Tamoxifen-Induced Anorexia Is Associated With Fatty Acid Synthase Inhibition in the Ventromedial Nucleus of the Hypothalamus and Accumulation of Malonyl-CoA

  1. Miguel López1,
  2. Christopher J. Lelliott1,
  3. Sulay Tovar2,
  4. Wendy Kimber1,
  5. Rosalía Gallego3,
  6. Sam Virtue1,
  7. Margaret Blount1,
  8. Maria J. Vázquez2,
  9. Nick Finer1,
  10. Trevor J. Powles4,
  11. Stephen O’Rahilly1,
  12. Asish K. Saha5,
  13. Carlos Diéguez2 and
  14. Antonio J. Vidal-Puig1
  1. 1Department of Clinical Biochemistry, University of Cambridge, Addenbrooke’s Hospital, Cambridge, U.K
  2. 2Department of Physiology, School of Medicine, University of Santiago de Compostela, Santiago de Compostela, Spain
  3. 3Department of Morphological Sciences, School of Medicine, University of Santiago de Compostela, Santiago de Compostela, Spain
  4. 4Parkside Oncology Clinic, London, U.K
  5. 5Diabetes Research Unit, EBRC-827, Boston Medical Centre, Boston, Massachusetts
  1. Address correspondence and reprint requests to Antonio J. Vidal-Puig, PhD, MD, Department of Clinical Biochemistry, University of Cambridge, Addenbrooke’s Hospital, Hills Road Cambridge, CB2 2QR, U.K. E-mail: ajv22{at}cam.ac.uk

Abstract

Fatty acid metabolism in the hypothalamus has recently been shown to regulate feeding. The selective estrogen receptor modulator tamoxifen (TMX) exerts a potent anorectic effect. Here, we show that the anorectic effect of TMX is associated with the accumulation of malonyl-CoA in the hypothalamus and inhibition of fatty acid synthase (FAS) expression specifically in the ventromedial nucleus of the hypothalamus (VMN). Furthermore, we demonstrate that FAS mRNA expression is physiologically regulated by fasting and refeeding in the VMN but not in other hypothalamic nuclei. Thus, the VMN appears to be the hypothalamic site where regulation of FAS and feeding converge. Supporting the potential clinical relevance of these observations, reanalysis of a primary breast cancer prevention study showed that obese women treated with TMX gained significantly less body weight over a 6-year period than obese women given placebo. The finding that TMX can modulate appetite through alterations in FAS expression and malonyl-CoA levels suggests a link between hypothalamic sex steroid receptors, fatty acid metabolism, and feeding behavior.

Footnotes

  • M.L. and C.J.L. contributed equally to this work.

  • Additional information for this article can be found in an online appendix at http://diabetes.diabetesjournals.org.

  • The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

    • Accepted February 1, 2006.
    • Received October 18, 2005.
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