Limits...
Effects of hypothalamic neurodegeneration on energy balance.

Xu AW, Kaelin CB, Morton GJ, Ogimoto K, Stanhope K, Graham J, Baskin DG, Havel P, Schwartz MW, Barsh GS - PLoS Biol. (2005)

Bottom Line: To investigate the role of hypothalamic neuronal circuits in this process, we used a Cre-lox strategy to create mice with specific and progressive degeneration of hypothalamic neurons that express agouti-related protein (Agrp) or proopiomelanocortin (Pomc), neuropeptides that promote positive or negative energy balance, respectively, through their opposing effects on melanocortin receptor signaling.Agrp-ablation female mice exhibit reduced adiposity with normal compensatory hyperphagia, while animals ablated for both Pomc and Agrp neurons exhibit an additive interaction phenotype.These findings provide new insight into the roles of hypothalamic neurons in energy balance regulation, and provide a model for understanding defects in human energy balance associated with neurodegeneration and aging.

View Article: PubMed Central - PubMed

Affiliation: Department of Genetics, Stanford University School of Medicine, Stanford, California, USA.

ABSTRACT
Normal aging in humans and rodents is accompanied by a progressive increase in adiposity. To investigate the role of hypothalamic neuronal circuits in this process, we used a Cre-lox strategy to create mice with specific and progressive degeneration of hypothalamic neurons that express agouti-related protein (Agrp) or proopiomelanocortin (Pomc), neuropeptides that promote positive or negative energy balance, respectively, through their opposing effects on melanocortin receptor signaling. In previous studies, Pomc mutant mice became obese, but Agrp mutant mice were surprisingly normal, suggesting potential compensation by neuronal circuits or genetic redundancy. Here we find that Pomc-ablation mice develop obesity similar to that described for Pomc knockout mice, but also exhibit defects in compensatory hyperphagia similar to what occurs during normal aging. Agrp-ablation female mice exhibit reduced adiposity with normal compensatory hyperphagia, while animals ablated for both Pomc and Agrp neurons exhibit an additive interaction phenotype. These findings provide new insight into the roles of hypothalamic neurons in energy balance regulation, and provide a model for understanding defects in human energy balance associated with neurodegeneration and aging.

Show MeSH

Related in: MedlinePlus

Pattern of R26R Activation in Mice Carrying the PomcCre or AgrpCre TransgeneWhole brains from Tg.PomcCre/+; R26R/+ or Tg.AgrCre/+; R26R/+ mice of the indicated age were fixed and stained with Xgal as described in [9]. Photographs show the ventral brain surface, and coronal sections (not shown) indicate that Xgal-stained neurons lie in the arcuate nucleus of the hypothalamus. As assessed by the extent of Xgal staining, Cre-induced recombination in Pomc neurons is complete by embryonic day 17.5; however, Cre-induced recombination in Agrp neurons is just beginning at 2 wk of age (arrows) and is not complete until 3–4 wk of age.
© Copyright Policy
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC1287504&req=5

pbio-0030415-g001: Pattern of R26R Activation in Mice Carrying the PomcCre or AgrpCre TransgeneWhole brains from Tg.PomcCre/+; R26R/+ or Tg.AgrCre/+; R26R/+ mice of the indicated age were fixed and stained with Xgal as described in [9]. Photographs show the ventral brain surface, and coronal sections (not shown) indicate that Xgal-stained neurons lie in the arcuate nucleus of the hypothalamus. As assessed by the extent of Xgal staining, Cre-induced recombination in Pomc neurons is complete by embryonic day 17.5; however, Cre-induced recombination in Agrp neurons is just beginning at 2 wk of age (arrows) and is not complete until 3–4 wk of age.

Mentions: In the arcuate nucleus of the hypothalamus, activation of R26R by the PomcCre transgene became apparent by embryonic day 17.5; activation of R26R by the AgrpCre transgene, however, was not detectable until 2–3 wk of age (Figure 1). These results correspond to what has been described previously for normal development of the melanocortinergic system, with the hypothalamic Pomc system becoming established during fetal brain development, but the Agrp system developing after birth [19,20]. Activation of R26R by the PomcCre transgene also occurs in the nucleus tract solitarius of the hindbrain, and the anterior and intermediate lobe of the pituitary in neonatal animals (unpublished data), which are areas in which Pomc is normally expressed. The early onset of Pomc expression in the arcuate nucleus suggests that the Pomc neurons may play a role in the development of the hypothalamus. Expression of Pomc has also been reported in the skin, but we did not detect activation of the R26R transgene outside the brain or pituitary gland.


Effects of hypothalamic neurodegeneration on energy balance.

Xu AW, Kaelin CB, Morton GJ, Ogimoto K, Stanhope K, Graham J, Baskin DG, Havel P, Schwartz MW, Barsh GS - PLoS Biol. (2005)

Pattern of R26R Activation in Mice Carrying the PomcCre or AgrpCre TransgeneWhole brains from Tg.PomcCre/+; R26R/+ or Tg.AgrCre/+; R26R/+ mice of the indicated age were fixed and stained with Xgal as described in [9]. Photographs show the ventral brain surface, and coronal sections (not shown) indicate that Xgal-stained neurons lie in the arcuate nucleus of the hypothalamus. As assessed by the extent of Xgal staining, Cre-induced recombination in Pomc neurons is complete by embryonic day 17.5; however, Cre-induced recombination in Agrp neurons is just beginning at 2 wk of age (arrows) and is not complete until 3–4 wk of age.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC1287504&req=5

pbio-0030415-g001: Pattern of R26R Activation in Mice Carrying the PomcCre or AgrpCre TransgeneWhole brains from Tg.PomcCre/+; R26R/+ or Tg.AgrCre/+; R26R/+ mice of the indicated age were fixed and stained with Xgal as described in [9]. Photographs show the ventral brain surface, and coronal sections (not shown) indicate that Xgal-stained neurons lie in the arcuate nucleus of the hypothalamus. As assessed by the extent of Xgal staining, Cre-induced recombination in Pomc neurons is complete by embryonic day 17.5; however, Cre-induced recombination in Agrp neurons is just beginning at 2 wk of age (arrows) and is not complete until 3–4 wk of age.
Mentions: In the arcuate nucleus of the hypothalamus, activation of R26R by the PomcCre transgene became apparent by embryonic day 17.5; activation of R26R by the AgrpCre transgene, however, was not detectable until 2–3 wk of age (Figure 1). These results correspond to what has been described previously for normal development of the melanocortinergic system, with the hypothalamic Pomc system becoming established during fetal brain development, but the Agrp system developing after birth [19,20]. Activation of R26R by the PomcCre transgene also occurs in the nucleus tract solitarius of the hindbrain, and the anterior and intermediate lobe of the pituitary in neonatal animals (unpublished data), which are areas in which Pomc is normally expressed. The early onset of Pomc expression in the arcuate nucleus suggests that the Pomc neurons may play a role in the development of the hypothalamus. Expression of Pomc has also been reported in the skin, but we did not detect activation of the R26R transgene outside the brain or pituitary gland.

Bottom Line: To investigate the role of hypothalamic neuronal circuits in this process, we used a Cre-lox strategy to create mice with specific and progressive degeneration of hypothalamic neurons that express agouti-related protein (Agrp) or proopiomelanocortin (Pomc), neuropeptides that promote positive or negative energy balance, respectively, through their opposing effects on melanocortin receptor signaling.Agrp-ablation female mice exhibit reduced adiposity with normal compensatory hyperphagia, while animals ablated for both Pomc and Agrp neurons exhibit an additive interaction phenotype.These findings provide new insight into the roles of hypothalamic neurons in energy balance regulation, and provide a model for understanding defects in human energy balance associated with neurodegeneration and aging.

View Article: PubMed Central - PubMed

Affiliation: Department of Genetics, Stanford University School of Medicine, Stanford, California, USA.

ABSTRACT
Normal aging in humans and rodents is accompanied by a progressive increase in adiposity. To investigate the role of hypothalamic neuronal circuits in this process, we used a Cre-lox strategy to create mice with specific and progressive degeneration of hypothalamic neurons that express agouti-related protein (Agrp) or proopiomelanocortin (Pomc), neuropeptides that promote positive or negative energy balance, respectively, through their opposing effects on melanocortin receptor signaling. In previous studies, Pomc mutant mice became obese, but Agrp mutant mice were surprisingly normal, suggesting potential compensation by neuronal circuits or genetic redundancy. Here we find that Pomc-ablation mice develop obesity similar to that described for Pomc knockout mice, but also exhibit defects in compensatory hyperphagia similar to what occurs during normal aging. Agrp-ablation female mice exhibit reduced adiposity with normal compensatory hyperphagia, while animals ablated for both Pomc and Agrp neurons exhibit an additive interaction phenotype. These findings provide new insight into the roles of hypothalamic neurons in energy balance regulation, and provide a model for understanding defects in human energy balance associated with neurodegeneration and aging.

Show MeSH
Related in: MedlinePlus