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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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Food Intake and Energy Expenditure in Animals with Pomc- or Agrp-Specific Tfam Deficiency(A and B) Daily food intake was measured for 7 d as described in Materials and Methods. For (A), numbers of animals used (control and Pomc-Tfam mutant) were 6-mo-old male (n = 13, n = 7); 6-mo-old female (n = 10, n = 6); > 8-mo-old male (n = 10, n = 6); and > 8-mo-old female (n= 13, n = 6).(C, D) O2 consumption was measured over a 24-h period as described in Materials and Methods; panels illustrate results from a single control and a single Pomc-Tfam mutant animal before and after (10–12 d) corticosterone replacement; these results are representative of four control and four mutant animals that were examined.(E) Daily food intake was significantly increased after corticosterone replacement in Pomc-Tfam mutant animals (n = 6) but not in control (n = 9) animals.(F) Measurement of total serum T4 levels in control (n = 7) and Pomc-Tfam mutant (n = 5) animals.*, p ≤ 0.05; **, p ≤ 0.01. Error bars = standard error of the mean.
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pbio-0030415-g007: Food Intake and Energy Expenditure in Animals with Pomc- or Agrp-Specific Tfam Deficiency(A and B) Daily food intake was measured for 7 d as described in Materials and Methods. For (A), numbers of animals used (control and Pomc-Tfam mutant) were 6-mo-old male (n = 13, n = 7); 6-mo-old female (n = 10, n = 6); > 8-mo-old male (n = 10, n = 6); and > 8-mo-old female (n= 13, n = 6).(C, D) O2 consumption was measured over a 24-h period as described in Materials and Methods; panels illustrate results from a single control and a single Pomc-Tfam mutant animal before and after (10–12 d) corticosterone replacement; these results are representative of four control and four mutant animals that were examined.(E) Daily food intake was significantly increased after corticosterone replacement in Pomc-Tfam mutant animals (n = 6) but not in control (n = 9) animals.(F) Measurement of total serum T4 levels in control (n = 7) and Pomc-Tfam mutant (n = 5) animals.*, p ≤ 0.05; **, p ≤ 0.01. Error bars = standard error of the mean.

Mentions: Using dual energy X-ray absorptiometry (DEXA) or MRI to measure adipose versus nonadipose tissue, we observed that in 7- to 10-mo-old animals, loss of Pomc-expressing cells caused an increase in both compartments, with a relative effect that was slightly greater on fat than on lean body mass (Figure 6A and 6B). Agrp ablation caused a small but significant decrease of fat mass in females but not in males (Figure 6D). We also measured rates of food intake and energy expenditure in Pomc-ablation animals, and observed an effect on both components of the energy balance equation. Pomc-ablation mice consumed approximately 10% more than control animals, and exhibited rates of O2 consumption approximately 10% less than control animals (Figure 7).


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)

Food Intake and Energy Expenditure in Animals with Pomc- or Agrp-Specific Tfam Deficiency(A and B) Daily food intake was measured for 7 d as described in Materials and Methods. For (A), numbers of animals used (control and Pomc-Tfam mutant) were 6-mo-old male (n = 13, n = 7); 6-mo-old female (n = 10, n = 6); > 8-mo-old male (n = 10, n = 6); and > 8-mo-old female (n= 13, n = 6).(C, D) O2 consumption was measured over a 24-h period as described in Materials and Methods; panels illustrate results from a single control and a single Pomc-Tfam mutant animal before and after (10–12 d) corticosterone replacement; these results are representative of four control and four mutant animals that were examined.(E) Daily food intake was significantly increased after corticosterone replacement in Pomc-Tfam mutant animals (n = 6) but not in control (n = 9) animals.(F) Measurement of total serum T4 levels in control (n = 7) and Pomc-Tfam mutant (n = 5) 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-g007: Food Intake and Energy Expenditure in Animals with Pomc- or Agrp-Specific Tfam Deficiency(A and B) Daily food intake was measured for 7 d as described in Materials and Methods. For (A), numbers of animals used (control and Pomc-Tfam mutant) were 6-mo-old male (n = 13, n = 7); 6-mo-old female (n = 10, n = 6); > 8-mo-old male (n = 10, n = 6); and > 8-mo-old female (n= 13, n = 6).(C, D) O2 consumption was measured over a 24-h period as described in Materials and Methods; panels illustrate results from a single control and a single Pomc-Tfam mutant animal before and after (10–12 d) corticosterone replacement; these results are representative of four control and four mutant animals that were examined.(E) Daily food intake was significantly increased after corticosterone replacement in Pomc-Tfam mutant animals (n = 6) but not in control (n = 9) animals.(F) Measurement of total serum T4 levels in control (n = 7) and Pomc-Tfam mutant (n = 5) animals.*, p ≤ 0.05; **, p ≤ 0.01. Error bars = standard error of the mean.
Mentions: Using dual energy X-ray absorptiometry (DEXA) or MRI to measure adipose versus nonadipose tissue, we observed that in 7- to 10-mo-old animals, loss of Pomc-expressing cells caused an increase in both compartments, with a relative effect that was slightly greater on fat than on lean body mass (Figure 6A and 6B). Agrp ablation caused a small but significant decrease of fat mass in females but not in males (Figure 6D). We also measured rates of food intake and energy expenditure in Pomc-ablation animals, and observed an effect on both components of the energy balance equation. Pomc-ablation mice consumed approximately 10% more than control animals, and exhibited rates of O2 consumption approximately 10% less than control animals (Figure 7).

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