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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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Increased body weight of Stat5fl/fl; Nestin-Cre mice.Body weight curves of males (A, Stat5fl/fl, n = 14; Stat5fl/fl; Nestin-Cre, n = 8) and females (B, Stat5fl/fl, n = 5; Stat5fl/fl; Nestin-Cre n = 6). Two Way Repeated Measured ANOVA test revealed that the effect of the genotype on body weight was significant in males (F(1,103) = 5.77, P = 0.024) and females (F9(1,36) = 64.6, P<0.001) (B). Panels C and D show body weights at various ages combined from several cohorts of mice. Values are mean±SEM, n = 5–37 per group. Two Way ANOVA analysis of variance for each age group shows a significant effect of genotype on body weight at all ages tested: 8 weeks−F(1,70) = 4.5, P = 0.037; 10 weeks−F(1,89) = 24.3, P<0.001; 12 weeks−F(1,99) = 6.4, P = 0.013; 14 weeks−F(1,80) = 8.98, P = 0.004; 16 weeks−F(1,87) = 14.9; P<0.001; 18 weeks−F(1,22) = 56.1, P<0.001; 20 weeks−F(1,13) = 37.1, P<0.001; 22 weeks−F(1,20) = 18.6, P<0.001. The effect of gender on body weight was significant at weeks 8 through 16 (with F values ranging from 24 to 87, P<0.001). The interaction between genotype and gender was detected at week 10 only (F(1,89) = 11,2, P = 0.01).
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pone-0001639-g002: Increased body weight of Stat5fl/fl; Nestin-Cre mice.Body weight curves of males (A, Stat5fl/fl, n = 14; Stat5fl/fl; Nestin-Cre, n = 8) and females (B, Stat5fl/fl, n = 5; Stat5fl/fl; Nestin-Cre n = 6). Two Way Repeated Measured ANOVA test revealed that the effect of the genotype on body weight was significant in males (F(1,103) = 5.77, P = 0.024) and females (F9(1,36) = 64.6, P<0.001) (B). Panels C and D show body weights at various ages combined from several cohorts of mice. Values are mean±SEM, n = 5–37 per group. Two Way ANOVA analysis of variance for each age group shows a significant effect of genotype on body weight at all ages tested: 8 weeks−F(1,70) = 4.5, P = 0.037; 10 weeks−F(1,89) = 24.3, P<0.001; 12 weeks−F(1,99) = 6.4, P = 0.013; 14 weeks−F(1,80) = 8.98, P = 0.004; 16 weeks−F(1,87) = 14.9; P<0.001; 18 weeks−F(1,22) = 56.1, P<0.001; 20 weeks−F(1,13) = 37.1, P<0.001; 22 weeks−F(1,20) = 18.6, P<0.001. The effect of gender on body weight was significant at weeks 8 through 16 (with F values ranging from 24 to 87, P<0.001). The interaction between genotype and gender was detected at week 10 only (F(1,89) = 11,2, P = 0.01).

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 weight of Stat5fl/fl; Nestin-Cre mice.Body weight curves of males (A, Stat5fl/fl, n = 14; Stat5fl/fl; Nestin-Cre, n = 8) and females (B, Stat5fl/fl, n = 5; Stat5fl/fl; Nestin-Cre n = 6). Two Way Repeated Measured ANOVA test revealed that the effect of the genotype on body weight was significant in males (F(1,103) = 5.77, P = 0.024) and females (F9(1,36) = 64.6, P<0.001) (B). Panels C and D show body weights at various ages combined from several cohorts of mice. Values are mean±SEM, n = 5–37 per group. Two Way ANOVA analysis of variance for each age group shows a significant effect of genotype on body weight at all ages tested: 8 weeks−F(1,70) = 4.5, P = 0.037; 10 weeks−F(1,89) = 24.3, P<0.001; 12 weeks−F(1,99) = 6.4, P = 0.013; 14 weeks−F(1,80) = 8.98, P = 0.004; 16 weeks−F(1,87) = 14.9; P<0.001; 18 weeks−F(1,22) = 56.1, P<0.001; 20 weeks−F(1,13) = 37.1, P<0.001; 22 weeks−F(1,20) = 18.6, P<0.001. The effect of gender on body weight was significant at weeks 8 through 16 (with F values ranging from 24 to 87, P<0.001). The interaction between genotype and gender was detected at week 10 only (F(1,89) = 11,2, P = 0.01).
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pone-0001639-g002: Increased body weight of Stat5fl/fl; Nestin-Cre mice.Body weight curves of males (A, Stat5fl/fl, n = 14; Stat5fl/fl; Nestin-Cre, n = 8) and females (B, Stat5fl/fl, n = 5; Stat5fl/fl; Nestin-Cre n = 6). Two Way Repeated Measured ANOVA test revealed that the effect of the genotype on body weight was significant in males (F(1,103) = 5.77, P = 0.024) and females (F9(1,36) = 64.6, P<0.001) (B). Panels C and D show body weights at various ages combined from several cohorts of mice. Values are mean±SEM, n = 5–37 per group. Two Way ANOVA analysis of variance for each age group shows a significant effect of genotype on body weight at all ages tested: 8 weeks−F(1,70) = 4.5, P = 0.037; 10 weeks−F(1,89) = 24.3, P<0.001; 12 weeks−F(1,99) = 6.4, P = 0.013; 14 weeks−F(1,80) = 8.98, P = 0.004; 16 weeks−F(1,87) = 14.9; P<0.001; 18 weeks−F(1,22) = 56.1, P<0.001; 20 weeks−F(1,13) = 37.1, P<0.001; 22 weeks−F(1,20) = 18.6, P<0.001. The effect of gender on body weight was significant at weeks 8 through 16 (with F values ranging from 24 to 87, P<0.001). The interaction between genotype and gender was detected at week 10 only (F(1,89) = 11,2, P = 0.01).
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