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  • Review Article
  • Published:

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

A Corrigendum to this article was published on 01 May 2004

Key Points

  • 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.

Abstract

Patients with the metabolic syndrome are characterized by insulin resistance, obesity and a predisposition to hypertension, dyslipidaemia, pancreatic β-cell dysfunction, type 2 diabetes and premature atherosclerosis. Here we review the hypothesis that a common feature linking these multiple abnormalities is dysregulation of the AMP-activated protein kinase (AMPK)/malonyl-CoA fuel-sensing and signalling network. It is proposed that such dysregulation leads to alterations in cellular fatty-acid metabolism that in turn cause ectopic lipid accumulation, cellular dysfunction and ultimately disease. Evidence is also presented that factors that activate AMP kinase and/or reduce malonyl-CoA levels might reverse these abnormalities or prevent them from occurring.

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Figure 1: Regulation of malonyl-CoA and cytosolic FA-CoA by AMPK.
Figure 2: Regulation of ACC and, secondarily, the concentration of malonyl-CoA by AMPK and cytosolic citrate.
Figure 3: AMPK activation and its effects on cellular energy state.
Figure 4: Effects of AMPK activation on events that could account for its ability to diminish lipid accumulation, cell dysfunction and insulin resistance.
Figure 5

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Acknowledgements

This work was supported by grants from the National Institutes of Health (to N.R. and M.P.), the Juvenile Diabetes Research Foundation (to N.R. and M.P.) and the Canadian Institute of Health Research (to M.P.)

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DATABASES

LocusLink

ACC

AMPK

CPT1

eNOS

FAS

GLUT4

HMG-CoA reductase

MCD

SREBP1c

STK11

VCAM1

Glossary

METABOLIC SYNDROME

A state of metabolic dysregulation characterized by insulin resistance, hyperinsulinaemia, central obesity and a predisposition to type 2 diabetes, dyslipidaemia, hypertension, premature atherosclerosis and other diseases.

INSULIN RESISTANCE

A state in which insulin at a physiological concentration does not exert its usual biological effect. In some instances, the effect of insulin on certain processes (for example, glycogen synthesis) can be impaired, whereas its effect on others (for example, diacylglycerol synthesis) can be normal or even enhanced.

ZUCKER DIABETIC FATTY RAT

(ZDF) rat. A rodent with both a mutant, functionally deficient leptin receptor and a genetic defect that predisposes it to diabetes, as it becomes obese and lipid accumulates in the pancreatic β-cell.

EUGLYCAEMIC–HYPERINSULINAEMIC CLAMP

A widely used technique to assess whole-body (and tissue) insulin sensitivity in humans and experimental animals.

DENERVATED MUSCLE

Muscle with a nerve supply that has been severed or made non-functional by other means.

ANAPLEROTIC

Reactions that lead to the net synthesis of Krebs (citric acid) cycle intermediates, for example, the carboxylation of pyruvate to form oxaloacetate.

MALONYL-CoA/FA-CoA HYPOTHESIS

A theory that proposes that a sustained increase in the concentrations of malonyl-CoA, and secondarily long-chain fatty acid-CoA (FA-CoA), lead to insulin resistance and cellular dysfunction in many tissues. The theory also proposes that a transient stimulation of malonyl-CoA/FA-CoA signalling is involved in glucose- and fatty-acid-stimulated insulin release by the pancreatic β-cell.

GLUCOLIPOTOXICITY HYPOTHESIS

A theory proposing that elevated glucose, in particular post-prandial hyperglycemia, and fatty acids synergize in causing β-cell death and multiple tissue defects.

VO2 MAX

The amount of O2 consumed by an individual when performing aerobic exercise at maximal capacity.

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Ruderman, N., Prentki, M. AMP kinase and malonyl-CoA: targets for therapy of the metabolic syndrome. Nat Rev Drug Discov 3, 340–351 (2004). https://doi.org/10.1038/nrd1344

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