Loss of cytokine-STAT5 signaling in the CNS and pituitary gland alters energy balance and leads to obesity.
Signal transducers and activators of transcription (STATs) are critical components of cytokine signaling pathways. STAT5A and STAT5B (STAT5), the most promiscuous members of this family, are highly expressed in specific populations of hypothalamic neurons in regions known to mediate the actions of cytokines in the regulation of energy balance. To test the hypothesis that STAT5 signaling is essential to energy homeostasis, we used Cre-mediated recombination to delete the Stat5 locus in the CNS. Mutant males and females developed severe obesity with hyperphagia, impaired thermal regulation in response to cold, hyperleptinemia and insulin resistance. Furthermore, central administration of GM-CSF mediated the nuclear accumulation of STAT5 in hypothalamic neurons and reduced food intake in control but not in mutant mice. These results demonstrate that STAT5 mediates energy homeostasis in response to endogenous cytokines such as GM-CSF.
Lee
Ji-Yeon
JY
Laboratory of Genetics and Physiology, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland, USA.
Muenzberg
Heike
H
Gavrilova
Oksana
O
Reed
Jacquelyn A
JA
Berryman
Darlene
D
Villanueva
Eneida C
EC
Louis
Gwendolyn W
GW
Leinninger
Gina M
GM
Bertuzzi
Stefano
S
Seeley
Randy J
RJ
Robinson
Gertraud W
GW
Myers
Martin G
MG
Hennighausen
Lothar
L
D021581:Active Transport, Cell Nucleus; D000818:Animals; D002490:Central Nervous System / Q000378:metabolism*; D016207:Cytokines / Q000502:physiology; D004734:Energy Metabolism; D005260:Female; D006706:Homeostasis; D007031:Hypothalamus / Q000166:cytology; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D009474:Neurons / Q000378:metabolism; D009765:Obesity / Q000209:etiology*; D010902:Pituitary Gland / Q000378:metabolism*; D050799:STAT5 Transcription Factor / Q000502:physiology*; D015398:Signal Transduction
D016207:Cytokines; D050799:STAT5 Transcription Factor; C494093:Stat5a protein, mouse; C494096:Stat5b protein, mouse