Characterization of cardiac malonyl-CoA decarboxylase and its putative role in regulating fatty acid oxidation

Dyck, Jason R.B.; Barr, Amy; Barr, Rick L.; Kolattukudy, Pappachan E.; Lopaschuk, Gary D.

doi:10.1152/ajpheart.1998.275.6.h2122

Cited by 108 publications

(167 citation statements)

References 18 publications

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“…7D), ruling out a potential contribution of blood glucose to the changes in Arc malonyl-CoA level. Malonyl-CoA is synthesized by carboxylation of acetyl-CoA by ACC and degraded by malonyl-CoA decarboxylase (MCD) (26), and malonyl-CoA is the substrate for fatty acid synthase (FAS) in fatty acid biosynthesis (9). To explore the mechanism for the up-regulation of malonyl-CoA level by leptin, we evaluated whether ICV leptin would produce changes in FAS or MCD.…”

Section: Icv Leptin Increases Malonyl-coa Level In the Arc And Increasesmentioning

confidence: 99%

Leptin activates hypothalamic acetyl-CoA carboxylase to inhibit food intake

Gao

Kinzig

Aja

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

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187

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Hypothalamic fatty acid metabolism has recently been implicated in the controls of food intake and energy homeostasis. We report that intracerebroventricular (ICV) injection of leptin, concomitant with inhibiting AMP-activated kinase (AMPK), activates acetyl-CoA carboxylase (ACC), the key regulatory enzyme in fatty acid biosynthesis, in the arcuate nucleus (Arc) and paraventricular nucleus (PVN) in the hypothalamus. Arc overexpression of constitutively active AMPK prevents the Arc ACC activation in response to ICV leptin, supporting the hypothesis that AMPK lies upstream of ACC in leptin's Arc intracellular signaling pathway. Inhibiting hypothalamic ACC with 5-tetradecyloxy-2-furoic acid, a specific ACC inhibitor, blocks leptin-mediated decreases in food intake, body weight, and mRNA level of the orexigenic neuropeptide NPY. These results show that hypothalamic ACC activation makes an important contribution to leptin's anorectic effects. Furthermore, we find that ICV leptin up-regulates the level of malonyl-CoA (the intermediate of fatty acid biosynthesis) specifically in the Arc and increases the level of palmitoyl-CoA (a major product of fatty acid biosynthesis) specifically in the PVN. The rises of both levels are blocked by 5-tetradecyloxy-2-furoic acid along with the blockade of leptinmediated hypophagia. These data suggest malonyl-CoA as a downstream mediator of ACC in leptin's signaling pathway in the Arc and imply that palmitoyl-CoA, instead of malonyl-CoA, could be an effector in relaying ACC signaling in the PVN. Together, these findings highlight site-specific impacts of hypothalamic ACC activation in leptin's anorectic signaling cascade.carnitine palmitoyltransferase ͉ long-chain fatty acyl CoA ͉ malonyl CoA ͉ oleic acid ͉ malonyl CoA decarboxylase E nergy balance is maintained by hypothalamic systems responding to hormonal and neural signals that sense body energy status (1). Leptin is an anorexigenic hormone secreted mainly from adipocytes that controls food intake and energy homeostasis primarily by acting at hypothalamic nuclei such as the arcuate nucleus (Arc) (1, 2). The Arc, the primary nucleus in the hypothalamus in mediating leptin's control of energy balance, contains first-order neurons that express leptin receptors and a variety of feeding-related neuropeptides such as neuropeptide Y (NPY), agouti-related peptide (AgRP), and ␣-melanocyte stimulating hormone (␣-MSH) (1). Leptin exerts its anorectic effects by modulating the levels of these neuropeptides. Activation of signal transducer and activator of transcription 3 (STAT3) and activation of phosphatidylinositol 3-kinase have been shown to play critical roles in leptin's hypothalamic intracellular signaling pathways (3, 4).Further aspects of leptin's hypothalamic intracellular signaling have been identified. Minokoshi et al. (5) have demonstrated that exogenous administration of leptin inhibits AMP-activated kinase (AMPK) in the Arc, and, based on the finding that constitutive activity of AMPK in the Arc prevents leptin's anorectic acti...

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Section: Icv Leptin Increases Malonyl-coa Level In the Arc And Increasesmentioning

confidence: 99%

Leptin activates hypothalamic acetyl-CoA carboxylase to inhibit food intake

Gao

Kinzig

Aja

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

187

178

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“…16 Extraction of CoA esters and the measurement of malonyl CoA levels were performed as previously described. 7 Quantitative Reverse Transcriptase-Polymerase Chain Reaction Analysis RNA extraction and quantitative reverse transcriptase-polymerase chain reaction (RT-PCR) of samples were performed by previously described methods.…”

Section: Activity and Malonyl Coenzyme A Measurementsmentioning

confidence: 99%

Absence of Malonyl Coenzyme A Decarboxylase in Mice Increases Cardiac Glucose Oxidation and Protects the Heart From Ischemic Injury

et al. 2006

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Background-Acute pharmacological inhibition of cardiac malonyl coenzyme A decarboxylase (MCD) protects the heart from ischemic damage by inhibiting fatty acid oxidation and stimulating glucose oxidation. However, it is unknown whether chronic inhibition of MCD results in altered cardiac function, energy metabolism, or ischemic cardioprotection. Methods and Results-Mcd-deficient mice were produced and assessed for in vivo cardiac function as well as ex vivo cardiac function, energy metabolism, and ischemic tolerance. In vivo and ex vivo cardiac function was similar in wild-type and mcd Ϫ/Ϫ mice. Ex vivo working hearts from mcd Ϫ/Ϫ and wild-type mice displayed no significant differences in rates of fatty acid oxidation, glucose oxidation, or glycolysis. However, cardiac deletion of mcd resulted in an increased expression of genes regulating fatty acid utilization that may compensate for the loss of MCD protein and likely contributes to the absence of changes in energy metabolism in the aerobic heart. Despite the lack of changes in fatty acid utilization, hearts from mcd Ϫ/Ϫ mice displayed a marked preference for glucose utilization after ischemia, which correlated with a significant cardioprotection of ischemic hearts from mcd Ϫ/Ϫ mice compared with wild-type mice. Conclusions-Deletion of MCD markedly increases glucose oxidation and improves functional recovery of the heart after ischemia. As a result, chronic pharmacological inhibition of MCD may be a viable approach to treat myocardial ischemia. (Circulation. 2006;114:1721-1728.)

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“…Malonyl-CoA is synthesized from acetyl CoA in the heart by acetyl-CoA carboxylase, 15 whereas degradation of malonyl-CoA occurs by the reverse reaction through decarboxylation back to acetyl CoA by the enzyme malonyl-CoA decarboxylase. 16 Interestingly, both enzymes involved in the control of cardiac malonyl-CoA levels have been suggested to be under phosphorylation control by AMPK. Phosphorylation of acetyl CoA carboxylase by AMPK has been well documented 12 and although controversial, it has been suggested that malonyl CoA decarboxylase is also a phosphorylation target of AMPK.…”

Section: Introductionmentioning

confidence: 99%

AMP-activated protein kinase control of energy metabolism in the ischemic heart

Lopaschuk

2008

Int J Obes

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Myocardial ischemia produces an energy-deficient state in heart muscle, which if not corrected can lead to cardiomyocyte death. AMP-activated protein kinase (AMPK) is a key kinase that can increase energy production in the ischemic heart. During ischemia a rapid activation of AMPK occurs, resulting in an activation of both myocardial glucose uptake and glycolysis, as well as an increase in fatty acid oxidation. This activation of AMPK has the potential to increase energy production, thereby protecting the heart during ischemic stress. However, at clinically relevant high levels of fatty acids, ischemia-induced activation of AMPK also stimulates fatty acid oxidation during and following ischemia. This can contribute to ischemic injury secondary to an inhibition of glucose oxidation, which results in a decrease in cardiac efficiency. As a result, AMPK activation has the potential to be either beneficial or harmful in the ischemic heart.

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Characterization of cardiac malonyl-CoA decarboxylase and its putative role in regulating fatty acid oxidation

Cited by 108 publications

References 18 publications

Leptin activates hypothalamic acetyl-CoA carboxylase to inhibit food intake

Leptin activates hypothalamic acetyl-CoA carboxylase to inhibit food intake

Absence of Malonyl Coenzyme A Decarboxylase in Mice Increases Cardiac Glucose Oxidation and Protects the Heart From Ischemic Injury

AMP-activated protein kinase control of energy metabolism in the ischemic heart

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