Limits...
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.

Show MeSH

Related in: MedlinePlus

Food intake of Stat5fl/fl and Stat5fl/fl; Nestin-Cre mice was measured in a set of male mice (n = 6 per group) at the age of 8-weeks (A) and 16 weeks (B).Data show the total grams of food consumed per mouse per day. Mice were housed individually for all measurements. Values are mean±SEM. At 8 weeks of age, Stat5fl/f weighed 25.6±3.1 g and Stat5fl/fl; Nestin-Cre was 23.9+3.2 g; at 16 weeks body weights were 28.1±3.3 vs 29.2±3.7 respectively. By Two Way Repeated Measured ANOVA there were no effect of genotype on body weight in this cohort of male mice, however the effect of genotype on food intake was significantly different (F(1,10) = 5.7, p = 0.038. All pairwise multiple comparison (Holm-Sidak test) revealed that food intake was significantly different between two groups at 16 weeks of age (P = 0.0.005, t = 3.2), but not at 8 weeks of age.
© Copyright Policy
Related In: Results  -  Collection


getmorefigures.php?uid=PMC2237899&req=5

pone-0001639-g006: Food intake of Stat5fl/fl and Stat5fl/fl; Nestin-Cre mice was measured in a set of male mice (n = 6 per group) at the age of 8-weeks (A) and 16 weeks (B).Data show the total grams of food consumed per mouse per day. Mice were housed individually for all measurements. Values are mean±SEM. At 8 weeks of age, Stat5fl/f weighed 25.6±3.1 g and Stat5fl/fl; Nestin-Cre was 23.9+3.2 g; at 16 weeks body weights were 28.1±3.3 vs 29.2±3.7 respectively. By Two Way Repeated Measured ANOVA there were no effect of genotype on body weight in this cohort of male mice, however the effect of genotype on food intake was significantly different (F(1,10) = 5.7, p = 0.038. All pairwise multiple comparison (Holm-Sidak test) revealed that food intake was significantly different between two groups at 16 weeks of age (P = 0.0.005, t = 3.2), but not at 8 weeks of age.

Mentions: To determine whether the increased body weight was associated with increased food consumption, we measured daily food intake every 4 weeks between the ages of 8 and 16 weeks. This analysis detected increased food intake in male but not in female Stat5fl/fl; Nestin-Cre mice during this period (Figure 6). At the age of 26 weeks both mutant males and females ate significantly more than controls per animal. When the data were normalized to lean mass, the difference remained significant in females (Table 2). To test whether changes in energy expenditure could also contribute to obesity in Stat5fl/fl; Nestin-Cre mice, we measured oxygen consumption and activity. At the age of 12 weeks oxygen consumption was comparable in control and mutant mice (data not shown). At 26 weeks of age, male Stat5fl/fl; Nestin-Cre were 60% heavier and were consuming more oxygen per mouse (Table 2). Oxygen consumption normalized to lean mass was significantly reduced in male Stat5fl/fl; Nestin-Cre compared to the control mice, but not in female mice (Table 2). In contrast, there was no difference in total activity, suggesting that changes in energy expenditure in males are likely attributable to reduced basal metabolic rates. Since increased food intake in males was observed prior to changes in energy expenditure, the data suggest that hyperphagia might be the primary cause of obesity in both male and female mice.


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)

Food intake of Stat5fl/fl and Stat5fl/fl; Nestin-Cre mice was measured in a set of male mice (n = 6 per group) at the age of 8-weeks (A) and 16 weeks (B).Data show the total grams of food consumed per mouse per day. Mice were housed individually for all measurements. Values are mean±SEM. At 8 weeks of age, Stat5fl/f weighed 25.6±3.1 g and Stat5fl/fl; Nestin-Cre was 23.9+3.2 g; at 16 weeks body weights were 28.1±3.3 vs 29.2±3.7 respectively. By Two Way Repeated Measured ANOVA there were no effect of genotype on body weight in this cohort of male mice, however the effect of genotype on food intake was significantly different (F(1,10) = 5.7, p = 0.038. All pairwise multiple comparison (Holm-Sidak test) revealed that food intake was significantly different between two groups at 16 weeks of age (P = 0.0.005, t = 3.2), but not at 8 weeks of age.
© Copyright Policy
Related In: Results  -  Collection

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

pone-0001639-g006: Food intake of Stat5fl/fl and Stat5fl/fl; Nestin-Cre mice was measured in a set of male mice (n = 6 per group) at the age of 8-weeks (A) and 16 weeks (B).Data show the total grams of food consumed per mouse per day. Mice were housed individually for all measurements. Values are mean±SEM. At 8 weeks of age, Stat5fl/f weighed 25.6±3.1 g and Stat5fl/fl; Nestin-Cre was 23.9+3.2 g; at 16 weeks body weights were 28.1±3.3 vs 29.2±3.7 respectively. By Two Way Repeated Measured ANOVA there were no effect of genotype on body weight in this cohort of male mice, however the effect of genotype on food intake was significantly different (F(1,10) = 5.7, p = 0.038. All pairwise multiple comparison (Holm-Sidak test) revealed that food intake was significantly different between two groups at 16 weeks of age (P = 0.0.005, t = 3.2), but not at 8 weeks of age.
Mentions: To determine whether the increased body weight was associated with increased food consumption, we measured daily food intake every 4 weeks between the ages of 8 and 16 weeks. This analysis detected increased food intake in male but not in female Stat5fl/fl; Nestin-Cre mice during this period (Figure 6). At the age of 26 weeks both mutant males and females ate significantly more than controls per animal. When the data were normalized to lean mass, the difference remained significant in females (Table 2). To test whether changes in energy expenditure could also contribute to obesity in Stat5fl/fl; Nestin-Cre mice, we measured oxygen consumption and activity. At the age of 12 weeks oxygen consumption was comparable in control and mutant mice (data not shown). At 26 weeks of age, male Stat5fl/fl; Nestin-Cre were 60% heavier and were consuming more oxygen per mouse (Table 2). Oxygen consumption normalized to lean mass was significantly reduced in male Stat5fl/fl; Nestin-Cre compared to the control mice, but not in female mice (Table 2). In contrast, there was no difference in total activity, suggesting that changes in energy expenditure in males are likely attributable to reduced basal metabolic rates. Since increased food intake in males was observed prior to changes in energy expenditure, the data suggest that hyperphagia might be the primary cause of obesity in both male and female mice.

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