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PNAS 105 (18): 6531-6536

Copyright © 2008 by the National Academy of Sciences.

BIOLOGICAL SCIENCES / APPLIED BIOLOGICAL SCIENCES

Mice lacking angiotensin-converting enzyme have increased energy expenditure, with reduced fat mass and improved glucose clearance

Anura P. Jayasooriya*,{dagger}, Michael L. Mathai*,{ddagger},§,¶, Lesley L. Walker*, Denovan P. Begg||,**, Derek A. Denton,{dagger}{dagger},{ddagger}{ddagger}, David Cameron-Smith**, Gary F. Egan*, Michael J. McKinley*,§§, Paula D. Rodger||, Andrew J. Sinclair**, John D. Wark¶¶, Harrison S. Weisinger||, Mark Jois||, and Richard S. Weisinger*,||

{dagger}{dagger}Dean's Ganglion, {ddagger}Centre for Neuroscience, §§Department of Physiology, and ¶¶Royal Melbourne Hospital, Faculty of Medicine, and *Howard Florey Institute, University of Melbourne, Victoria 3010, Australia; {dagger}Faculty of Veterinary Medicine, University of Peradeniya, Peradeniya 20400, Sri Lanka; §School of Biomedical and Health Sciences, Victoria University, Victoria 3021, Australia; ||School of Psychological Science, La Trobe University, Victoria 3086, Australia; **School of Exercise and Nutrition Sciences, Deakin University, Victoria 3125, Australia; and {ddagger}{ddagger}Baker Heart Research Institute, Prahran, Victoria 3004, Australia

Contributed by Derek A. Denton, March 17, 2008

Received for publication November 9, 2007.

Abstract: In addition to its role in the storage of fat, adipose tissue acts as an endocrine organ, and it contains a functional renin-angiotensin system (RAS). Angiotensin-converting enzyme (ACE) plays a key role in the RAS by converting angiotensin I to the bioactive peptide angiotensin II (Ang II). In the present study, the effect of targeting the RAS in body energy homeostasis and glucose tolerance was determined in homozygous mice in which the gene for ACE had been deleted (ACE–/–) and compared with wild-type littermates. Compared with wild-type littermates, ACE–/– mice had lower body weight and a lower proportion of body fat, especially in the abdomen. ACE–/– mice had greater fed-state total energy expenditure (TEE) and resting energy expenditure (REE) than wild-type littermates. There were pronounced increases in gene expression of enzymes related to lipolysis and fatty acid oxidation (lipoprotein lipase, carnitine palmitoyl transferase, long-chain acetyl CoA dehydrogenase) in the liver of ACE–/– mice and also lower plasma leptin. In contrast, no differences were detected in daily food intake, activity, fed-state plasma lipids, or proportion of fat excreted in fecal matter. In conclusion, the reduction in ACE activity is associated with a decreased accumulation of body fat, especially in abdominal fat depots. The decreased body fat in ACE–/– mice is independent of food intake and appears to be due to a high energy expenditure related to increased metabolism of fatty acids in the liver, with the additional effect of increased glucose tolerance.

Key Words: fatty acid metabolism • obesity • ACE knockout mice • glucose tolerance

Author contributions: A.P.J. and M.L.M. contributed equally to this work; M.L.M., A.J.S., and R.S.W. designed research; A.P.J., L.L.W., D.P.B., D.C.-S., and P.D.R. performed research; D.A.D., G.F.E., J.D.W., and R.S.W. contributed new reagents/analytic tools; H.S.W., M.J., and R.S.W. analyzed data; and A.P.J., M.L.M., D.P.B., and M.J.M. wrote the paper.

The authors declare no conflict of interest.

To whom correspondence may be addressed: E-mail: michael.mathai{at}florey.edu.au or ddenton{at}unimelb.edu.au

© 2008 by The National Academy of Sciences of the USA

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