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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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Compensatory Refeeding and Neuropeptide mRNA levels in Pomc-Specific and Agrp-Specific Tfam Deficiency(A–D) 24-h compensatory refeeding after a 48-h fast was measured as described in Materials and Methods; data are shown either as (A and B) the ratio of food consumed over 24 h (refeeding) to normal daily food intake (averaged over 7 h prior to food deprivation), or as (C and D) percentage of weight recovery after 24 h of refeeding. For the Pomc-Tfam experiment (A and C), number of animals used was n = 23 (control) and n = 13 (Pomc-Tfam mutant); for the Agrp-Tfam experiment (B and D), number of animals used was n = 21 (control) and n = 15 (Agrp-Tfam).(E) The same refeeding defects were observed in Pomc-Tfam mutants after corticosterone replacement (control, n = 9; Pomc-Tfam mutant, n = 6).(F) Expression of Pomc, Agrp, and Npy in Pomc-Tfam mutants. Mice were fasted for 48 h 10 d after implanting corticosterone pellets, and expression of Pomc, Agrp, and Npy in the hypothalamus was measured by semi-quantitative RT-PCR. Values are shown as relative levels compared to free-fed controls. Numbers of animals used were n = 5 (control fed); n = 5 (control fasted); n = 3 (mutant fed); and n = 3 (mutant fasted).*, p ≤ 0.05; **, p ≤ 0.01. Error bars = standard error of the mean.
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pbio-0030415-g008: Compensatory Refeeding and Neuropeptide mRNA levels in Pomc-Specific and Agrp-Specific Tfam Deficiency(A–D) 24-h compensatory refeeding after a 48-h fast was measured as described in Materials and Methods; data are shown either as (A and B) the ratio of food consumed over 24 h (refeeding) to normal daily food intake (averaged over 7 h prior to food deprivation), or as (C and D) percentage of weight recovery after 24 h of refeeding. For the Pomc-Tfam experiment (A and C), number of animals used was n = 23 (control) and n = 13 (Pomc-Tfam mutant); for the Agrp-Tfam experiment (B and D), number of animals used was n = 21 (control) and n = 15 (Agrp-Tfam).(E) The same refeeding defects were observed in Pomc-Tfam mutants after corticosterone replacement (control, n = 9; Pomc-Tfam mutant, n = 6).(F) Expression of Pomc, Agrp, and Npy in Pomc-Tfam mutants. Mice were fasted for 48 h 10 d after implanting corticosterone pellets, and expression of Pomc, Agrp, and Npy in the hypothalamus was measured by semi-quantitative RT-PCR. Values are shown as relative levels compared to free-fed controls. Numbers of animals used were n = 5 (control fed); n = 5 (control fasted); n = 3 (mutant fed); and n = 3 (mutant fasted).*, p ≤ 0.05; **, p ≤ 0.01. Error bars = standard error of the mean.

Mentions: Because Pomc neurons serve as primary hypothalamic sensors for adiposity signals, we suspected that hyperphagia and reduced energy expenditure in Pomc-ablation mice were caused by an underlying abnormality in the hypothalamic circuitry that normally maintains peripheral energy stores. To test this idea directly, we examined the ability of 6-mo-old mutant and control animals to increase food intake acutely following a period of food deprivation. After a 48-h fast, animals normally compensate with a transient hyperphagia sufficient to restore adipose depots to prefasting levels, a phenomenon typically associated with a 2-fold increase in food intake over 24 h. We found that Pomc-ablation mice exhibit an impaired compensatory refeeding response, consuming approximately 25% less than expected (Figure 8A); conversely, Agrp-ablation mice exhibited a normal refeeding response (Figure 8B). These effects also were apparent in weight gain after refeeding; control and Agrp-ablation mice were able to recover their body weight precisely within 24 h after fasting, while Pomc-ablation mice were not (Figure 8C and 8D).


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)

Compensatory Refeeding and Neuropeptide mRNA levels in Pomc-Specific and Agrp-Specific Tfam Deficiency(A–D) 24-h compensatory refeeding after a 48-h fast was measured as described in Materials and Methods; data are shown either as (A and B) the ratio of food consumed over 24 h (refeeding) to normal daily food intake (averaged over 7 h prior to food deprivation), or as (C and D) percentage of weight recovery after 24 h of refeeding. For the Pomc-Tfam experiment (A and C), number of animals used was n = 23 (control) and n = 13 (Pomc-Tfam mutant); for the Agrp-Tfam experiment (B and D), number of animals used was n = 21 (control) and n = 15 (Agrp-Tfam).(E) The same refeeding defects were observed in Pomc-Tfam mutants after corticosterone replacement (control, n = 9; Pomc-Tfam mutant, n = 6).(F) Expression of Pomc, Agrp, and Npy in Pomc-Tfam mutants. Mice were fasted for 48 h 10 d after implanting corticosterone pellets, and expression of Pomc, Agrp, and Npy in the hypothalamus was measured by semi-quantitative RT-PCR. Values are shown as relative levels compared to free-fed controls. Numbers of animals used were n = 5 (control fed); n = 5 (control fasted); n = 3 (mutant fed); and n = 3 (mutant fasted).*, 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-g008: Compensatory Refeeding and Neuropeptide mRNA levels in Pomc-Specific and Agrp-Specific Tfam Deficiency(A–D) 24-h compensatory refeeding after a 48-h fast was measured as described in Materials and Methods; data are shown either as (A and B) the ratio of food consumed over 24 h (refeeding) to normal daily food intake (averaged over 7 h prior to food deprivation), or as (C and D) percentage of weight recovery after 24 h of refeeding. For the Pomc-Tfam experiment (A and C), number of animals used was n = 23 (control) and n = 13 (Pomc-Tfam mutant); for the Agrp-Tfam experiment (B and D), number of animals used was n = 21 (control) and n = 15 (Agrp-Tfam).(E) The same refeeding defects were observed in Pomc-Tfam mutants after corticosterone replacement (control, n = 9; Pomc-Tfam mutant, n = 6).(F) Expression of Pomc, Agrp, and Npy in Pomc-Tfam mutants. Mice were fasted for 48 h 10 d after implanting corticosterone pellets, and expression of Pomc, Agrp, and Npy in the hypothalamus was measured by semi-quantitative RT-PCR. Values are shown as relative levels compared to free-fed controls. Numbers of animals used were n = 5 (control fed); n = 5 (control fasted); n = 3 (mutant fed); and n = 3 (mutant fasted).*, p ≤ 0.05; **, p ≤ 0.01. Error bars = standard error of the mean.
Mentions: Because Pomc neurons serve as primary hypothalamic sensors for adiposity signals, we suspected that hyperphagia and reduced energy expenditure in Pomc-ablation mice were caused by an underlying abnormality in the hypothalamic circuitry that normally maintains peripheral energy stores. To test this idea directly, we examined the ability of 6-mo-old mutant and control animals to increase food intake acutely following a period of food deprivation. After a 48-h fast, animals normally compensate with a transient hyperphagia sufficient to restore adipose depots to prefasting levels, a phenomenon typically associated with a 2-fold increase in food intake over 24 h. We found that Pomc-ablation mice exhibit an impaired compensatory refeeding response, consuming approximately 25% less than expected (Figure 8A); conversely, Agrp-ablation mice exhibited a normal refeeding response (Figure 8B). These effects also were apparent in weight gain after refeeding; control and Agrp-ablation mice were able to recover their body weight precisely within 24 h after fasting, while Pomc-ablation mice were not (Figure 8C and 8D).

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