Hypothalamic-Specific Manipulation of Fto, the Ortholog of the Human Obesity Gene FTO, Affects Food Intake in Rats

Autor: Xiaoye Shan, Yi Chun Loraine Tung, Giles S.H. Yeo, Eduard Ayuso, Anthony P. Coll, Fatima Bosch, Stephen O'Rahilly
Jazyk: angličtina
Rok vydání: 2010
Předmět:
medicine.medical_specialty
endocrine system diseases
Physiology
media_common.quotation_subject
Hypothalamus
lcsh:Medicine
Alpha-Ketoglutarate-Dependent Dioxygenase FTO
Adipose tissue
030209 endocrinology & metabolism
Biology
Mixed Function Oxygenases
Diabetes and Endocrinology/Obesity
03 medical and health sciences
0302 clinical medicine
Internal medicine
Gene expression
medicine
Animals
Homeostasis
Obesity
lcsh:Science
030304 developmental biology
media_common
2. Zero hunger
0303 health sciences
Neuroscience/Behavioral Neuroscience
Multidisciplinary
Leptin receptor
Arc (protein)
lcsh:R
digestive
oral
and skin physiology

Oxo-Acid-Lyases
nutritional and metabolic diseases
Appetite
Feeding Behavior
pathological conditions
signs and symptoms

medicine.disease
Rats
Genetics and Genomics/Gene Function
Endocrinology
Obesitat
lcsh:Q
Fto
Energy Intake
Energy Metabolism
Research Article
Zdroj: PLoS ONE; Vol 5
PLoS ONE
PLoS ONE, Vol 5, Iss 1, p e8771 (2010)
Dipòsit Digital de Documents de la UAB
Universitat Autònoma de Barcelona
ISSN: 1932-6203
DOI: 10.1371/journal.pone.0008771
Popis: Altres ajuts: CLINIGENE/LSHB-CT-2006-018933 Altres ajuts: UK/MRC-CORD Sequence variants in the first intron of FTO are strongly associated with human obesity and human carriers of the risk alleles show evidence for increased appetite and food intake. Mice globally lacking Fto display a complex phenotype characterised by both increased energy expenditure and increased food intake. The site of action of FTO on energy balance is unclear. Fasting reduces levels of Fto mRNA in the arcuate nucleus (ARC) of the hypothalamus, a site where Fto expression is particularly high. In this study, we have extended this nutritional link by demonstrating that consumption of a high fat diet (45%) results in a 2.5 fold increase in Arc Fto expression. We have further explored the role of hypothalamic Fto in the control of food intake by using stereotactic injections coupled with AAV technology to bi-directionally modulate Fto expression. An over expression of Fto protein by 2.5-fold in the ARC results in a 14% decrease in average daily food intake in the first week. In contrast, knocking down Arc Fto expression by 40% increases food intake by 16%. mRNA levels of Agrp, Pomc and Npy, ARC-expressed genes classically associated with the control of food intake, were not affected by the manipulation of Fto expression. However, over expression of Fto resulted in a 4-fold increase in the mRNA levels of Stat3, a signalling molecule critical for leptin receptor signalling, suggesting a possible candidate for the mediation of Fto's actions. These data provide further support for the notion that FTO itself can influence key components of energy balance, and is therefore a strong candidate for the mediation of the robust association between FTO intronic variants and adiposity. Importantly, this provide the first indication that selective alteration of FTO levels in the hypothalamus can influence food intake, a finding consistent with the reported effects of FTO alleles on appetite and food intake in man.
Databáze: OpenAIRE