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

Nature Reviews Drug Discovery volume 3, pages 695–710 (2004)Cite this article

Key Points

  • 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.

Abstract

Obesity is a complex disease that is regulated by both central and peripheral mechanisms. New medicines for the treatment and prevention of obesity will need to overcome the powerful compensatory responses of the overlapping, and often redundant, networks that have evolved to safeguard efficient energy use. Despite great progress in the identification of central signals that regulate satiety, and considerable investment in the development of appetite-controlling medications, success has been modest so far. Here we review the main enzymes that are involved in different stages of lipid metabolism — from digestion and absorption through synthesis and storage to mobilization and oxidation — which might be successfully targeted by new pharmacotherapies.

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Figure 1: Adipocytes at the crossroads of energy homeostasis.
Figure 2: The process of dietary lipid digestion and absorption.
Figure 3: Lipid storage and mobilization in adipocytes.
Figure 4: Interconnection of metabolic pathways involved in lipid synthesis in the endoplasmic reticulum and lipid oxidation in mitochondria of liver and skeletal muscle.
Figure 5: The structures of the carboxyltransferase domain of the yeast acetyl-CoA carboxylase and the mouse carnitine acetyltransferase.

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Acknowledgements

The authors would like to apologize to all authors whose work could not be cited owing to space limitations.

Author information

Authors and Affiliations

  1. Endocrine Research, Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, 46285, Indiana, USA

    Yuguang Shi & Paul Burn

  2. The Bayer Research Center, Bayer Health Care, 400 Morgan Lane, West Haven, 06516, Connecticut, USA

    Paul Burn

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Correspondence to Paul Burn.

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Y.S. is employed by Eli Lilly and Co., and P.B. is employed by Bayer Healthcare.

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DATABASES

Entrez Gene

Acc2

AGPAT2

Dgat1

Dgat2

Fas

HSL

MGAT1

MGAT2

MGAT3

Scd1

OMIM

chylomicron-retention disease

lethal restrictive dermopathy

obesity

osteoarthritis

type 2 diabetes

Swiss-Prot

ADRP

CD36

CPT1

FATP4

IFABP

Perilipin

SCD1

TIP47

UCP2

UCP3

FURTHER INFORMATION

Encyclopedia of Life Sciences

Lipoprotein metabolism: structure and function

obesity

triacylglycerols

NIH Obesity Research

FDA Obesity Initiative

Glossary

DYSLIPIDAEMIA

Disorders in lipoprotein metabolism, which are classified as hypercholesterolaemia, hypertriglyceridaemia, combined hyperlipidaemia and low levels of high-density lipoprotein (HDL) cholesterol.

HYPERURICAEMIA

A build-up of uric acid (a by-product of metabolism) in the blood.

ANOREXIGENIC

Causing loss of appetite.

OREXIGENIC

Stimulating appetite.

POSTPRANDIAL TRIGLYCERIDAEMIA

An abnormally high level of circulating triglycerides after eating.

EMULSIFICATION

Increases the surface area of the oil–water interface, which promotes the breakdown of triglycerides by pancreatic lipase.

OROSENSORY

Perception of taste and smell.

GLYCAEMIC CONTROL

The regulation of blood glucose.

STEATORRHOEA

An excessive amount of lipid in the faeces.

CHYLOMICRON

A microscopic particle of triglyceride, cholesterol esters and apolipoproteins that is produced in the intestine and which functions as a transport vehicle.

HYPERCHOLESTEROLAEMIA

The presence of an abnormal amount of cholesterol in the cells and plasma of the blood; this is associated with the risk of atherosclerosis.

ABETALIPOPROTEINAEMIA

An autosomal recessive disorder of lipoprotein metabolism in which lipoproteins containing apolipoprotein B (chylomicrons, very-low-density lipoproteins and low-density lipoproteins) are not synthesized; the disorder is characterized by the presence of acanthocytes in plasma, hypocholesterolaemia, progressive ataxic neuropathy, pigmentary retinal degeneration, defective intestinal lipid absorption and deficiency of fat-soluble vitamins.

LIPODYSTROPHY

A collection of rare conditions resulting from defective fat metabolism and characterized by atrophy of the subcutaneous fat.

LIPOPAENIA

An abnormally small amount, or a deficiency, of lipids in the body.

HYPERGLYCAEMIA

An abnormally high level of glucose in the blood; this occurs when the body does not have enough insulin (insulin deficiency) or cannot use the insulin that it does have (insulin resistance) to metabolize glucose.

HYPERINSULINAEMIA

Excessively high insulin levels in the blood, which can be caused by hypersecretion of a β-cell tumour (insulinoma), autoantibodies against insulin, defective insulin receptor, or the overuse of exogenous insulin or hypoglycaemic agents.

RESPIRATORY QUOTIENT

The ratio of the volume of carbon dioxide expired to the volume of oxygen consumed by an organism or cell over a given period of time.

HYPOKETOTIC HYPOGLYCAEMIA

Low serum ketone concentrations accompanied by low blood glucose.

HEPATOCARDIOMUSCULAR DISEASE

An inherited genetic disease caused by mutation of CPT2 and characterized by hypoketotic hypoglycaemia, liver failure, cardiomyopathy, and peripheral myopathy.

HYPERAMMONAEMIA

A metabolic disorder that is characterized by an elevated level of ammonia in the blood.

HYPERPHAGIA

The propensity to overeat.

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Shi, Y., Burn, P. Lipid metabolic enzymes: emerging drug targets for the treatment of obesity. Nat Rev Drug Discov 3, 695–710 (2004). https://doi.org/10.1038/nrd1469

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