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

Analysis of fat depots and adipocyte size fat analysis from 22 week-old female mice.Subcutaneous (A) and visceral (B) fat were increased in Stat5fl/fl; Nestin-Cre mice, compared to Stat5fl/fl control mice. (C) Unpaired t-test was used for comparison of fat pad weights from Stat5fl/fl; Nestin-Cre and Stat5fl/fl control mice. Ing (inguinal, t(8) = 5.6, P<0.001), ParaM (parametrial, t(8) = 4.1, P = 0.004), Retro (retroperitoneal, t(8) = 2.9, P = 0.019), Mes (mesenteric, t(8) = 5.3, P<0.001)) and P-renal (perirenal, t(8) = 3.2, P<0.013). See figure 3 for body composition and body weight data. (D–E) Images of cross-sectional adipocytes from Stat5fl/fl (D) and Stat5fl/fl; Nestin-Cre mice (E). (F) Comparison of cell size distribution between two different genotypes for each fat pad. Values are mean cross-sectional area of each fat pad±SEM (n = 3–5 mice per group). Cross-sectional areas less than 100 µm2 were considered artifacts generated during image processing and were not used for statistical analysis. Adipocytes from Stat5fl/fl; Nestin-Cr mice were significantly larger in inguinal fat (t(8) = 5.3, p,0.001), parametrial fat (t(8) = 2.8, p = 0.02) and mesenteric fat (t(6) = 3.1, 0.02).
© Copyright Policy
Related In: Results  -  Collection


getmorefigures.php?uid=PMC2237899&req=5

pone-0001639-g004: Analysis of fat depots and adipocyte size fat analysis from 22 week-old female mice.Subcutaneous (A) and visceral (B) fat were increased in Stat5fl/fl; Nestin-Cre mice, compared to Stat5fl/fl control mice. (C) Unpaired t-test was used for comparison of fat pad weights from Stat5fl/fl; Nestin-Cre and Stat5fl/fl control mice. Ing (inguinal, t(8) = 5.6, P<0.001), ParaM (parametrial, t(8) = 4.1, P = 0.004), Retro (retroperitoneal, t(8) = 2.9, P = 0.019), Mes (mesenteric, t(8) = 5.3, P<0.001)) and P-renal (perirenal, t(8) = 3.2, P<0.013). See figure 3 for body composition and body weight data. (D–E) Images of cross-sectional adipocytes from Stat5fl/fl (D) and Stat5fl/fl; Nestin-Cre mice (E). (F) Comparison of cell size distribution between two different genotypes for each fat pad. Values are mean cross-sectional area of each fat pad±SEM (n = 3–5 mice per group). Cross-sectional areas less than 100 µm2 were considered artifacts generated during image processing and were not used for statistical analysis. Adipocytes from Stat5fl/fl; Nestin-Cr mice were significantly larger in inguinal fat (t(8) = 5.3, p,0.001), parametrial fat (t(8) = 2.8, p = 0.02) and mesenteric fat (t(6) = 3.1, 0.02).

Mentions: At 22 weeks of age, both subcutaneous (Figure 4A) and visceral (Figure 4B) fat mass were increased in Stat5fl/fl;Nestin-Cre mice compared to Stat5fl/fl control mice. Individual fat pads from control and mutant female mice were dissected and weighed to evaluate the distribution of fat mass. The weight of all 5 fat pads (inguinal, parametrial, retroperitoneal, mesenteric and perirenal) in mutant mice was at least doubled in mutant compared to control animals (Figure 4C). To determine whether increased adipose tissue mass was the result of an increased size of individual adipocytes, increased cell number or a combination of both, cell sizes were measured from paraffin embedded sections. In inguinal, parametrial and mesenteric fat pads, the mean cross-sectional areas of adipocytes in Stat5fl/fl; Nestin-Cre mice were significantly larger than this in Stat5fl/fl mice (Figure 4D–F), suggesting increased lipid storage contributes to the increased fat mass in these animals.


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)

Analysis of fat depots and adipocyte size fat analysis from 22 week-old female mice.Subcutaneous (A) and visceral (B) fat were increased in Stat5fl/fl; Nestin-Cre mice, compared to Stat5fl/fl control mice. (C) Unpaired t-test was used for comparison of fat pad weights from Stat5fl/fl; Nestin-Cre and Stat5fl/fl control mice. Ing (inguinal, t(8) = 5.6, P<0.001), ParaM (parametrial, t(8) = 4.1, P = 0.004), Retro (retroperitoneal, t(8) = 2.9, P = 0.019), Mes (mesenteric, t(8) = 5.3, P<0.001)) and P-renal (perirenal, t(8) = 3.2, P<0.013). See figure 3 for body composition and body weight data. (D–E) Images of cross-sectional adipocytes from Stat5fl/fl (D) and Stat5fl/fl; Nestin-Cre mice (E). (F) Comparison of cell size distribution between two different genotypes for each fat pad. Values are mean cross-sectional area of each fat pad±SEM (n = 3–5 mice per group). Cross-sectional areas less than 100 µm2 were considered artifacts generated during image processing and were not used for statistical analysis. Adipocytes from Stat5fl/fl; Nestin-Cr mice were significantly larger in inguinal fat (t(8) = 5.3, p,0.001), parametrial fat (t(8) = 2.8, p = 0.02) and mesenteric fat (t(6) = 3.1, 0.02).
© Copyright Policy
Related In: Results  -  Collection

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

pone-0001639-g004: Analysis of fat depots and adipocyte size fat analysis from 22 week-old female mice.Subcutaneous (A) and visceral (B) fat were increased in Stat5fl/fl; Nestin-Cre mice, compared to Stat5fl/fl control mice. (C) Unpaired t-test was used for comparison of fat pad weights from Stat5fl/fl; Nestin-Cre and Stat5fl/fl control mice. Ing (inguinal, t(8) = 5.6, P<0.001), ParaM (parametrial, t(8) = 4.1, P = 0.004), Retro (retroperitoneal, t(8) = 2.9, P = 0.019), Mes (mesenteric, t(8) = 5.3, P<0.001)) and P-renal (perirenal, t(8) = 3.2, P<0.013). See figure 3 for body composition and body weight data. (D–E) Images of cross-sectional adipocytes from Stat5fl/fl (D) and Stat5fl/fl; Nestin-Cre mice (E). (F) Comparison of cell size distribution between two different genotypes for each fat pad. Values are mean cross-sectional area of each fat pad±SEM (n = 3–5 mice per group). Cross-sectional areas less than 100 µm2 were considered artifacts generated during image processing and were not used for statistical analysis. Adipocytes from Stat5fl/fl; Nestin-Cr mice were significantly larger in inguinal fat (t(8) = 5.3, p,0.001), parametrial fat (t(8) = 2.8, p = 0.02) and mesenteric fat (t(6) = 3.1, 0.02).
Mentions: At 22 weeks of age, both subcutaneous (Figure 4A) and visceral (Figure 4B) fat mass were increased in Stat5fl/fl;Nestin-Cre mice compared to Stat5fl/fl control mice. Individual fat pads from control and mutant female mice were dissected and weighed to evaluate the distribution of fat mass. The weight of all 5 fat pads (inguinal, parametrial, retroperitoneal, mesenteric and perirenal) in mutant mice was at least doubled in mutant compared to control animals (Figure 4C). To determine whether increased adipose tissue mass was the result of an increased size of individual adipocytes, increased cell number or a combination of both, cell sizes were measured from paraffin embedded sections. In inguinal, parametrial and mesenteric fat pads, the mean cross-sectional areas of adipocytes in Stat5fl/fl; Nestin-Cre mice were significantly larger than this in Stat5fl/fl mice (Figure 4D–F), suggesting increased lipid storage contributes to the increased fat mass in these animals.

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