Get 20M+ Full-Text Papers For Less Than $1.50/day. Start a 7-Day Trial for You or Your Team.

Learn More →

AMP kinase and malonyl-CoA: targets for therapy of the metabolic syndrome

AMP kinase and malonyl-CoA: targets for therapy of the metabolic syndrome The metabolic syndrome (MS) is characterized by insulin resistance, hyperinsulinemia, dyslipidaemia and a predisposition to type 2 diabetes, hypertension, premature atherosclerosis and other diseases, such as non-alcoholic fatty liver. Patients with this syndrome are usually overtly obese or have more subtle manifestations of increased adiposity, such as an increase in visceral fat. This syndrome has reached an epidemic level in our modern society due to a number of environmental factors, in particular over-nutrition and inactivity. A major collaborative effort between basic researchers, clinicians, dieticians, health-care authorities and the pharmaceutical industry is required to halt progression of this devastating clustering of diseases. The precise reason that so many abnormalities occur in people with the MS remains to be determined; however, an increasing body of evidence indicates that a common factor could be a dysregulation of cellular lipid metabolism in association with ectopic fat deposition in multiple tissues, that becomes increasingly manifest in the presence of a high caloric intake and/or inactivity. We have proposed that a common causal factor could be dysregulation of the AMP-activated protein kinase (AMPK)/malonyl-coenzymeA (malonyl-CoA) fuel-sensing and signalling network due to either a decrease in AMPK activity and/or a failure of AMPK activity to increase in response to stress. Both fuel surfeit and reduced AMPK activity result in increased cellular malonyl-CoA levels, which reduces fat oxidation and favours abnormal tissue accumulation of lipids. In support of this notion, decreased AMPK activity and/or increased malonyl-CoA levels in insulin-resistant tissues of rodents in a wide variety of conditions have been observed. In addition, therapies that activate AMPK and possibly reduce malonyl-CoA levels, including exercise, leptin, adiponectin, metformin, 5-aminoimidazole-4-carboxamide riboside and thiazolinediones, have been useful in treating insulin resistance and many of the disorders associated with the MS in humans and experimental animals. The fact that many of the pathologies associated with the MS can be prevented or reduced by agents or strategies that increase AMPK activity and/or reduce malonyl-CoA indicate that the AMPK/malonyl-CoA fuel-sensing and signalling network is a prime target for therapy of the MS. Effort should be directed at the identification of novel drugs targeting enzymes and transcription factors implicated in this signalling system. Most importantly, a concerted public health effort should be made to prevent or curb this syndrome, as its incidence would be dramatically reduced with adequate nutritional and exercise habits. http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Nature Reviews Drug Discovery Springer Journals

AMP kinase and malonyl-CoA: targets for therapy of the metabolic syndrome

Download PDF
12 pages

Loading next page...
 
/lp/springer-journals/amp-kinase-and-malonyl-coa-targets-for-therapy-of-the-metabolic-9z0zw0bgnt

References (200)

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/nrd1344
Publisher site
See Article on Publisher Site

Abstract

The metabolic syndrome (MS) is characterized by insulin resistance, hyperinsulinemia, dyslipidaemia and a predisposition to type 2 diabetes, hypertension, premature atherosclerosis and other diseases, such as non-alcoholic fatty liver. Patients with this syndrome are usually overtly obese or have more subtle manifestations of increased adiposity, such as an increase in visceral fat. This syndrome has reached an epidemic level in our modern society due to a number of environmental factors, in particular over-nutrition and inactivity. A major collaborative effort between basic researchers, clinicians, dieticians, health-care authorities and the pharmaceutical industry is required to halt progression of this devastating clustering of diseases. The precise reason that so many abnormalities occur in people with the MS remains to be determined; however, an increasing body of evidence indicates that a common factor could be a dysregulation of cellular lipid metabolism in association with ectopic fat deposition in multiple tissues, that becomes increasingly manifest in the presence of a high caloric intake and/or inactivity. We have proposed that a common causal factor could be dysregulation of the AMP-activated protein kinase (AMPK)/malonyl-coenzymeA (malonyl-CoA) fuel-sensing and signalling network due to either a decrease in AMPK activity and/or a failure of AMPK activity to increase in response to stress. Both fuel surfeit and reduced AMPK activity result in increased cellular malonyl-CoA levels, which reduces fat oxidation and favours abnormal tissue accumulation of lipids. In support of this notion, decreased AMPK activity and/or increased malonyl-CoA levels in insulin-resistant tissues of rodents in a wide variety of conditions have been observed. In addition, therapies that activate AMPK and possibly reduce malonyl-CoA levels, including exercise, leptin, adiponectin, metformin, 5-aminoimidazole-4-carboxamide riboside and thiazolinediones, have been useful in treating insulin resistance and many of the disorders associated with the MS in humans and experimental animals. The fact that many of the pathologies associated with the MS can be prevented or reduced by agents or strategies that increase AMPK activity and/or reduce malonyl-CoA indicate that the AMPK/malonyl-CoA fuel-sensing and signalling network is a prime target for therapy of the MS. Effort should be directed at the identification of novel drugs targeting enzymes and transcription factors implicated in this signalling system. Most importantly, a concerted public health effort should be made to prevent or curb this syndrome, as its incidence would be dramatically reduced with adequate nutritional and exercise habits.

Journal

Nature Reviews Drug Discovery – Springer Journals

Published: Apr 1, 2004

There are no references for this article.