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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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Related in: MedlinePlus

Effect of Pomc- and/or Agrp-Specific Tfam Mutations on Body Weight(A–D) show longitudinal measurements of body weight in animals of the indicated genotype and sex. (E) and (F) show comparisons of single (Pomc-specific) and double (Pomc- and Agrp-specific) Tfam deficiency for 6- and 9-mo-old animals.*, p ≤ 0.05; **, p ≤ 0.01. Error bars = standard error of the mean.
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pbio-0030415-g005: Effect of Pomc- and/or Agrp-Specific Tfam Mutations on Body Weight(A–D) show longitudinal measurements of body weight in animals of the indicated genotype and sex. (E) and (F) show comparisons of single (Pomc-specific) and double (Pomc- and Agrp-specific) Tfam deficiency for 6- and 9-mo-old animals.*, p ≤ 0.05; **, p ≤ 0.01. Error bars = standard error of the mean.

Mentions: Pomc-ablation mice exhibited a progressive adult-onset obesity in which increased weight gain compared to controls was first detectable at 4 mo of age, and the magnitude of the effect was greater in females (∼30% increase in body weight) than in males (∼15% increase in body weight) (Figure 5A and 5B). Agrp-ablation mice exhibited little difference in body weight compared to control animals, although at every time point, the mean body weight for mutant animals was slightly less than control animals for both males (Figure 5C) and females (Figure 5D). A more significant role for Agrp neurons in total body weight was uncovered by examining double-ablation mice; animals deficient for both neuronal subtypes weigh more than control animals but less than Pomc single-ablation mice in both males (Figure 5E) and females (Figure 5F).


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)

Effect of Pomc- and/or Agrp-Specific Tfam Mutations on Body Weight(A–D) show longitudinal measurements of body weight in animals of the indicated genotype and sex. (E) and (F) show comparisons of single (Pomc-specific) and double (Pomc- and Agrp-specific) Tfam deficiency for 6- and 9-mo-old animals.*, p ≤ 0.05; **, 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-g005: Effect of Pomc- and/or Agrp-Specific Tfam Mutations on Body Weight(A–D) show longitudinal measurements of body weight in animals of the indicated genotype and sex. (E) and (F) show comparisons of single (Pomc-specific) and double (Pomc- and Agrp-specific) Tfam deficiency for 6- and 9-mo-old animals.*, p ≤ 0.05; **, p ≤ 0.01. Error bars = standard error of the mean.
Mentions: Pomc-ablation mice exhibited a progressive adult-onset obesity in which increased weight gain compared to controls was first detectable at 4 mo of age, and the magnitude of the effect was greater in females (∼30% increase in body weight) than in males (∼15% increase in body weight) (Figure 5A and 5B). Agrp-ablation mice exhibited little difference in body weight compared to control animals, although at every time point, the mean body weight for mutant animals was slightly less than control animals for both males (Figure 5C) and females (Figure 5D). A more significant role for Agrp neurons in total body weight was uncovered by examining double-ablation mice; animals deficient for both neuronal subtypes weigh more than control animals but less than Pomc single-ablation mice in both males (Figure 5E) and females (Figure 5F).

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