Tamoxifen-induced anorexia is associated with fatty acid synthase inhibition in the ventromedial nucleus of the hypothalamus and accumulation of malonyl-CoA.
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.
López
Miguel
M
Department of Clinical Biochemistry, University of Cambridge, Addenbrooke's Hospital, Hills Road, Cambridge CB2 2QR, U.K.
Lelliott
Christopher J
CJ
Tovar
Sulay
S
Kimber
Wendy
W
Gallego
Rosalía
R
Virtue
Sam
S
Blount
Margaret
M
Vázquez
Maria J
MJ
Finer
Nick
N
Powles
Trevor J
TJ
O'Rahilly
Stephen
S
Saha
Asish K
AK
Diéguez
Carlos
C
Vidal-Puig
Antonio J
AJ
D000818:Animals; D000855:Anorexia / Q000139:chemically induced* / Q000201:enzymology / Q000378:metabolism; D001835:Body Weight / Q000187:drug effects; D002149:Energy Intake / Q000187:drug effects; D064429:Fatty Acid Synthases / Q000037:antagonists & inhibitors*; D005247:Feeding Behavior / Q000187:drug effects; D008316:Malonyl Coenzyme A / Q000378:metabolism*; D011333:Pro-Opiomelanocortin / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D013629:Tamoxifen / Q000494:pharmacology*; D014697:Ventromedial Hypothalamic Nucleus / Q000187:drug effects / Q000378:metabolism*; D015431:Weight Loss / Q000187:drug effects
D013629:Tamoxifen; D008316:Malonyl Coenzyme A; D011333:Pro-Opiomelanocortin; D064429:Fatty Acid Synthases