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Lipid metabolic enzymes: emerging drug targets for the treatment of obesity

Lipid metabolic enzymes: emerging drug targets for the treatment of obesity Obesity is a complex disease that is rapidly increasing in the Western world and is inextricably linked to type 2 diabetes, heart disease, inflammatory diseases and cancer. There are two long-term treatments for obesity: sibutramine, which acts centrally by suppressing appetite; and orlistat, which acts on a peripheral target that is involved in dietary fat absorption. The hydrolysis, transport and de novo synthesis pathways that are involved in lipid homeostasis present a pool of enzymes and transporters, some of which have been shown to be druggable, including acyl CoA:cholesterol acyltransferase (ACAT) and carnitine palmitoyl transferase (CPT1). The chemical structure of the inhibitors of these enzymes could prove useful in the design of new obesity drugs. Improved mobilization of fat has potential as an anti-obesity strategy, but needs to be balanced with increased fat metabolism to avoid problems with lipotoxicity. The malonyl-CoA/CPT1 axis is involved in regulating fatty-acid β-oxidation and merits further investigation. The most promising target in this pathway is acyl-CoA carboxylase-2 (ACC2): knockout of this enzyme in mice results in increased fatty-acid oxidation and resistance to diabetes-induced obesity, lower fatty-acid levels and improved insulin sensitivity. http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Nature Reviews Drug Discovery Springer Journals

Lipid metabolic enzymes: emerging drug targets for the treatment of obesity

Shi, Yuguang; Burn, Paul
Nature Reviews Drug Discovery , Volume 3 (8) – Aug 1, 2004
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References (172)

Publisher
Springer Journals
Copyright
Copyright © 2004 by Nature Publishing Group
Subject
Biomedicine; Biomedicine, general; Pharmacology/Toxicology; Biotechnology; Medicinal Chemistry; Molecular Medicine; Cancer Research
ISSN
1474-1776
eISSN
1474-1784
DOI
10.1038/nrd1469
Publisher site
See Article on Publisher Site

Abstract

Obesity is a complex disease that is rapidly increasing in the Western world and is inextricably linked to type 2 diabetes, heart disease, inflammatory diseases and cancer. There are two long-term treatments for obesity: sibutramine, which acts centrally by suppressing appetite; and orlistat, which acts on a peripheral target that is involved in dietary fat absorption. The hydrolysis, transport and de novo synthesis pathways that are involved in lipid homeostasis present a pool of enzymes and transporters, some of which have been shown to be druggable, including acyl CoA:cholesterol acyltransferase (ACAT) and carnitine palmitoyl transferase (CPT1). The chemical structure of the inhibitors of these enzymes could prove useful in the design of new obesity drugs. Improved mobilization of fat has potential as an anti-obesity strategy, but needs to be balanced with increased fat metabolism to avoid problems with lipotoxicity. The malonyl-CoA/CPT1 axis is involved in regulating fatty-acid β-oxidation and merits further investigation. The most promising target in this pathway is acyl-CoA carboxylase-2 (ACC2): knockout of this enzyme in mice results in increased fatty-acid oxidation and resistance to diabetes-induced obesity, lower fatty-acid levels and improved insulin sensitivity.

Journal

Nature Reviews Drug Discovery – Springer Journals

Published: Aug 1, 2004

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