Hypothalamic FTO is associated with the regulation of energy intake not feeding reward.
BACKGROUND
Polymorphism in the FTO gene is strongly associated with obesity, but little is known about the molecular bases of this relationship. We investigated whether hypothalamic FTO is involved in energy-dependent overconsumption of food. We determined FTO mRNA levels in rodent models of short- and long-term intake of palatable fat or sugar, deprivation, diet-induced increase in body weight, baseline preference for fat versus sugar as well as in same-weight animals differing in the inherent propensity to eat calories especially upon availability of diverse diets, using quantitative PCR. FTO gene expression was also studied in organotypic hypothalamic cultures treated with anorexigenic amino acid, leucine. In situ hybridization (ISH) was utilized to study FTO signal in reward- and hunger-related sites, colocalization with anorexigenic oxytocin, and c-Fos immunoreactivity in FTO cells at initiation and termination of a meal.


RESULTS
Deprivation upregulated FTO mRNA, while leucine downregulated it. Consumption of palatable diets or macronutrient preference did not affect FTO expression. However, the propensity to ingest more energy without an effect on body weight was associated with lower FTO mRNA levels. We found that 4-fold higher number of FTO cells displayed c-Fos at meal termination as compared to initiation in the paraventricular and arcuate nuclei of re-fed mice. Moreover, ISH showed that FTO is present mainly in hunger-related sites and it shows a high degree of colocalization with anorexigenic oxytocin.


CONCLUSIONS
We conclude that FTO mRNA is present mainly in sites related to hunger/satiation control; changes in hypothalamic FTO expression are associated with cues related to energy intake rather than feeding reward. In line with that, neurons involved in feeding termination express FTO. Interestingly, baseline FTO expression appears linked not only with energy intake but also energy metabolism.
Olszewski
Pawel K
PK
Department of Neuroscience, Functional Pharmacology, Uppsala University, Uppsala, Sweden. olsze005@umn.edu
Fredriksson
Robert
R
Olszewska
Agnieszka M
AM
Stephansson
Olga
O
Alsiö
Johan
J
Radomska
Katarzyna J
KJ
Levine
Allen S
AS
Schiöth
Helgi B
HB
D000071516:Alpha-Ketoglutarate-Dependent Dioxygenase FTO; D000704:Analysis of Variance; D000818:Animals; D001835:Body Weight; D004032:Diet; D004435:Eating / Q000502:physiology; D002149:Energy Intake / Q000502:physiology*; D005217:Fat Emulsions, Intravenous / Q000008:administration & dosage; D005247:Feeding Behavior / Q000502:physiology*; D007031:Hypothalamus / Q000187:drug effects / Q000378:metabolism*; D017403:In Situ Hybridization; D007930:Leucine / Q000494:pharmacology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D006899:Mixed Function Oxygenases; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D009924:Organ Culture Techniques; D007652:Oxo-Acid-Lyases / Q000235:genetics / Q000378:metabolism*; D010121:Oxytocin / Q000378:metabolism; D016760:Proto-Oncogene Proteins c-fos / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012201:Reward; D013395:Sucrose / Q000008:administration & dosage
D005217:Fat Emulsions, Intravenous; D016760:Proto-Oncogene Proteins c-fos; D012333:RNA, Messenger; D010121:Oxytocin; D013395:Sucrose; D006899:Mixed Function Oxygenases; C524916:FTO protein, mouse; D000071516:Alpha-Ketoglutarate-Dependent Dioxygenase FTO; D007652:Oxo-Acid-Lyases; D007930:Leucine