Evaluation of Liver Fatty Acid Oxidation in the Leptin-Deficient Obese Mouse Amy E. Brix,* Ada Elgavish,* Tim R. Nagy,† Barbara A. Gower,† William J. Rhead,‡ ,1 and Philip A. Wood* ,2 *Departments of Genomics and Pathobiology, and †Department of Nutrition Sciences, University of Alabama at Birmingham, Birmingham, Alabama 35294; and ‡Department of Pediatrics, University of Iowa, Iowa City, Iowa Received November 30, 2001 We hypothesized that liver fatty acid oxidation (FAO) is compromised in the leptin-deficient obese (Lep ob /Lep ob ) mouse model, and that this would be further challenged when these mice were fed a high-fat diet. Obese mice had a 3.8-fold increased body fat content and a 9-fold increased liver fat content as compared to control mice when both groups were fed a low-fat diet. The expression of liver FAO enzymes, carnitine palmitoyltransferase- 1a, long-chain acyl-CoA dehydrogenase, medium- chain acyl-CoA dehydrogenase, and short-chain acyl-CoA dehydrogenase, was not affected in obese mice as compared to controls on either a low-fat or a high-fat diet. The expression of very-long-chain acyl-CoA dehydrogenase was elevated in obese mice on the control diet, as compared to control mice. For all measures evaluated, increasing the level of fat in the diet had a smaller effect than leptin defi- ciency. In summary, despite obese mice having an excess of fat available for mitochondrial -oxida- tion in liver, overall energy balance appeared to dictate that the net liver FAO remained at control levels. © 2002 Elsevier Science (USA) Key Words: dyslipidemia; hepatosteatosis; mito- chondrial fatty acid oxidation enzyme expression. Obesity is an increasing problem in Western soci- ety (1). The relationships among obesity, insulin resistance, and type 2 diabetes mellitus are unclear and controversial (2– 4). The metabolic mechanisms underlying the development of each of these patho- logic conditions remain confusing, in particular the distinction between causes and effects. Three main mechanisms are believed to underlie the development of obesity (1,5): (1) relative increase in energy intake; (2) relative decrease in energy expenditure; and (3) preferential partitioning of in- gested calories to fat storage. There is evidence that any of these abnormalities is sufficient to cause obe- sity (1,5). Whereas the first two mechanisms can be influenced by change in behavior, the third one is likely to be influenced by multiple genetic mecha- nisms (1) that are not as easily modified. Successful management of obesity depends on the elucidation of these mechanisms and their relative contribution to the obese phenotype. There has been considerable interest in the role that fatty acid oxidation (FAO) may play in the pathogenesis of obesity (3,6 –9). Furthermore, it ap- pears that leptin may have a role in the molecular regulation of FAO by altering the level of expression of the enzymes required for mitochondrial FAO (9 – 12). Therefore, FAO may not only be involved in the regulation of lipid metabolism, but also may be a crucial factor in the development of obesity. Blood lipids are frequently abnormal in obese individuals and may play a role in development of insulin resis- tance (2,4). In the studies reported here, we tested the hypothesis that fatty acid oxidation is compro- mised in the leptin-deficient obese (Lep ob /Lep ob ) mouse model, thus leading to obesity and dyslipid- 1 Current address: Department of Pediatrics, Medical College of Wisconsin, Milwaukee, WI. 2 To whom correspondence should be addressed at UAB Genomics and Pathobiology, VH 402-1670 University Boulevard, 1530 3rd Avenue South, Birmingham, AL 35294-0019. Fax: (205) 975-4418. E-mail: paw@uab.edu. Molecular Genetics and Metabolism 75, 219 –226 (2002) doi:10.1006/mgme.2002.3298, available online at http://www.idealibrary.com on 219 1096-7192/02 $35.00 © 2002 Elsevier Science (USA) All rights reserved.