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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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Potential role for Stat5 in OX-expressing LHA neurons in mice.(A) Histochemical sections from perfused wild-type male mice were subjected to immunostaining for OX (green, left) and STAT5B (red, middle). Right panel shows merged images demonstrating co-localization of prominent STAT5B expression with OX-expression in the LHA. Insets: magnified view of co-labeled neurons. F = fornix. (B) Total RNA prepared from whole hypothalamus tissue from and Stat5fl/f (ff) and Stat5fl/fl; Nestin-Cre (ffnc) mice treated with vehicle (veh) or GM-CSF (GM) was subjected to semi-quantitative real-time PCR for POMC, AgRP, NPY and OX mRNA expression. n>5; *p = 0.01 versus Wt Veh, S5, Veh by ANOVA F(3, 55) = 4.383 with Fisher's LSD test.
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pone-0001639-g010: Potential role for Stat5 in OX-expressing LHA neurons in mice.(A) Histochemical sections from perfused wild-type male mice were subjected to immunostaining for OX (green, left) and STAT5B (red, middle). Right panel shows merged images demonstrating co-localization of prominent STAT5B expression with OX-expression in the LHA. Insets: magnified view of co-labeled neurons. F = fornix. (B) Total RNA prepared from whole hypothalamus tissue from and Stat5fl/f (ff) and Stat5fl/fl; Nestin-Cre (ffnc) mice treated with vehicle (veh) or GM-CSF (GM) was subjected to semi-quantitative real-time PCR for POMC, AgRP, NPY and OX mRNA expression. n>5; *p = 0.01 versus Wt Veh, S5, Veh by ANOVA F(3, 55) = 4.383 with Fisher's LSD test.

Mentions: While our prior analysis of Arc mRNA expression did not reveal a role for STAT5 in the regulation of Arc neuropeptide gene expression, we noticed a population of highly STAT5-immunoreactive neurons dorsal to the fornix in LHA of wild-type animals (Figure 1A). Our subsequent analysis demonstrated this to be almost exclusively STAT5B (data not shown). Since our qPCR analysis also demonstrated the most complete reduction of STAT5 mRNA expression in the LHA, we examined the potential role for STAT5 in the LHA (Figure 10). We initially examined the co-localization of STAT5B in the LHA with the appetite- and activity-regulating neuropeptide, orexin (OX) by immunofluorescence (Figure 10A), revealing the virtually complete overlap of neurons demonstrating the prominent expression of STAT5B with those containing immunoreactive OX. These data suggest the potential importance of STAT5 in the regulation of these LHA OX neurons, prompting us to examine the regulation of Arc neuropeptide and Hcrt gene expression in RNA prepared from the hypothalami of the control and Stat5fl/fl; Nestin-Cre mice following i3vt GM-CSF treatment (Figure 10B). This analysis confirmed our previous finding that Arc neuropeptide mRNA expression is normal in Stat5fl/fl; Nestin-Cre mice, and also demonstrated the reduced expression of OX mRNA in the hypothalamus of vehicle-treated Stat5fl/fl; Nestin-Cre mice compared to controls. Acute i3vt GM-CSF treatment restored the hypothalamic expression of OX to normal levels in Stat5fl/fl; Nestin-Cre mice, however, suggesting that STAT5 mediates GM-CSF-induced anorexia by OX-independent mechanisms, and that GM-CSF can regulate OX mRNA expression independently of STAT5. Overall, however, STAT5B is highly expressed in LHA OX neurons and regulates baseline OX expression, suggesting that STAT5 in LHA OX neurons may be important for the regulation of energy balance.


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)

Potential role for Stat5 in OX-expressing LHA neurons in mice.(A) Histochemical sections from perfused wild-type male mice were subjected to immunostaining for OX (green, left) and STAT5B (red, middle). Right panel shows merged images demonstrating co-localization of prominent STAT5B expression with OX-expression in the LHA. Insets: magnified view of co-labeled neurons. F = fornix. (B) Total RNA prepared from whole hypothalamus tissue from and Stat5fl/f (ff) and Stat5fl/fl; Nestin-Cre (ffnc) mice treated with vehicle (veh) or GM-CSF (GM) was subjected to semi-quantitative real-time PCR for POMC, AgRP, NPY and OX mRNA expression. n>5; *p = 0.01 versus Wt Veh, S5, Veh by ANOVA F(3, 55) = 4.383 with Fisher's LSD test.
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Related In: Results  -  Collection

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pone-0001639-g010: Potential role for Stat5 in OX-expressing LHA neurons in mice.(A) Histochemical sections from perfused wild-type male mice were subjected to immunostaining for OX (green, left) and STAT5B (red, middle). Right panel shows merged images demonstrating co-localization of prominent STAT5B expression with OX-expression in the LHA. Insets: magnified view of co-labeled neurons. F = fornix. (B) Total RNA prepared from whole hypothalamus tissue from and Stat5fl/f (ff) and Stat5fl/fl; Nestin-Cre (ffnc) mice treated with vehicle (veh) or GM-CSF (GM) was subjected to semi-quantitative real-time PCR for POMC, AgRP, NPY and OX mRNA expression. n>5; *p = 0.01 versus Wt Veh, S5, Veh by ANOVA F(3, 55) = 4.383 with Fisher's LSD test.
Mentions: While our prior analysis of Arc mRNA expression did not reveal a role for STAT5 in the regulation of Arc neuropeptide gene expression, we noticed a population of highly STAT5-immunoreactive neurons dorsal to the fornix in LHA of wild-type animals (Figure 1A). Our subsequent analysis demonstrated this to be almost exclusively STAT5B (data not shown). Since our qPCR analysis also demonstrated the most complete reduction of STAT5 mRNA expression in the LHA, we examined the potential role for STAT5 in the LHA (Figure 10). We initially examined the co-localization of STAT5B in the LHA with the appetite- and activity-regulating neuropeptide, orexin (OX) by immunofluorescence (Figure 10A), revealing the virtually complete overlap of neurons demonstrating the prominent expression of STAT5B with those containing immunoreactive OX. These data suggest the potential importance of STAT5 in the regulation of these LHA OX neurons, prompting us to examine the regulation of Arc neuropeptide and Hcrt gene expression in RNA prepared from the hypothalami of the control and Stat5fl/fl; Nestin-Cre mice following i3vt GM-CSF treatment (Figure 10B). This analysis confirmed our previous finding that Arc neuropeptide mRNA expression is normal in Stat5fl/fl; Nestin-Cre mice, and also demonstrated the reduced expression of OX mRNA in the hypothalamus of vehicle-treated Stat5fl/fl; Nestin-Cre mice compared to controls. Acute i3vt GM-CSF treatment restored the hypothalamic expression of OX to normal levels in Stat5fl/fl; Nestin-Cre mice, however, suggesting that STAT5 mediates GM-CSF-induced anorexia by OX-independent mechanisms, and that GM-CSF can regulate OX mRNA expression independently of STAT5. Overall, however, STAT5B is highly expressed in LHA OX neurons and regulates baseline OX expression, suggesting that STAT5 in LHA OX neurons may be important for the regulation of energy balance.

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