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Loss of cytokine-STAT5 signaling in the CNS and pituitary gland alters energy balance and leads to obesity.

Lee JY, Muenzberg H, Gavrilova O, Reed JA, Berryman D, Villanueva EC, Louis GW, Leinninger GM, Bertuzzi S, Seeley RJ, Robinson GW, Myers MG, Hennighausen L - PLoS ONE (2008)

Bottom Line: 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.These results demonstrate that STAT5 mediates energy homeostasis in response to endogenous cytokines such as GM-CSF.

View Article: PubMed Central - PubMed

Affiliation: Laboratory of Genetics and Physiology, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland, USA.

ABSTRACT
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.

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Related in: MedlinePlus

Summary diagram of cytokine signaling pathways controlling body weight.While leptin preferentially signals through STAT3, GM-CSF utilizes STAT5. However, since the GM-CSF- mice develop milder symptoms than the STAT5-mutant mice described in this study, we propose that some of the STAT5 signaling is induced by leptin or yet another unknown pathway.
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pone-0001639-g011: Summary diagram of cytokine signaling pathways controlling body weight.While leptin preferentially signals through STAT3, GM-CSF utilizes STAT5. However, since the GM-CSF- mice develop milder symptoms than the STAT5-mutant mice described in this study, we propose that some of the STAT5 signaling is induced by leptin or yet another unknown pathway.

Mentions: As shown in this study, deletion of STAT5 in the CNS of mice results in increased food intake, significant obesity by 17 weeks of age, and impairment of the anorexic response to GM-CSF administration. While a large body of evidence has pointed towards a key role for hypothalamic STAT3 in the regulation of energy balance, the current results suggest an important role for STAT5 in the regulation of feeding and body fat stores in response to endogenous signals (summary diagram Figure 11). Specifically, we observed a link between STAT5 and GM-CSF, which is known to play a role in the regulation of energy balance. Loss of STAT5 in the CNS results not only in increased food intake, but also alters the regulation of energy expenditure, as demonstrated by the reduced metabolic rate in males and reduced tolerance to prolonged cold exposure.


Loss of cytokine-STAT5 signaling in the CNS and pituitary gland alters energy balance and leads to obesity.

Lee JY, Muenzberg H, Gavrilova O, Reed JA, Berryman D, Villanueva EC, Louis GW, Leinninger GM, Bertuzzi S, Seeley RJ, Robinson GW, Myers MG, Hennighausen L - PLoS ONE (2008)

Summary diagram of cytokine signaling pathways controlling body weight.While leptin preferentially signals through STAT3, GM-CSF utilizes STAT5. However, since the GM-CSF- mice develop milder symptoms than the STAT5-mutant mice described in this study, we propose that some of the STAT5 signaling is induced by leptin or yet another unknown pathway.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2237899&req=5

pone-0001639-g011: Summary diagram of cytokine signaling pathways controlling body weight.While leptin preferentially signals through STAT3, GM-CSF utilizes STAT5. However, since the GM-CSF- mice develop milder symptoms than the STAT5-mutant mice described in this study, we propose that some of the STAT5 signaling is induced by leptin or yet another unknown pathway.
Mentions: As shown in this study, deletion of STAT5 in the CNS of mice results in increased food intake, significant obesity by 17 weeks of age, and impairment of the anorexic response to GM-CSF administration. While a large body of evidence has pointed towards a key role for hypothalamic STAT3 in the regulation of energy balance, the current results suggest an important role for STAT5 in the regulation of feeding and body fat stores in response to endogenous signals (summary diagram Figure 11). Specifically, we observed a link between STAT5 and GM-CSF, which is known to play a role in the regulation of energy balance. Loss of STAT5 in the CNS results not only in increased food intake, but also alters the regulation of energy expenditure, as demonstrated by the reduced metabolic rate in males and reduced tolerance to prolonged cold exposure.

Bottom Line: 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.These results demonstrate that STAT5 mediates energy homeostasis in response to endogenous cytokines such as GM-CSF.

View Article: PubMed Central - PubMed

Affiliation: Laboratory of Genetics and Physiology, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland, USA.

ABSTRACT
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.

Show MeSH
Related in: MedlinePlus