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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

Stat5fl/fl; Nestin-Cre mice are defective in cold-induced thermogenesis.26 week-old Stat5fl/fl and Stat5fl/fl; Nestin-Cre males (A) and females (B) were housed at 4°C for 6 hours and rectal temperature was measured at 60-min intervals. The reduced cold tolerance in both males and females was statistically significant. N = 4/group. Statistical analysis was done using ‘Two Way Repeated Measures ANOVA’ followed by the ‘Holm-Sidak test’. The effect of genotype was significant in both females (F(1, 36) = 12.4, P = 0.013) and males (18.2, P = 0.005). The effect of length of cold exposure was also significant in females (F(6,36) = 9.5, P<0.001) and males (F(6,36) = 6.9, P<0.001
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pone-0001639-g007: Stat5fl/fl; Nestin-Cre mice are defective in cold-induced thermogenesis.26 week-old Stat5fl/fl and Stat5fl/fl; Nestin-Cre males (A) and females (B) were housed at 4°C for 6 hours and rectal temperature was measured at 60-min intervals. The reduced cold tolerance in both males and females was statistically significant. N = 4/group. Statistical analysis was done using ‘Two Way Repeated Measures ANOVA’ followed by the ‘Holm-Sidak test’. The effect of genotype was significant in both females (F(1, 36) = 12.4, P = 0.013) and males (18.2, P = 0.005). The effect of length of cold exposure was also significant in females (F(6,36) = 9.5, P<0.001) and males (F(6,36) = 6.9, P<0.001

Mentions: The CNS pathways that regulate food intake and energy balance overlap at many points with the systems that regulate body temperature. For example, STAT3 and cytokines such as leptin each contribute to regulate energy balance and the ability to maintain body temperature [3], [18]. We thus examined whether neuronal STAT5 similarly contributes to cold tolerance. Stat5fl/fl; Nestin-Cre and control female mice had body weights of 36.2 g and 25.6g, respectively. Mutant and control males had body weights of 50.3 g and 31.8 g, respectively. 26 week-old mice were housed at 4°C for 6 hours and body temperatures were measured every hour. While the body temperature of littermate controls dropped ∼0.7°C over the 6 hour period, the body temperature of mutant males decreased by ∼1.4°C (Figure 7A) and that of females by 2.0°C (Figure 7B). These data establish that neuronal STAT5 contributes to the regulation of body temperature, as well as to the control of food intake and body adiposity.


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)

Stat5fl/fl; Nestin-Cre mice are defective in cold-induced thermogenesis.26 week-old Stat5fl/fl and Stat5fl/fl; Nestin-Cre males (A) and females (B) were housed at 4°C for 6 hours and rectal temperature was measured at 60-min intervals. The reduced cold tolerance in both males and females was statistically significant. N = 4/group. Statistical analysis was done using ‘Two Way Repeated Measures ANOVA’ followed by the ‘Holm-Sidak test’. The effect of genotype was significant in both females (F(1, 36) = 12.4, P = 0.013) and males (18.2, P = 0.005). The effect of length of cold exposure was also significant in females (F(6,36) = 9.5, P<0.001) and males (F(6,36) = 6.9, P<0.001
© Copyright Policy
Related In: Results  -  Collection

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getmorefigures.php?uid=PMC2237899&req=5

pone-0001639-g007: Stat5fl/fl; Nestin-Cre mice are defective in cold-induced thermogenesis.26 week-old Stat5fl/fl and Stat5fl/fl; Nestin-Cre males (A) and females (B) were housed at 4°C for 6 hours and rectal temperature was measured at 60-min intervals. The reduced cold tolerance in both males and females was statistically significant. N = 4/group. Statistical analysis was done using ‘Two Way Repeated Measures ANOVA’ followed by the ‘Holm-Sidak test’. The effect of genotype was significant in both females (F(1, 36) = 12.4, P = 0.013) and males (18.2, P = 0.005). The effect of length of cold exposure was also significant in females (F(6,36) = 9.5, P<0.001) and males (F(6,36) = 6.9, P<0.001
Mentions: The CNS pathways that regulate food intake and energy balance overlap at many points with the systems that regulate body temperature. For example, STAT3 and cytokines such as leptin each contribute to regulate energy balance and the ability to maintain body temperature [3], [18]. We thus examined whether neuronal STAT5 similarly contributes to cold tolerance. Stat5fl/fl; Nestin-Cre and control female mice had body weights of 36.2 g and 25.6g, respectively. Mutant and control males had body weights of 50.3 g and 31.8 g, respectively. 26 week-old mice were housed at 4°C for 6 hours and body temperatures were measured every hour. While the body temperature of littermate controls dropped ∼0.7°C over the 6 hour period, the body temperature of mutant males decreased by ∼1.4°C (Figure 7A) and that of females by 2.0°C (Figure 7B). These data establish that neuronal STAT5 contributes to the regulation of body temperature, as well as to the control of food intake and body adiposity.

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