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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

Glucose and insulin tolerance tests in 22 week-old Stat5fl/fl and Stat5fl/fl; Nestin-Cre mice.(A) Glucose tolerance tests were performed on fasted 22 week-old female mice after an i.p. injection of 2 g/kg BW glucose. Results are expressed as average blood glucose level±SEM of 5 females of each group. The effect of genotype was significant (Two Way Repeated Measured ANOVA with Holm-Sidak test: (F(1,24) = 6.6, p = 0.033. (B) Insulin tolerance test on 22 week-old females. Mice were fasted for 9 hours followed by the administration of 0.75U insulin per kg body weight. Results are expressed as average blood glucose level±SEM of 5 females of each group. The effect of genotype was significant (Two Way Repeated Measured ANOVA Holm-Sidak test: (F(1,24) = 7.3, p = 0.022). GTT and ITT were perform on the same set of Stat5fl/f and Stat5fl/fl; Nestin-Cre mice weighing mice 27.1±3.8 and 41.5±4.2 g, respectively.
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pone-0001639-g005: Glucose and insulin tolerance tests in 22 week-old Stat5fl/fl and Stat5fl/fl; Nestin-Cre mice.(A) Glucose tolerance tests were performed on fasted 22 week-old female mice after an i.p. injection of 2 g/kg BW glucose. Results are expressed as average blood glucose level±SEM of 5 females of each group. The effect of genotype was significant (Two Way Repeated Measured ANOVA with Holm-Sidak test: (F(1,24) = 6.6, p = 0.033. (B) Insulin tolerance test on 22 week-old females. Mice were fasted for 9 hours followed by the administration of 0.75U insulin per kg body weight. Results are expressed as average blood glucose level±SEM of 5 females of each group. The effect of genotype was significant (Two Way Repeated Measured ANOVA Holm-Sidak test: (F(1,24) = 7.3, p = 0.022). GTT and ITT were perform on the same set of Stat5fl/f and Stat5fl/fl; Nestin-Cre mice weighing mice 27.1±3.8 and 41.5±4.2 g, respectively.

Mentions: Serum analysis of fed mice demonstrated elevated levels of TG, FFA, insulin and leptin in 22 week-old mice Stat5fl/fl; Nestin-Cre mice (Table 1). Notably, insulin and leptin levels were increased approximately 8-fold and 4.5-fold, respectively. Consistent with the increase in circulating insulin, Stat5fl/fl; Nestin-Cre mice were glucose intolerant and insulin resistant (Figure 5). Thus, similar to many other mouse models of obesity, Stat5fl/fl; Nestin-Cre mice demonstrated some features of metabolic syndrome, including hyperlipidemia, hyperinsulinemia, insulin resistance and glucose intolerance. With the caveat that GH secretion in rodents is pulsatile, single measurements of GH levels suggests no differences between control and mutant mice. Normal IGF-1 levels (Table 1) and body lengths (Figure 3C) further argue for normal GH levels.


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)

Glucose and insulin tolerance tests in 22 week-old Stat5fl/fl and Stat5fl/fl; Nestin-Cre mice.(A) Glucose tolerance tests were performed on fasted 22 week-old female mice after an i.p. injection of 2 g/kg BW glucose. Results are expressed as average blood glucose level±SEM of 5 females of each group. The effect of genotype was significant (Two Way Repeated Measured ANOVA with Holm-Sidak test: (F(1,24) = 6.6, p = 0.033. (B) Insulin tolerance test on 22 week-old females. Mice were fasted for 9 hours followed by the administration of 0.75U insulin per kg body weight. Results are expressed as average blood glucose level±SEM of 5 females of each group. The effect of genotype was significant (Two Way Repeated Measured ANOVA Holm-Sidak test: (F(1,24) = 7.3, p = 0.022). GTT and ITT were perform on the same set of Stat5fl/f and Stat5fl/fl; Nestin-Cre mice weighing mice 27.1±3.8 and 41.5±4.2 g, respectively.
© Copyright Policy
Related In: Results  -  Collection

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

pone-0001639-g005: Glucose and insulin tolerance tests in 22 week-old Stat5fl/fl and Stat5fl/fl; Nestin-Cre mice.(A) Glucose tolerance tests were performed on fasted 22 week-old female mice after an i.p. injection of 2 g/kg BW glucose. Results are expressed as average blood glucose level±SEM of 5 females of each group. The effect of genotype was significant (Two Way Repeated Measured ANOVA with Holm-Sidak test: (F(1,24) = 6.6, p = 0.033. (B) Insulin tolerance test on 22 week-old females. Mice were fasted for 9 hours followed by the administration of 0.75U insulin per kg body weight. Results are expressed as average blood glucose level±SEM of 5 females of each group. The effect of genotype was significant (Two Way Repeated Measured ANOVA Holm-Sidak test: (F(1,24) = 7.3, p = 0.022). GTT and ITT were perform on the same set of Stat5fl/f and Stat5fl/fl; Nestin-Cre mice weighing mice 27.1±3.8 and 41.5±4.2 g, respectively.
Mentions: Serum analysis of fed mice demonstrated elevated levels of TG, FFA, insulin and leptin in 22 week-old mice Stat5fl/fl; Nestin-Cre mice (Table 1). Notably, insulin and leptin levels were increased approximately 8-fold and 4.5-fold, respectively. Consistent with the increase in circulating insulin, Stat5fl/fl; Nestin-Cre mice were glucose intolerant and insulin resistant (Figure 5). Thus, similar to many other mouse models of obesity, Stat5fl/fl; Nestin-Cre mice demonstrated some features of metabolic syndrome, including hyperlipidemia, hyperinsulinemia, insulin resistance and glucose intolerance. With the caveat that GH secretion in rodents is pulsatile, single measurements of GH levels suggests no differences between control and mutant mice. Normal IGF-1 levels (Table 1) and body lengths (Figure 3C) further argue for normal GH levels.

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