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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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Reduced STAT5 expression in hypothalamic neurons in Stat5fl/fl; Nestin-Cre male mice.(A) Immunohistochemical analyses with αSTAT5 antibodies were performed on hypothalamic tissues from Stat5fl/fl control (ff, left panels) and Stat5fl/fl; Nestin-Cre (ffnc, right panels) mice. Note the prominent expression of STAT5 isoforms in discrete neurons and the dramatic reduction in STAT5-positive cells in ffnc mice. Upper panels show hypothalamic sections rostral to those shown in lower panels. 3V = third cerebral ventricle, ME = median eminence, f = fornix; all other abbreviations as defined in the text. (B) Immunostaining for STAT5 (green, top), the neural marker, Hu (red, middle) and merged images (bottom) in the LHA ff and ffnc animals. This demonstrates the co-localization/expression of STAT5 in neurons of ff animals and the absence of STAT5 from many Hu-positive neurons in ffnc mice. (C) Total RNA from microdissected hypothalamic subregions of ff and ffnc mice was subjected to semi-quantitative real-time PCR for STAT5A and STAT5B mRNA expression, confirming the reduction in the expression of both STAT5 isoforms in each region.
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pone-0001639-g001: Reduced STAT5 expression in hypothalamic neurons in Stat5fl/fl; Nestin-Cre male mice.(A) Immunohistochemical analyses with αSTAT5 antibodies were performed on hypothalamic tissues from Stat5fl/fl control (ff, left panels) and Stat5fl/fl; Nestin-Cre (ffnc, right panels) mice. Note the prominent expression of STAT5 isoforms in discrete neurons and the dramatic reduction in STAT5-positive cells in ffnc mice. Upper panels show hypothalamic sections rostral to those shown in lower panels. 3V = third cerebral ventricle, ME = median eminence, f = fornix; all other abbreviations as defined in the text. (B) Immunostaining for STAT5 (green, top), the neural marker, Hu (red, middle) and merged images (bottom) in the LHA ff and ffnc animals. This demonstrates the co-localization/expression of STAT5 in neurons of ff animals and the absence of STAT5 from many Hu-positive neurons in ffnc mice. (C) Total RNA from microdissected hypothalamic subregions of ff and ffnc mice was subjected to semi-quantitative real-time PCR for STAT5A and STAT5B mRNA expression, confirming the reduction in the expression of both STAT5 isoforms in each region.

Mentions: Immunohistochemical analysis using antisera reactive with both STAT5 isoforms demonstrated the prominent presence of STAT5 in discrete neuronal populations in a number of areas in the adult brain including basal ganglia, septum, cortex (not shown) and hypothalamus (Figure 1A). Particularly relevant to the phenotype described in this study, we detected STAT5 in a limited number of cells within areas of the hypothalamus known to regulate feeding and energy balance (Figure 1A), including the Arc, dorsomedial and ventromedial hypothalamic nuclei (DMH and VMH), and the LHA, suggesting a potential role for Stat5 in energy homeostasis.


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)

Reduced STAT5 expression in hypothalamic neurons in Stat5fl/fl; Nestin-Cre male mice.(A) Immunohistochemical analyses with αSTAT5 antibodies were performed on hypothalamic tissues from Stat5fl/fl control (ff, left panels) and Stat5fl/fl; Nestin-Cre (ffnc, right panels) mice. Note the prominent expression of STAT5 isoforms in discrete neurons and the dramatic reduction in STAT5-positive cells in ffnc mice. Upper panels show hypothalamic sections rostral to those shown in lower panels. 3V = third cerebral ventricle, ME = median eminence, f = fornix; all other abbreviations as defined in the text. (B) Immunostaining for STAT5 (green, top), the neural marker, Hu (red, middle) and merged images (bottom) in the LHA ff and ffnc animals. This demonstrates the co-localization/expression of STAT5 in neurons of ff animals and the absence of STAT5 from many Hu-positive neurons in ffnc mice. (C) Total RNA from microdissected hypothalamic subregions of ff and ffnc mice was subjected to semi-quantitative real-time PCR for STAT5A and STAT5B mRNA expression, confirming the reduction in the expression of both STAT5 isoforms in each region.
© Copyright Policy
Related In: Results  -  Collection

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

pone-0001639-g001: Reduced STAT5 expression in hypothalamic neurons in Stat5fl/fl; Nestin-Cre male mice.(A) Immunohistochemical analyses with αSTAT5 antibodies were performed on hypothalamic tissues from Stat5fl/fl control (ff, left panels) and Stat5fl/fl; Nestin-Cre (ffnc, right panels) mice. Note the prominent expression of STAT5 isoforms in discrete neurons and the dramatic reduction in STAT5-positive cells in ffnc mice. Upper panels show hypothalamic sections rostral to those shown in lower panels. 3V = third cerebral ventricle, ME = median eminence, f = fornix; all other abbreviations as defined in the text. (B) Immunostaining for STAT5 (green, top), the neural marker, Hu (red, middle) and merged images (bottom) in the LHA ff and ffnc animals. This demonstrates the co-localization/expression of STAT5 in neurons of ff animals and the absence of STAT5 from many Hu-positive neurons in ffnc mice. (C) Total RNA from microdissected hypothalamic subregions of ff and ffnc mice was subjected to semi-quantitative real-time PCR for STAT5A and STAT5B mRNA expression, confirming the reduction in the expression of both STAT5 isoforms in each region.
Mentions: Immunohistochemical analysis using antisera reactive with both STAT5 isoforms demonstrated the prominent presence of STAT5 in discrete neuronal populations in a number of areas in the adult brain including basal ganglia, septum, cortex (not shown) and hypothalamus (Figure 1A). Particularly relevant to the phenotype described in this study, we detected STAT5 in a limited number of cells within areas of the hypothalamus known to regulate feeding and energy balance (Figure 1A), including the Arc, dorsomedial and ventromedial hypothalamic nuclei (DMH and VMH), and the LHA, suggesting a potential role for Stat5 in energy homeostasis.

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