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Altered hypothalamic protein expression in a rat model of Huntington's disease.

Cong WN, Cai H, Wang R, Daimon CM, Maudsley S, Raber K, Canneva F, von Hörsten S, Martin B - PLoS ONE (2012)

Bottom Line: Our results demonstrate that there are significant alterations in HD rat hypothalamic protein expression such as glial fibrillary acidic protein (GFAP), heat shock protein-70, the oxidative damage protein glutathione peroxidase (Gpx4), glycogen synthase1 (Gys1) and the lipid synthesis enzyme acylglycerol-3-phosphate O-acyltransferase 1 (Agpat1).These early metabolic and lipid alterations are likely prodromal signs of hypothalamic dysfunction.Gaining a greater understanding of the hypothalamic and metabolic alterations that occur in HD, could lead to the development of novel therapeutics for early interventional treatment of HD.

View Article: PubMed Central - PubMed

Affiliation: Metabolism Unit, National Institute on Aging, National Institutes of Health, Baltimore, Maryland, United States of America.

ABSTRACT
Huntington's disease (HD) is a neurodegenerative disorder, which is characterized by progressive motor impairment and cognitive alterations. Changes in energy metabolism, neuroendocrine function, body weight, euglycemia, appetite function, and circadian rhythm can also occur. It is likely that the locus of these alterations is the hypothalamus. We used the HD transgenic (tg) rat model bearing 51 CAG repeats, which exhibits similar HD symptomology as HD patients to investigate hypothalamic function. We conducted detailed hypothalamic proteome analyses and also measured circulating levels of various metabolic hormones and lipids in pre-symptomatic and symptomatic animals. Our results demonstrate that there are significant alterations in HD rat hypothalamic protein expression such as glial fibrillary acidic protein (GFAP), heat shock protein-70, the oxidative damage protein glutathione peroxidase (Gpx4), glycogen synthase1 (Gys1) and the lipid synthesis enzyme acylglycerol-3-phosphate O-acyltransferase 1 (Agpat1). In addition, there are significant alterations in various circulating metabolic hormones and lipids in pre-symptomatic animals including, insulin, leptin, triglycerides and HDL, before any motor or cognitive alterations are apparent. These early metabolic and lipid alterations are likely prodromal signs of hypothalamic dysfunction. Gaining a greater understanding of the hypothalamic and metabolic alterations that occur in HD, could lead to the development of novel therapeutics for early interventional treatment of HD.

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Altered plasma glycemic hormone and appetite hormone levels in tgHD rats.(A) Mean blood glucose concentrations for WT and tgHD rats across three ages. (B) Mean plasma insulin concentrations in WT and tgHD rats across three ages. (C) Mean plasma adiponectin concentrations in WT and tgHD rats across three ages. (D) Mean plasma leptin concentrations in WT and tgHD rats across three ages. (E) Mean plasma total ghrelin concentrations in WT and tgHD rats across three ages. Values are mean ± SEM, *: p<0.05; tgHD vs. WT, #: p<0.05; ##: p<0.01; 9-month or 12 month tgHD vs. 3-month tgHD, n = 5 per group.
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pone-0047240-g001: Altered plasma glycemic hormone and appetite hormone levels in tgHD rats.(A) Mean blood glucose concentrations for WT and tgHD rats across three ages. (B) Mean plasma insulin concentrations in WT and tgHD rats across three ages. (C) Mean plasma adiponectin concentrations in WT and tgHD rats across three ages. (D) Mean plasma leptin concentrations in WT and tgHD rats across three ages. (E) Mean plasma total ghrelin concentrations in WT and tgHD rats across three ages. Values are mean ± SEM, *: p<0.05; tgHD vs. WT, #: p<0.05; ##: p<0.01; 9-month or 12 month tgHD vs. 3-month tgHD, n = 5 per group.

Mentions: We assessed longitudinal circulating levels of glucose, insulin, adiponectin, ghrelin (total), and leptin in rats aged 3-months (pre-symptomatic), 9-months (early-symptomatic) and 12 months (symptomatic). Longitudinal analysis demonstrated that tgHD rats possessed comparable levels of circulating glucose, compared to the WT rats across all three ages (Fig. 1A). However, significantly lower insulin levels were detected in both 3-month and 12-month tgHD rats, compared to the WT controls (p = 0.013, 3-month tgHD vs. 3-month WT; p = 0.028, 12-month tgHD vs. 12-month WT, Fig. 1B). Longitudinally, both tgHDs and WTs exhibited a progressive reduction in plasma insulin levels (p = 0.0069, 12-month tgHD vs. 3-month tgHD; p = 0.009, 9-month WT vs. 3-month WT; p = 0.008, 12-month WT vs. 3-month WT). There was no significant difference in plasma adiponectin levels between tgHDs and WTs across all three ages. When compared to 3-month tgHD animals, the 9-month tgHD rats displayed a significant decrease in adiponectin levels (Fig. 1C). In order to better understand peripheral metabolic alterations in tgHD rats, we further evaluated levels of leptin and ghrelin, two major appetite-modulating hormones. Compared to WT animals, the 3-month old tgHD rats demonstrated a significant decrease in plasma leptin levels (p = 0.044, Fig. 1D). There was also a trend towards reduction in the 12-month tgHD rats (p = 0.067), as well. Interestingly, compared to the 3-month tgHD animals, 9-month tgHD rats revealed a significant increase in leptin levels (p = 0.0067, Fig. 1D). Longitudinally, both tgHD rats and WT rats displayed a progressive elevation in plasma ghrelin levels (p = 0.028, 9-month tgHD vs. 3-month tgHD; p = 0.043, 12-month tgHD vs. 3month tgHD; p = 0.002, 12-month WT vs. 3-month WT) (Fig. 1E). The euglycemic hormone alterations demonstrated in the tgHD rats are similar to what has been shown previously in mouse models of HD (N171-82Q, [15]). Additionally, we also performed two-way ANOVA analysis. Two-way ANOVA analysis allows us to simultaneously consider the effects from two independent factors, i.e. genotype and age. With 2-way ANOVA analysis, as shown in Table S1, similar results were obtained: significantly lower insulin levels were detected in 3-month tgHD rats, compared with age-matched WTs. Compared to 12-month WT animals, the 12-month tgHD rats demonstrated a significant decrease in plasma leptin levels. Longitudinally, 9 month tgHD rats demonstrated significantly higher leptin levels compared to 3-month tgHD animals. A significant age-dependent increase in ghrelin was also found in both tgHD and WT rats.


Altered hypothalamic protein expression in a rat model of Huntington's disease.

Cong WN, Cai H, Wang R, Daimon CM, Maudsley S, Raber K, Canneva F, von Hörsten S, Martin B - PLoS ONE (2012)

Altered plasma glycemic hormone and appetite hormone levels in tgHD rats.(A) Mean blood glucose concentrations for WT and tgHD rats across three ages. (B) Mean plasma insulin concentrations in WT and tgHD rats across three ages. (C) Mean plasma adiponectin concentrations in WT and tgHD rats across three ages. (D) Mean plasma leptin concentrations in WT and tgHD rats across three ages. (E) Mean plasma total ghrelin concentrations in WT and tgHD rats across three ages. Values are mean ± SEM, *: p<0.05; tgHD vs. WT, #: p<0.05; ##: p<0.01; 9-month or 12 month tgHD vs. 3-month tgHD, n = 5 per group.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3475691&req=5

pone-0047240-g001: Altered plasma glycemic hormone and appetite hormone levels in tgHD rats.(A) Mean blood glucose concentrations for WT and tgHD rats across three ages. (B) Mean plasma insulin concentrations in WT and tgHD rats across three ages. (C) Mean plasma adiponectin concentrations in WT and tgHD rats across three ages. (D) Mean plasma leptin concentrations in WT and tgHD rats across three ages. (E) Mean plasma total ghrelin concentrations in WT and tgHD rats across three ages. Values are mean ± SEM, *: p<0.05; tgHD vs. WT, #: p<0.05; ##: p<0.01; 9-month or 12 month tgHD vs. 3-month tgHD, n = 5 per group.
Mentions: We assessed longitudinal circulating levels of glucose, insulin, adiponectin, ghrelin (total), and leptin in rats aged 3-months (pre-symptomatic), 9-months (early-symptomatic) and 12 months (symptomatic). Longitudinal analysis demonstrated that tgHD rats possessed comparable levels of circulating glucose, compared to the WT rats across all three ages (Fig. 1A). However, significantly lower insulin levels were detected in both 3-month and 12-month tgHD rats, compared to the WT controls (p = 0.013, 3-month tgHD vs. 3-month WT; p = 0.028, 12-month tgHD vs. 12-month WT, Fig. 1B). Longitudinally, both tgHDs and WTs exhibited a progressive reduction in plasma insulin levels (p = 0.0069, 12-month tgHD vs. 3-month tgHD; p = 0.009, 9-month WT vs. 3-month WT; p = 0.008, 12-month WT vs. 3-month WT). There was no significant difference in plasma adiponectin levels between tgHDs and WTs across all three ages. When compared to 3-month tgHD animals, the 9-month tgHD rats displayed a significant decrease in adiponectin levels (Fig. 1C). In order to better understand peripheral metabolic alterations in tgHD rats, we further evaluated levels of leptin and ghrelin, two major appetite-modulating hormones. Compared to WT animals, the 3-month old tgHD rats demonstrated a significant decrease in plasma leptin levels (p = 0.044, Fig. 1D). There was also a trend towards reduction in the 12-month tgHD rats (p = 0.067), as well. Interestingly, compared to the 3-month tgHD animals, 9-month tgHD rats revealed a significant increase in leptin levels (p = 0.0067, Fig. 1D). Longitudinally, both tgHD rats and WT rats displayed a progressive elevation in plasma ghrelin levels (p = 0.028, 9-month tgHD vs. 3-month tgHD; p = 0.043, 12-month tgHD vs. 3month tgHD; p = 0.002, 12-month WT vs. 3-month WT) (Fig. 1E). The euglycemic hormone alterations demonstrated in the tgHD rats are similar to what has been shown previously in mouse models of HD (N171-82Q, [15]). Additionally, we also performed two-way ANOVA analysis. Two-way ANOVA analysis allows us to simultaneously consider the effects from two independent factors, i.e. genotype and age. With 2-way ANOVA analysis, as shown in Table S1, similar results were obtained: significantly lower insulin levels were detected in 3-month tgHD rats, compared with age-matched WTs. Compared to 12-month WT animals, the 12-month tgHD rats demonstrated a significant decrease in plasma leptin levels. Longitudinally, 9 month tgHD rats demonstrated significantly higher leptin levels compared to 3-month tgHD animals. A significant age-dependent increase in ghrelin was also found in both tgHD and WT rats.

Bottom Line: Our results demonstrate that there are significant alterations in HD rat hypothalamic protein expression such as glial fibrillary acidic protein (GFAP), heat shock protein-70, the oxidative damage protein glutathione peroxidase (Gpx4), glycogen synthase1 (Gys1) and the lipid synthesis enzyme acylglycerol-3-phosphate O-acyltransferase 1 (Agpat1).These early metabolic and lipid alterations are likely prodromal signs of hypothalamic dysfunction.Gaining a greater understanding of the hypothalamic and metabolic alterations that occur in HD, could lead to the development of novel therapeutics for early interventional treatment of HD.

View Article: PubMed Central - PubMed

Affiliation: Metabolism Unit, National Institute on Aging, National Institutes of Health, Baltimore, Maryland, United States of America.

ABSTRACT
Huntington's disease (HD) is a neurodegenerative disorder, which is characterized by progressive motor impairment and cognitive alterations. Changes in energy metabolism, neuroendocrine function, body weight, euglycemia, appetite function, and circadian rhythm can also occur. It is likely that the locus of these alterations is the hypothalamus. We used the HD transgenic (tg) rat model bearing 51 CAG repeats, which exhibits similar HD symptomology as HD patients to investigate hypothalamic function. We conducted detailed hypothalamic proteome analyses and also measured circulating levels of various metabolic hormones and lipids in pre-symptomatic and symptomatic animals. Our results demonstrate that there are significant alterations in HD rat hypothalamic protein expression such as glial fibrillary acidic protein (GFAP), heat shock protein-70, the oxidative damage protein glutathione peroxidase (Gpx4), glycogen synthase1 (Gys1) and the lipid synthesis enzyme acylglycerol-3-phosphate O-acyltransferase 1 (Agpat1). In addition, there are significant alterations in various circulating metabolic hormones and lipids in pre-symptomatic animals including, insulin, leptin, triglycerides and HDL, before any motor or cognitive alterations are apparent. These early metabolic and lipid alterations are likely prodromal signs of hypothalamic dysfunction. Gaining a greater understanding of the hypothalamic and metabolic alterations that occur in HD, could lead to the development of novel therapeutics for early interventional treatment of HD.

Show MeSH
Related in: MedlinePlus