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Review ArticleReview Article

Targeting Intermediary Metabolism in the Hypothalamus as a Mechanism to Regulate Appetite

Gary D. Lopaschuk, John R. Ussher and Jagdip S. Jaswal
Pharmacological Reviews June 2010, 62 (2) 237-264; DOI: https://doi.org/10.1124/pr.109.002428
Gary D. Lopaschuk
Cardiovascular Research Centre, Mazankowski Alberta Heart Institute, University of Alberta, Edmonton, Alberta, Canada
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John R. Ussher
Cardiovascular Research Centre, Mazankowski Alberta Heart Institute, University of Alberta, Edmonton, Alberta, Canada
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Jagdip S. Jaswal
Cardiovascular Research Centre, Mazankowski Alberta Heart Institute, University of Alberta, Edmonton, Alberta, Canada
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Abstract

The central nervous system mediates energy balance (energy intake and energy expenditure) in the body; the hypothalamus has a key role in this process. Recent evidence has demonstrated an important role for hypothalamic malonyl CoA in mediating energy balance. Malonyl CoA is generated by the carboxylation of acetyl CoA by acetyl CoA carboxylase and is then either incorporated into long-chain fatty acids by fatty acid synthase, or converted back to acetyl-CoA by malonyl CoA decarboxylase. Increased hypothalamic malonyl CoA is an indicator of energy surplus, resulting in a decrease in food intake and an increase in energy expenditure. In contrast, a decrease in hypothalamic malonyl CoA signals an energy deficit, resulting in an increased appetite and a decrease in body energy expenditure. A number of hormonal and neural orexigenic and anorexigenic signaling pathways have now been shown to be associated with changes in malonyl CoA levels in the arcuate nucleus (ARC) of the hypothalamus. Despite compelling evidence that malonyl CoA is an important mediator in the hypothalamic ARC control of food intake and regulation of energy balance, the mechanism(s) by which this occurs has not been established. Malonyl CoA inhibits carnitine palmitoyltransferase-1 (CPT-1), and it has been proposed that the substrate of CPT-1, long-chain acyl CoA(s), may act as a mediator(s) of appetite and energy balance. However, recent evidence has challenged the role of long-chain acyl CoA(s) in this process, as well as the involvement of CPT-1 in hypothalamic malonyl CoA signaling. A better understanding of how malonyl CoA regulates energy balance should provide novel approaches to targeting intermediary metabolism in the hypothalamus as a mechanism to control appetite and body weight. Here, we review the data supporting an important role for malonyl CoA in mediating hypothalamic control of energy balance, and recent evidence suggesting that targeting malonyl CoA synthesis or degradation may be a novel approach to favorably modify appetite and weight gain.

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  • This article is available online at http://pharmrev.aspetjournals.org.

    doi:10.1124/pr.109.002428.

  • Copyright © 2010 by The American Society for Pharmacology and Experimental Therapeutics
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Pharmacological Reviews: 62 (2)
Pharmacological Reviews
Vol. 62, Issue 2
1 Jun 2010
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Review ArticleReview Article

Targeting Intermediary Metabolism in the Hypothalamus as a Mechanism to Regulate Appetite

Gary D. Lopaschuk, John R. Ussher and Jagdip S. Jaswal
Pharmacological Reviews June 1, 2010, 62 (2) 237-264; DOI: https://doi.org/10.1124/pr.109.002428

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Review ArticleReview Article

Targeting Intermediary Metabolism in the Hypothalamus as a Mechanism to Regulate Appetite

Gary D. Lopaschuk, John R. Ussher and Jagdip S. Jaswal
Pharmacological Reviews June 1, 2010, 62 (2) 237-264; DOI: https://doi.org/10.1124/pr.109.002428
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  • Article
    • Abstract
    • I. Introduction
    • II. Hypothalamic Metabolism and the Regulation of Appetite
    • III. Signaling Pathways Involved in the Hypothalamic Regulation of Appetite
    • IV. Alterations in Hypothalamic 5′AMP-Activated Protein Kinase and Malonyl CoA That Modify Feeding Behavior and Influence Obesity
    • V. Optimizing Hypothalamic Intermediary Metabolism as a Pharmacological Intervention to Modify Appetite
    • VI. Summary
    • Acknowledgments.
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