Hypothalamic Fkbp51 is induced by fasting, and elevated hypothalamic expression promotes obese phenotypes.
To discover hypothalamic genes that might play a role in regulating energy balance, we carried out a microarray screen for genes induced by a 48-h fast in male C57Bl/6J mouse hypothalamus. One such gene was Fkbp51 (FK506 binding protein 5; Locus NP_034350). The product of this gene is of interest because it blocks glucocorticoid action, suggesting that fasting-induced elevation of this gene in the hypothalamus may reduce glucocorticoid negative feedback, leading to elevated glucocorticoid levels, thus promoting obese phenotypes. Subsequent analysis demonstrated that a 48-h fast induces Fkbp51 in ventromedial, paraventricular, and arcuate hypothalamic nuclei of mice and rats. To assess if hypothalamic Fkbp51 promotes obesity, the gene was transferred to the hypothalamus via an adeno-associated virus vector. Within 2 wk following Fkbp51 overexpression, mice on a high-fat diet exhibited elevated body weight, without hyperphagia, relative to mice receiving the control mCherry vector. Body weight remained elevated for more than 8 wk and was associated with elevated corticosterone and impaired glucose tolerance. These studies suggest that elevated hypothalamic Fkbp51 promotes obese phenotypes.
Fishberg Dept. of Neuroscience, Mount Sinai School of Medicine, New York, NY 10029, USA.
Linda
L
Yang
Fumiko
F
Isoda
Kelvin
K
Yen
Steven P
SP
Kleopoulos
William
W
Janssen
Xiaoning
X
Fan
Jason
J
Mastaitis
Ambrose
A
Dunn-Meynell
Barry
B
Levin
Rory
R
McCrimmon
Robert
R
Sherwin
Sergei
S
Musatov
Charles V
CV
Mobbs
D000818:Animals; D001111:Arcuate Nucleus of Hypothalamus / Q000378:metabolism; D003345:Corticosterone / Q000097:blood; D002149:Energy Intake; D005215:Fasting / Q000378:metabolism*; D020869:Gene Expression Profiling; D018149:Glucose Intolerance / Q000097:blood / Q000378:metabolism; D007031:Hypothalamus / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009765:Obesity / Q000097:blood / Q000378:metabolism*; D020411:Oligonucleotide Array Sequence Analysis; D010286:Paraventricular Hypothalamic Nucleus / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D022021:Tacrolimus Binding Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D015854:Up-Regulation; D014697:Ventromedial Hypothalamic Nucleus / Q000378:metabolism; D015430:Weight Gain; D000099159:Tacrolimus Binding Protein 5
D003345:Corticosterone; D012333:RNA, Messenger; D022021:Tacrolimus Binding Proteins; D000099159:Tacrolimus Binding Protein 5