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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.

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Expression of the R26R Cre Reporter Gene in Pomc- or Agrp-Specific Tfam Mutant AnimalsAnimals carrying the PomcCre or AgrpCre transgene together with the lacZ reporter allele for Cre recombination Gt(Rosa)26Sortm1Sor (R26R) were intercrossed with Tfam flox/flox animals. F2 progeny of the indicated genotype were sacrificed at 7 mo of age, and hypothalamic coronal sections stained for Xgal. In this situation, Xgal staining serves as an autonomous histologic marker, and loss of Xgal staining in Tfam mutant animals is therefore secondary to cell death. Sections are representative of three to four per genotype group that were examined. The panel on the lower right shows the number of Agrp-expressing neurons in the control and Agrp-Tfam mutants as determined by fluorescence in situ hybridization to Agrp mRNA.**, p ≤ 0.01. Error bars = standard error of the mean.
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pbio-0030415-g004: Expression of the R26R Cre Reporter Gene in Pomc- or Agrp-Specific Tfam Mutant AnimalsAnimals carrying the PomcCre or AgrpCre transgene together with the lacZ reporter allele for Cre recombination Gt(Rosa)26Sortm1Sor (R26R) were intercrossed with Tfam flox/flox animals. F2 progeny of the indicated genotype were sacrificed at 7 mo of age, and hypothalamic coronal sections stained for Xgal. In this situation, Xgal staining serves as an autonomous histologic marker, and loss of Xgal staining in Tfam mutant animals is therefore secondary to cell death. Sections are representative of three to four per genotype group that were examined. The panel on the lower right shows the number of Agrp-expressing neurons in the control and Agrp-Tfam mutants as determined by fluorescence in situ hybridization to Agrp mRNA.**, p ≤ 0.01. Error bars = standard error of the mean.

Mentions: As an additional measure of ablation, we examined Xgal staining of hypothalamic sections from experimental and control mice that carried the R26R reporter gene, since, for example, loss of Agrp neurons from Tg.AgrpCre/+; Tfam flox/flox ; R26R/+ mice should be reflected in a reduced number of Xgal-positive neurons. For both Pomc-specific and Agrp-specific Tfam mutant mice, very few Xgal-positive cells were detectable; furthermore, mRNA in situ hybridization revealed a dramatic reduction in the number of Agrp-expressing cells (Figure 4). Thus, loss of Tfam induced by a PomcCre or AgrpCre transgene gives rise to postnatal loss of Pomc or Agrp neurons that is specific and extensive.


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)

Expression of the R26R Cre Reporter Gene in Pomc- or Agrp-Specific Tfam Mutant AnimalsAnimals carrying the PomcCre or AgrpCre transgene together with the lacZ reporter allele for Cre recombination Gt(Rosa)26Sortm1Sor (R26R) were intercrossed with Tfam flox/flox animals. F2 progeny of the indicated genotype were sacrificed at 7 mo of age, and hypothalamic coronal sections stained for Xgal. In this situation, Xgal staining serves as an autonomous histologic marker, and loss of Xgal staining in Tfam mutant animals is therefore secondary to cell death. Sections are representative of three to four per genotype group that were examined. The panel on the lower right shows the number of Agrp-expressing neurons in the control and Agrp-Tfam mutants as determined by fluorescence in situ hybridization to Agrp mRNA.**, p ≤ 0.01. Error bars = standard error of the mean.
© Copyright Policy
Related In: Results  -  Collection

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

pbio-0030415-g004: Expression of the R26R Cre Reporter Gene in Pomc- or Agrp-Specific Tfam Mutant AnimalsAnimals carrying the PomcCre or AgrpCre transgene together with the lacZ reporter allele for Cre recombination Gt(Rosa)26Sortm1Sor (R26R) were intercrossed with Tfam flox/flox animals. F2 progeny of the indicated genotype were sacrificed at 7 mo of age, and hypothalamic coronal sections stained for Xgal. In this situation, Xgal staining serves as an autonomous histologic marker, and loss of Xgal staining in Tfam mutant animals is therefore secondary to cell death. Sections are representative of three to four per genotype group that were examined. The panel on the lower right shows the number of Agrp-expressing neurons in the control and Agrp-Tfam mutants as determined by fluorescence in situ hybridization to Agrp mRNA.**, p ≤ 0.01. Error bars = standard error of the mean.
Mentions: As an additional measure of ablation, we examined Xgal staining of hypothalamic sections from experimental and control mice that carried the R26R reporter gene, since, for example, loss of Agrp neurons from Tg.AgrpCre/+; Tfam flox/flox ; R26R/+ mice should be reflected in a reduced number of Xgal-positive neurons. For both Pomc-specific and Agrp-specific Tfam mutant mice, very few Xgal-positive cells were detectable; furthermore, mRNA in situ hybridization revealed a dramatic reduction in the number of Agrp-expressing cells (Figure 4). Thus, loss of Tfam induced by a PomcCre or AgrpCre transgene gives rise to postnatal loss of Pomc or Agrp neurons that is specific and extensive.

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