title: Tamoxifen-induced anorexia is associated with fatty acid synthase inhibition in the ventromedial nucleus of the hypothalamus and accumulation of malonyl-CoA.
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.
authors.affiliation: Department of Clinical Biochemistry, University of Cambridge, Addenbrooke's Hospital, Hills Road, Cambridge CB2 2QR, U.K.
authors.forename: Miguel
authors.initials: M
authors.lastname: López
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Lelliott
authors.forename: Sulay
authors.initials: S
authors.lastname: Tovar
authors.forename: Wendy
authors.initials: W
authors.lastname: Kimber
authors.forename: Rosalía
authors.initials: R
authors.lastname: Gallego
authors.forename: Sam
authors.initials: S
authors.lastname: Virtue
authors.forename: Margaret
authors.initials: M
authors.lastname: Blount
authors.forename: Maria J
authors.initials: MJ
authors.lastname: Vázquez
authors.forename: Nick
authors.initials: N
authors.lastname: Finer
authors.forename: Trevor J
authors.initials: TJ
authors.lastname: Powles
authors.forename: Stephen
authors.initials: S
authors.lastname: O'Rahilly
authors.forename: Asish K
authors.initials: AK
authors.lastname: Saha
authors.forename: Carlos
authors.initials: C
authors.lastname: Diéguez
authors.forename: Antonio J
authors.initials: AJ
authors.lastname: Vidal-Puig
mesh_terms: 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
chemical_list: D013629:Tamoxifen; D008316:Malonyl Coenzyme A; D011333:Pro-Opiomelanocortin; D064429:Fatty Acid Synthases