Modulation of fatty acid metabolism as a potential approach to the treatment of obesity and the metabolic syndrome.
Increased de novo lipogenesis and reduced fatty acid oxidation are probable contributors to adipose accretion in obesity. Moreover, these perturbations have a role in leading to non-alcoholic steatohepatitis, dyslipidemia, and insulin resistance--via "lipotoxicity"-related mechanisms. Research in this area has prompted an effort to evaluate several discrete enzymes in these pathways as targets for future therapeutic intervention. Acetyl-CoA carboxylase 1 (ACC1) and ACC2 regulate fatty acid synthesis and indirectly control fatty acid oxidation via a key product, malonyl CoA. Based on mouse genetic and preclinical pharmacologic evidence, inhibition of ACC1 and/or ACC2 may be a useful approach to treat obesity and metabolic syndrome. Similarly, available data suggest that inhibition of other enzymes in this pathway, including fatty acid synthase, stearoyl CoA desaturase, and diacylglycerol acytransferase 1, will have beneficial effects. AMP-activated protein kinase is a master regulator of nutrient metabolism, which controls several aspects of lipid metabolism. Activation of AMPK in selected tissues is also a potential therapeutic approach. Inhibition of hormone-sensitive lipase is another possible approach. The rationale for modulating the activity of these enzymes and their relative merits (and downsides) as possible therapeutic targets are further discussed.
Kusunoki
Jun
J
Department of Metabolic Disorders, Banyu-Tsukuba Research Institute, Tsukuba, Japan.
Kanatani
Akio
A
Moller
David E
DE
D055372:AMP-Activated Protein Kinases; D000103:Acetyl-CoA Carboxylase / Q000037:antagonists & inhibitors / Q000502:physiology; D000818:Animals; D019440:Anti-Obesity Agents / Q000494:pharmacology / Q000627:therapeutic use*; D051048:Diacylglycerol O-Acyltransferase / Q000037:antagonists & inhibitors / Q000502:physiology; D004195:Disease Models, Animal; D004789:Enzyme Activation / Q000187:drug effects / Q000502:physiology; D064429:Fatty Acid Synthases / Q000037:antagonists & inhibitors / Q000502:physiology; D005227:Fatty Acids / Q000378:metabolism*; D006801:Humans; D008049:Lipase / Q000037:antagonists & inhibitors / Q000502:physiology; D050155:Lipogenesis / Q000502:physiology; D024821:Metabolic Syndrome / Q000188:drug therapy* / Q000209:etiology / Q000503:physiopathology; D051379:Mice; D009097:Multienzyme Complexes / Q000502:physiology; D009765:Obesity / Q000188:drug therapy* / Q000209:etiology / Q000503:physiopathology; D017346:Protein Serine-Threonine Kinases / Q000502:physiology; D013230:Stearoyl-CoA Desaturase / Q000037:antagonists & inhibitors / Q000502:physiology
D019440:Anti-Obesity Agents; D005227:Fatty Acids; D009097:Multienzyme Complexes; D013230:Stearoyl-CoA Desaturase; C494881:DGAT1 protein, human; D051048:Diacylglycerol O-Acyltransferase; D064429:Fatty Acid Synthases; D017346:Protein Serine-Threonine Kinases; D055372:AMP-Activated Protein Kinases; D008049:Lipase; D000103:Acetyl-CoA Carboxylase