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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

Expression of neuropeptide and regulatory genes in the Arc of Stat5fl/fl control (ff) and Stat5fl/fl ; Nestin-Cre (ffnc) female mice.Total RNA prepared from microdissected Arc tissue from ff and ffnc mice was subjected to semi-quantitative real-time PCR for POMC, AgRP, NPY and SOCS3 mRNA expression. n = 9–10; * t(17) = 3.7, p = 0.002 by students t test, all other comparisons, p = NS.
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pone-0001639-g008: Expression of neuropeptide and regulatory genes in the Arc of Stat5fl/fl control (ff) and Stat5fl/fl ; Nestin-Cre (ffnc) female mice.Total RNA prepared from microdissected Arc tissue from ff and ffnc mice was subjected to semi-quantitative real-time PCR for POMC, AgRP, NPY and SOCS3 mRNA expression. n = 9–10; * t(17) = 3.7, p = 0.002 by students t test, all other comparisons, p = NS.

Mentions: In order to determine the potential dysregulation of Arc gene expression in Stat5fl/fl; Nestin-Cre mice, we microdissected the Arc of control and Stat5fl/fl; Nestin-Cre animals and analyzed the expression of the neuropeptides POMC, AgRP, and NPY, and the obesogenic JAK/STAT inhibitor SOCS3 by semi-quantitative qPCR (Figure 8). This analysis demonstrated no significant difference in neuropeptide gene expression in the Arc of Stat5fl/fl; Nestin-Cre animals but revealed decreased SOCS3 mRNA expression in the Stat5fl/fl; Nestin-Cre mice. This reduction in Arc SOCS3 mRNA expression in the STAT5 mutant mice is consistent with results from other tissues in which deletion of STAT5 reduces the baseline expression of SOCS3 [19], and demonstrates the importance of STAT5 in the regulation of Socs3 gene expression in the hypothalamus as well as peripheral tissues. These data furthermore suggest that the regulation of energy balance by CNS STAT5-mediated transcriptional control is mediated by mRNAs other than those encoded by these Arc genes.


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)

Expression of neuropeptide and regulatory genes in the Arc of Stat5fl/fl control (ff) and Stat5fl/fl ; Nestin-Cre (ffnc) female mice.Total RNA prepared from microdissected Arc tissue from ff and ffnc mice was subjected to semi-quantitative real-time PCR for POMC, AgRP, NPY and SOCS3 mRNA expression. n = 9–10; * t(17) = 3.7, p = 0.002 by students t test, all other comparisons, p = NS.
© Copyright Policy
Related In: Results  -  Collection

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

pone-0001639-g008: Expression of neuropeptide and regulatory genes in the Arc of Stat5fl/fl control (ff) and Stat5fl/fl ; Nestin-Cre (ffnc) female mice.Total RNA prepared from microdissected Arc tissue from ff and ffnc mice was subjected to semi-quantitative real-time PCR for POMC, AgRP, NPY and SOCS3 mRNA expression. n = 9–10; * t(17) = 3.7, p = 0.002 by students t test, all other comparisons, p = NS.
Mentions: In order to determine the potential dysregulation of Arc gene expression in Stat5fl/fl; Nestin-Cre mice, we microdissected the Arc of control and Stat5fl/fl; Nestin-Cre animals and analyzed the expression of the neuropeptides POMC, AgRP, and NPY, and the obesogenic JAK/STAT inhibitor SOCS3 by semi-quantitative qPCR (Figure 8). This analysis demonstrated no significant difference in neuropeptide gene expression in the Arc of Stat5fl/fl; Nestin-Cre animals but revealed decreased SOCS3 mRNA expression in the Stat5fl/fl; Nestin-Cre mice. This reduction in Arc SOCS3 mRNA expression in the STAT5 mutant mice is consistent with results from other tissues in which deletion of STAT5 reduces the baseline expression of SOCS3 [19], and demonstrates the importance of STAT5 in the regulation of Socs3 gene expression in the hypothalamus as well as peripheral tissues. These data furthermore suggest that the regulation of energy balance by CNS STAT5-mediated transcriptional control is mediated by mRNAs other than those encoded by these Arc genes.

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