][Web of Science][Medline]
  55. Zhou Y.T., Grayburn P., Karim A., Shimabukuro M., Higa M., Baetens D., et al. Lipotoxic heart disease in obese rats: implications for human obesity. Proc Natl Acad Sci U S A (2000) 97:1784–1789.[Abstract/Free Full Text]
  56. Unger R.H. Lipotoxic diseases. Annu Rev Med (2002) 53:319–336.[CrossRef][Web of Science][Medline]
  57. Unger R.H. Hyperleptinemia: protecting the heart from lipid overload. Hypertension (2005) 45:1031–1034.[Abstract/Free Full Text]
  58. Abu-Elheiga L., Matzuk M.M., Abo-Hashema K.A., Wakil S.J. Continuous fatty acid oxidation and reduced fat storage in mice lacking acetyl-CoA carboxylase 2. Science (2001) 291:2613–2616.[Abstract/Free Full Text]
  59. Taegtmeyer H., McNulty P., Young M.E. Adaptation and maladaptation of the heart in diabetes: part I general concepts. Circulation (2002) 105:1727–1733.[Free Full Text]
  60. Unger R.H., Zhou Y.T., Orci L. Regulation of fatty acid homeostasis in cells: novel role of leptin. Proc Natl Acad Sci U S A (1999) 96:2327–2332.[Abstract/Free Full Text]
  61. Chiu H.C., Kovacs A., Ford D.A., Hsu F.F., Garcia R., Herrero P., et al. A novel mouse model of lipotoxic cardiomyopathy. J Clin Invest (2001) 107:813–822.[Web of Science][Medline]
  62. Chen H.C., Farese R.V. Jr. Fatty acids, triglycerides, and glucose metabolism: recent insights from knockout mice. Curr Opin Clin Nutr Metab Care (2002) 5:359–363.[CrossRef][Web of Science][Medline]
  63. Lee Y., Yu X., Gonzales F., Mangelsdorf D.J., Wang M.Y., Richardson C., et al. PPAR alpha is necessary for the lipopenic action of hyperleptinemia on white adipose and liver tissue. Proc Natl Acad Sci U S A (2002) 99:11848–11853.[Abstract/Free Full Text]
  64. Atkinson L.L., Fischer M.A., Lopaschuk G.D. Leptin activates cardiac fatty acid oxidation independent of changes in the AMP-activated protein kinase-acetyl-CoA carboxylase-malonyl-CoA axis. J Biol Chem (2002) 277:29424–29430.[Abstract/Free Full Text]
  65. Atkinson L.L., Kozak R., Kelly S.E., Onay Besikci A., Russell J.C., Lopaschuk G.D. Potential mechanisms and consequences of cardiac triacylglycerol accumulation in insulin-resistant rats. Am J Physiol Endocrinol Metab (2003) 284:923–930.
  66. Young M.E., McNulty P., Taegtmeyer H. Adaptation and maladaptation of the heart in diabetes: part II – potential mechanisms. Circulation (2002) 105:1861–1870.[Free Full Text]
  67. Young M.E., Guthrie P.H., Razeghi P., Leighton B., Abbasi S., Patil S., et al. Impaired long-chain fatty acid oxidation and contractile dysfunction in the obese Zucker rat heart. Diabetes (2002) 51:2587–2595.[Abstract/Free Full Text]
  68. Oakes N.D., Thalen P., Aasum E., Edgley A., Larsen T., Furler S.M., et al. Cardiac metabolism in mice: tracer method developments and in vivo application revealing profound metabolic inflexibility in diabetes. AJP- Endocrinol. Metab. (2006) 290:E870–E881.[CrossRef]
  69. Turpeinen A.K., Kuikka J.T., Vanninen E., Uusitupa M.I. Abnormal myocardial kinetics of 123I-heptadecanoic acid in subjects with impaired glucose tolerance. Diabetologia (1997) 40:541–549.[CrossRef][Web of Science][Medline]
  70. Mazumder P.K., O'Neill B.T., Roberts M.W., Buchanan J., Yun U.J., Cooksey R.C., et al. Impaired cardiac efficiency and increased fatty acid oxidation in insulin-resistant ob/ob mouse hearts. Diabetes (2004) 53:2366–2374.[Abstract/Free Full Text]
  71. Carroll R., Carley A.N., Dyck J.R., Severson D.L. Metabolic effects of insulin on cardiomyocytes from control and diabetic db/db mouse hearts. Am J Physiol Endocrinol Metab (2005) 288:900–906.
  72. Belke D.D., Larsen T.S., Gibbs E.M., Severson D.L. Altered metabolism causes cardiac dysfunction in perfused hearts from diabetic (db/db) mice. Am J Physiol Endocrinol Metab (2000) 279:1104–1113.
  73. Lopaschuk G.D., Russell J.C. Myocardial function and energy substrate metabolism in the insulin-resistant JCR:LA corpulent rat. J Appl Physiol (1991) 71:1302–1308.[Abstract/Free Full Text]
  74. Peterson L.R., Herrero P., Schechtman K.B., Racette S.B., Waggoner A.D., Kisrieva-Ware Z., et al. Effect of obesity and insulin resistance on myocardial substrate metabolism and efficiency in young women. Circulation (2004) 109:2191–2196.[Abstract/Free Full Text]
  75. Hearse D.J., Stewart D.A., Chain E.B. Diabetes and the survival and recovery of the anoxic myocardium. J Mol Cell Cardiol (1975) 7:397–415.[CrossRef][Web of Science][Medline]
  76. Feuvray D., Idell-Wenger J.A., Neely J.R. Effects of ischemia on rat myocardial function and metabolism in diabetes. Circ Res (1979) 44:322–329.[Free Full Text]
  77. Hekimian G., Feuvray D. Reduction of ischemia-induced acyl carnitine accumulation by TDGA and its influence on lactate dehydrogenase release in diabetic rat hearts. Diabetes (1986) 35:906–910.[CrossRef][Web of Science][Medline]
  78. Tani M., Neely J.R. Hearts from diabetic rats are more resistant to in vitro ischemia: possible role of altered Ca2+ metabolism. Circ Res (1988) 62:931–940.[Abstract/Free Full Text]
  79. Lopaschuk G.D., Saddik M., Barr R., Huang L., Barker C.C., Muzyka R.A. Effects of high levels of fatty acids on functional recovery of ischemic hearts from diabetic rats. Am J Physiol (1992) 263:E1046–E1053.[Web of Science][Medline]
  80. Paulson D.J., Kopp S.J., Peace D.G., Tow J.P. Improved postischemic recovery of cardiac pump function in exercised trained diabetic rats. J Appl Physiol (1988) 65:187–193.[Abstract/Free Full Text]
  81. Pieper G.M., Gross G.J. Diabetes alters postischemic response to a prostacyclin mimetic. Am J Physiol (1989) 256:H1353–H1360.[Web of Science][Medline]
  82. Lopaschuk G.D. Metabolic abnormalities in the diabetic heart. Heart Fail Rev (2002) 7:149–159.[CrossRef][Medline]
  83. Feuvray D., Lopaschuk G.D. Controversies on the sensitivity of the diabetic heart to ischemic injury: the sensitivity of the diabetic heart to ischemic injury is decreased. Cardiovasc Res (1997) 34:113–120.[Abstract/Free Full Text]
  84. Schwartz M.W., Woods S.C., Porte D., Seeley R.J., Baskin D.G. Central nervous system control of food intake. Nature (2000) 404:661–671.[Medline]
  85. Zigman J.M., Elmquist J.K. Minireview: from anorexia to obesity–the yin and yang of body weight control. Endocrinology (2003) 144:3749–3756.[Abstract/Free Full Text]
  86. Niswender K.D., Baskin D.G., Schwartz M.W. Insulin and its evolving partnership with leptin in the hypothalamic control of energy homeostasis. Trends Endocrinol Metab (2004) 15:362–369.[CrossRef][Web of Science][Medline]
  87. Morgan K., Obici S., Rossetti L. Hypothalamic responses to long-chain fatty acids are nutritionally regulated. J Biol Chem (2004) 279:31139–31148.[Abstract/Free Full Text]
  88. Langhans W., Damaske U., Scharrer E. Different metabolites might reduce food intake by the mitochondrial generation of reducing equivalents. Appetite (1985) 6:143–152.[Web of Science][Medline]
  89. Friedman J.M., Halaas J.L. Leptin and the regulation of body weight in mammals. Nature (1998) 395:763–770.[CrossRef][Medline]
  90. Lachey J.L., D'Alessio D.A., Rinaman L., Elmquist J.K., Drucker D.J., Seeley R.J. The role of central GLP-1 in mediating the effects of visceral illness: differential effects in rats and mice. Endocrinology (2004) 46:458–462.
  91. Minokoshi Y., Alquier T., Furukawa N., Kim Y.B., Lee A., Xue B., et al. AMP-kinase regulates food intake by responding to hormonal and nutrient signals in the hypothalamus. Nature (2004) 428:569–574.[CrossRef][Medline]
  92. Kubota N., Terauchi Y., Tobe K., Yano W., Suzuki R., Ueki K., et al. Insulin receptor substrate 2 plays a crucial role in beta cells and the hypothalamus. J Clin Invest (2004) 114:917–927.[CrossRef][Web of Science][Medline]
  93. Obici S., Feng Z., Karkanias G., Baskin D.G., Rossetti L. Decreasing hypothalamic insulin receptors causes hyperphagia and insulin resistance in rats. Nat Neurosci (2002) 5:566–572.[CrossRef][Web of Science][Medline]
  94. Kim M.S., Park J.Y., Namkoong C., Jang P.G., Ryu J.W., Song H.S., et al. Anti-obesity effects of alpha-lipoic acid mediated by suppression of hypothalamic AMP-activated protein kinase. Nat Med (2004) 10:727–733.[CrossRef][Web of Science][Medline]
  95. Qi Y., Takahashi N., Hileman S.M., Patel H.R., Berg A.H., Pajvani U.B., et al. Adiponectin acts in the brain to decrease body weight. Nat Med (2004) 10:524–529.[CrossRef][Web of Science][Medline]
  96. Kim E.K., Miller I., Aja S., Landree L.E., Pinn M., McFadden J., et al. C75, a fatty acid synthase inhibitor, reduces food intake via hypothalamic AMP-activated protein kinase. J Biol Chem (2004) 279:19970–19976.[Abstract/Free Full Text]
  97. Andersson U., Filipsson K., Abbott C.R., Woods A., Smith K., Bloom S.R., et al. AMP-activated protein kinase plays a role in the control of food intake. J Biol Chem (2004) 279:12005–12008.[Abstract/Free Full Text]
  98. McCrimmon R.J., Fan X., Ding Y., Zhu W., Jacob R.J., Sherwin R.S. Potential role for AMP-activated protein kinase in hypoglycemia sensing in the ventromedial hypothalamus. Diabetes (2004) 53:1953–1958.[Abstract/Free Full Text]
  99. Kola B., Hubina E., Tucci S.A., Kirkham T.C., Garcia E.A., Mitchell S.E., et al. Cannabinoids and ghrelin have both central and peripheral metabolic and cardiac effects via AMP-activated protein kinase. J Biol Chem (2005) 280:25196–25201.[Abstract/Free Full Text]
  100. Schwartz M.W. Neuronal pathways regulating food intake and body adiposity. Ann Endocrinol (Paris) (2002) 63:117–120.[Medline]
  101. Lee K., Li B., Xi X., Suh Y., Martin R.J. The role of neuronal energy status in the regulation of AMP-activated protein kinase, orexigenic neuropeptides expression and feeding behavior. Endocrinology (2005) 146:3–10.[Abstract/Free Full Text]
  102. Niswender K.D., Morrison C.D., Clegg D.J., Olson R., Baskin D.G., Myers M.G. Jr., et al. Insulin activation of phosphatidylinositol 3-kinase in the hypothalamic arcuate nucleus: a key mediator of insulin-induced anorexia. Diabetes (2003) 52:227–231.[CrossRef][Web of Science][Medline]
  103. Benoit S.C., Air E.L., Coolen L.M., Strauss R., Jackman A., Clegg D.J., et al. The catabolic action of insulin in the brain is mediated by melanocortins. J Neurosci (2002) 22:9048–9052.[Abstract/Free Full Text]
  104. Makinde A.O., Gamble J., Lopaschuk G.D. Upregulation of 5'-AMP-activated protein kinase is responsible for the increase in myocardial fatty acid oxidation rates following birth in the newborn rabbit. Circ Res (1997) 80:482–489.[Abstract/Free Full Text]
  105. Folmes C.D., Clanachan A.S., Lopaschuk G.D. Fatty acids attenuate insulin regulation of 5'-AMP-activated protein kinase and insulin cardioprotection after ischemia. Circ Res (2006) 99:61–68.[Abstract/Free Full Text]
  106. Clark H., Carling D., Saggerson D. Covalent activation of heart AMP-activated protein kinase in response to physiological concentrations of long-chain fatty acids. Eur J Biochem (2004) 271:2215–2224.[Web of Science][Medline]
  107. Hue L., Beauloye C., Marsin A.S., Bertrand L., Horman S., Rider M.H. Insulin and ischemia stimulate glycolysis by acting on the same targets through different and opposing signaling pathways. J Mol Cell Cardiol (2002) 34:1091–1097.[CrossRef][Web of Science][Medline]
  108. Witters L.A., Kemp B.E. Insulin activation of acetyl-CoA carboxylase accompanied by inhibition of the 5'-AMP-activated protein kinase. J Biol Chem (1992) 267:2864–2867.[Abstract/Free Full Text]
  109. Horman S., Vertommen D., Heath R., Neumann D., Mouton V., Woods A., et al. Insulin antagonizes ischemia-induced THR172 phosphorylation of AMP-activated protein kinase alpha-subunits in heart via hierarchical phosphorylation of SER485/491. J Biol Chem (2006) 281:5335–5340.[Abstract/Free Full Text]
  110. Hu Z., Cha S.H., Chohnan S., Lane M.D. Hypothalamic malonyl-CoA as a mediator of feeding behavior. Proc Natl Acad Sci U S A (2003) 100:12624–12629.[Abstract/Free Full Text]
  111. Kim E.K., Miller I., Landree L.E., Borisy-Rudin F.F., Brown P., Tihan T., et al. Expression of FAS within hypothalamic neurons: a model for decreased food intake after C75 treatment. Am J Physiol Endocrinol Metab (2002) 283:867–879.
  112. Landree L.E., Hanlon A.L., Strong D.W., Rumbaugh G., Miller I.M., Thupari J.N., et al. C75, a fatty acid synthase inhibitor, modulates AMP-activated protein kinase to alter neuronal energy metabolism. J Biol Chem (2004) 279:3817–3827.[Abstract/Free Full Text]
  113. Tu Y., Thupari J.N., Kim E.K., Pinn M.L., Moran T.H., Ronnett G.V., et al. C75 alters central and peripheral gene expression to reduce food intake and increase energy expenditure. Endocrinology (2005) 146:486–493.[CrossRef][Web of Science][Medline]
  114. Miller I., Ronnett G.V., Moran T.H., Aja S. Anorexigenic C75 alters c-Fos in mouse hypothalamic and hindbrain subnuclei. Neuroreport (2004) 15:925–929.[CrossRef][Web of Science][Medline]
  115. Cha S.H., Hu Z., Lane M.D. Long-term effects of a fatty acid synthase inhibitor on obese mice: food intake, hypothalamic neuropeptides, and UCP3. Biochem Biophys Res Commun (2004) 317:301–308.[CrossRef][Web of Science][Medline]
  116. Takahashi K.A., Smart J.L., Liu H., Cone R.D. The anorexigenic fatty acid synthase inhibitor, C75, is a nonspecific neuronal activator. Endocrinology (2004) 145:184–193.[Abstract/Free Full Text]
  117. Lam T.K., Gutierrez-Juarez R., Pocai A., Rossetti L. Regulation of blood glucose by hypothalamic pyruvate metabolism. Science (2005) 309:943–947.[Abstract/Free Full Text]
  118. Lam T.K., Schwartz G.J., Rossetti L. Hypothalamic sensing of fatty acids. Nat Neurosci (2005) 8:579–584.[CrossRef][Web of Science][Medline]
  119. Lam T.K., Pocai A., Gutierrez-Juarez R., Obici S., Bryan J., Aguilar-Bryan L., et al. Hypothalamic sensing of circulating fatty acids is required for glucose homeostasis. Nat Med (2005) 11:320–327.[CrossRef][Web of Science][Medline]
  120. He W., Lam T.K., Obici S., Rossetti L. Molecular disruption of hypothalamic nutrient sensing induces obesity. Nat Neurosci (2006) 9:227–233.[CrossRef][Web of Science][Medline]
  121. Obici S., Rossetti L. Minireview: nutrient sensing and the regulation of insulin action and energy balance. Endocrinology (2003) 144:5172–5178.[CrossRef][Web of Science][Medline]
  122. Cha S.H., Hu Z., Chohnan S., Lane M.D. Inhibition of hypothalamic fatty acid synthase triggers rapid activation of fatty acid oxidation in skeletal muscle. Proc Natl Acad Sci U S A (2005) 102:14557–14562.[Abstract/Free Full Text]

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