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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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Immunostaining of α-MSH or Agrp in Control and Tfam Mutant Animals of Different AgesHypothalami from control (Tfam flox/+; Tg.PomcCre/+ or Tfam flox/flox; +/+), Pomc-specific Tfam mutant (Tfam flox/flox; Tg.PomcCre/+), and Agrp-specific Tfam mutant (Tfam flox/flox; Tg.AgrpCre/+) animals were harvested at the indicated ages and immunostained for α-MSH or Agrp as indicated.IR, immmunoreactivity.
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pbio-0030415-g002: Immunostaining of α-MSH or Agrp in Control and Tfam Mutant Animals of Different AgesHypothalami from control (Tfam flox/+; Tg.PomcCre/+ or Tfam flox/flox; +/+), Pomc-specific Tfam mutant (Tfam flox/flox; Tg.PomcCre/+), and Agrp-specific Tfam mutant (Tfam flox/flox; Tg.AgrpCre/+) animals were harvested at the indicated ages and immunostained for α-MSH or Agrp as indicated.IR, immmunoreactivity.

Mentions: We examined the pattern and extent of immmunohistochemical staining for α–melanocyte-stimulating hormone (α-MSH) and Agrp in Tfam mutant and control mice at multiple time points. At 2 and 4 mo of age, α-MSH and Agrp neurons in Tfam mutant mice appeared no different from control mice (Figure 2). However, at 7 mo of age, we found that in Pomc-specific Tfam mutant mice, immunohistochemical staining for α-MSH was dramatically reduced compared to control animals, but immunohistochemical staining for Agrp was unaffected (Figure 3). Similarly, in Agrp-specific Tfam mutant mice, immunohistochemical staining for Agrp was dramatically reduced compared to control animals, but immunohistochemical staining for α-MSH was unaffected (Figure 3). In both cases, there was no detectable gliosis or effect on brain architecture, indicating that the ablation was highly specific.


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)

Immunostaining of α-MSH or Agrp in Control and Tfam Mutant Animals of Different AgesHypothalami from control (Tfam flox/+; Tg.PomcCre/+ or Tfam flox/flox; +/+), Pomc-specific Tfam mutant (Tfam flox/flox; Tg.PomcCre/+), and Agrp-specific Tfam mutant (Tfam flox/flox; Tg.AgrpCre/+) animals were harvested at the indicated ages and immunostained for α-MSH or Agrp as indicated.IR, immmunoreactivity.
© Copyright Policy
Related In: Results  -  Collection

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

pbio-0030415-g002: Immunostaining of α-MSH or Agrp in Control and Tfam Mutant Animals of Different AgesHypothalami from control (Tfam flox/+; Tg.PomcCre/+ or Tfam flox/flox; +/+), Pomc-specific Tfam mutant (Tfam flox/flox; Tg.PomcCre/+), and Agrp-specific Tfam mutant (Tfam flox/flox; Tg.AgrpCre/+) animals were harvested at the indicated ages and immunostained for α-MSH or Agrp as indicated.IR, immmunoreactivity.
Mentions: We examined the pattern and extent of immmunohistochemical staining for α–melanocyte-stimulating hormone (α-MSH) and Agrp in Tfam mutant and control mice at multiple time points. At 2 and 4 mo of age, α-MSH and Agrp neurons in Tfam mutant mice appeared no different from control mice (Figure 2). However, at 7 mo of age, we found that in Pomc-specific Tfam mutant mice, immunohistochemical staining for α-MSH was dramatically reduced compared to control animals, but immunohistochemical staining for Agrp was unaffected (Figure 3). Similarly, in Agrp-specific Tfam mutant mice, immunohistochemical staining for Agrp was dramatically reduced compared to control animals, but immunohistochemical staining for α-MSH was unaffected (Figure 3). In both cases, there was no detectable gliosis or effect on brain architecture, indicating that the ablation was highly specific.

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