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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

Increased body fat in Stat5fl/fl; Nestin-Cre mice.(A) Fat mass of 22 week-old males (n = 4/group) and females (n = 5/group). Left panel shows the amount of fat in grams. By Two Way ANOVA followed by Holm-Sidak test the effect of genotype was significant ( F(1,14) = 83.1, P<0.001). Right panel represents fat mass as a percentage of body weight (F(1,14) = 42.4, P<0.001 for the effect of genotype; F(1,14) = 8.0, P = 0.014 for the gender effect. (B) Lean mass of 22 week-old males and females in grams (left panel-( F(1,14) = 137, P<0.001 for the genotype effect; F(1,14) = 164, P<0.001 for the gender effect). Right panel presents lean mass as a percentage of total body weight (F(1,14) = 70.4, P<0.001, for the genotype effect, F(1,14) = 30.7 for the gender effect). Body weights were: Stat5fl/fl males 30.5±1.5, Stat5fl/fl; Nestin-Cre males–49.8±0.9 g; Stat5fl/fl females 25.3±1.3 g, Stat5fl/fl; Nestin-Cre females–39.4±1.5 g; F(1.14) = 143, P<0.001 for the genotype effect, F(1,14)+30 for the gender effect. (C) X-ray images of Stat5fl/fl; Nestin-Cre and Stat5fl/fl control male mice (right panel) showing similar size of bone length. There was no statistically significant difference in body length as shown in the graph (left panel).
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pone-0001639-g003: Increased body fat in Stat5fl/fl; Nestin-Cre mice.(A) Fat mass of 22 week-old males (n = 4/group) and females (n = 5/group). Left panel shows the amount of fat in grams. By Two Way ANOVA followed by Holm-Sidak test the effect of genotype was significant ( F(1,14) = 83.1, P<0.001). Right panel represents fat mass as a percentage of body weight (F(1,14) = 42.4, P<0.001 for the effect of genotype; F(1,14) = 8.0, P = 0.014 for the gender effect. (B) Lean mass of 22 week-old males and females in grams (left panel-( F(1,14) = 137, P<0.001 for the genotype effect; F(1,14) = 164, P<0.001 for the gender effect). Right panel presents lean mass as a percentage of total body weight (F(1,14) = 70.4, P<0.001, for the genotype effect, F(1,14) = 30.7 for the gender effect). Body weights were: Stat5fl/fl males 30.5±1.5, Stat5fl/fl; Nestin-Cre males–49.8±0.9 g; Stat5fl/fl females 25.3±1.3 g, Stat5fl/fl; Nestin-Cre females–39.4±1.5 g; F(1.14) = 143, P<0.001 for the genotype effect, F(1,14)+30 for the gender effect. (C) X-ray images of Stat5fl/fl; Nestin-Cre and Stat5fl/fl control male mice (right panel) showing similar size of bone length. There was no statistically significant difference in body length as shown in the graph (left panel).

Mentions: Metabolic parameters and body weight of Stat5fl/fl; Nestin-Cre mice were monitored from 8 to 22 weeks of age. Both male and female mutant mice gained significantly more weight than control litter mates (Figure 2). Although 8 week-old mutant females were already significantly heavier than controls, differences in weight were more profound after 16 weeks of age. While the weight of control female mice increased only 10% between 12 and 22 weeks, mutants almost doubled their weight during this time interval (Figure 2B). By 26 weeks of age, Stat5fl/fl; Nestin-Cre mice weighed on the average 65% (males) and 60% (females) more than their control litter mates. The total amount of fat in Stat5fl/fl; Nestin-Cre male and female mice increased 2.5- and 3.5-fold, respectively (Figure 3A, left panel). Notably, the lean mass of mutant male and female mice increased by 40% and 20%, respectively (Figure 3B). Total body fat (expressed as percentage of body weight) in male and female Stat5fl/fl; Nestin-Cre mice was 150% and 200%, respectively of that measured in control mice (Figure 3A, right panel). Body size, as measured by snout-anus length, of mutant and control mice was similar (Figure 3C).


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)

Increased body fat in Stat5fl/fl; Nestin-Cre mice.(A) Fat mass of 22 week-old males (n = 4/group) and females (n = 5/group). Left panel shows the amount of fat in grams. By Two Way ANOVA followed by Holm-Sidak test the effect of genotype was significant ( F(1,14) = 83.1, P<0.001). Right panel represents fat mass as a percentage of body weight (F(1,14) = 42.4, P<0.001 for the effect of genotype; F(1,14) = 8.0, P = 0.014 for the gender effect. (B) Lean mass of 22 week-old males and females in grams (left panel-( F(1,14) = 137, P<0.001 for the genotype effect; F(1,14) = 164, P<0.001 for the gender effect). Right panel presents lean mass as a percentage of total body weight (F(1,14) = 70.4, P<0.001, for the genotype effect, F(1,14) = 30.7 for the gender effect). Body weights were: Stat5fl/fl males 30.5±1.5, Stat5fl/fl; Nestin-Cre males–49.8±0.9 g; Stat5fl/fl females 25.3±1.3 g, Stat5fl/fl; Nestin-Cre females–39.4±1.5 g; F(1.14) = 143, P<0.001 for the genotype effect, F(1,14)+30 for the gender effect. (C) X-ray images of Stat5fl/fl; Nestin-Cre and Stat5fl/fl control male mice (right panel) showing similar size of bone length. There was no statistically significant difference in body length as shown in the graph (left panel).
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC2237899&req=5

pone-0001639-g003: Increased body fat in Stat5fl/fl; Nestin-Cre mice.(A) Fat mass of 22 week-old males (n = 4/group) and females (n = 5/group). Left panel shows the amount of fat in grams. By Two Way ANOVA followed by Holm-Sidak test the effect of genotype was significant ( F(1,14) = 83.1, P<0.001). Right panel represents fat mass as a percentage of body weight (F(1,14) = 42.4, P<0.001 for the effect of genotype; F(1,14) = 8.0, P = 0.014 for the gender effect. (B) Lean mass of 22 week-old males and females in grams (left panel-( F(1,14) = 137, P<0.001 for the genotype effect; F(1,14) = 164, P<0.001 for the gender effect). Right panel presents lean mass as a percentage of total body weight (F(1,14) = 70.4, P<0.001, for the genotype effect, F(1,14) = 30.7 for the gender effect). Body weights were: Stat5fl/fl males 30.5±1.5, Stat5fl/fl; Nestin-Cre males–49.8±0.9 g; Stat5fl/fl females 25.3±1.3 g, Stat5fl/fl; Nestin-Cre females–39.4±1.5 g; F(1.14) = 143, P<0.001 for the genotype effect, F(1,14)+30 for the gender effect. (C) X-ray images of Stat5fl/fl; Nestin-Cre and Stat5fl/fl control male mice (right panel) showing similar size of bone length. There was no statistically significant difference in body length as shown in the graph (left panel).
Mentions: Metabolic parameters and body weight of Stat5fl/fl; Nestin-Cre mice were monitored from 8 to 22 weeks of age. Both male and female mutant mice gained significantly more weight than control litter mates (Figure 2). Although 8 week-old mutant females were already significantly heavier than controls, differences in weight were more profound after 16 weeks of age. While the weight of control female mice increased only 10% between 12 and 22 weeks, mutants almost doubled their weight during this time interval (Figure 2B). By 26 weeks of age, Stat5fl/fl; Nestin-Cre mice weighed on the average 65% (males) and 60% (females) more than their control litter mates. The total amount of fat in Stat5fl/fl; Nestin-Cre male and female mice increased 2.5- and 3.5-fold, respectively (Figure 3A, left panel). Notably, the lean mass of mutant male and female mice increased by 40% and 20%, respectively (Figure 3B). Total body fat (expressed as percentage of body weight) in male and female Stat5fl/fl; Nestin-Cre mice was 150% and 200%, respectively of that measured in control mice (Figure 3A, right panel). Body size, as measured by snout-anus length, of mutant and control mice was similar (Figure 3C).

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