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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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Changes in plasma lipid levels in tgHD rats.(A) Mean plasma triglyceride levels for WT and tgHD rats across three ages. (B) Mean plasma total cholesterol levels in WT and tgHD rats across three ages. (C) Mean plasma HDL levels in WT and tgHD rats across three ages. (D) Mean plasma LDL levels in WT and tgHD rats across three ages. (E) Mean ratio of HDL/LDL in WT and tgHD rats across three ages. Values are mean ± SEM, * : p<0.05; * * : p<0.01; tgHD vs. WT, #: p<0.05; ##: p<0.01; ###: p<0.001; 9-month or 12 month tgHD vs. 3-month tgHD, n = 5 per group.
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pone-0047240-g003: Changes in plasma lipid levels in tgHD rats.(A) Mean plasma triglyceride levels for WT and tgHD rats across three ages. (B) Mean plasma total cholesterol levels in WT and tgHD rats across three ages. (C) Mean plasma HDL levels in WT and tgHD rats across three ages. (D) Mean plasma LDL levels in WT and tgHD rats across three ages. (E) Mean ratio of HDL/LDL in WT and tgHD rats across three ages. Values are mean ± SEM, * : p<0.05; * * : p<0.01; tgHD vs. WT, #: p<0.05; ##: p<0.01; ###: p<0.001; 9-month or 12 month tgHD vs. 3-month tgHD, n = 5 per group.

Mentions: We next analyzed plasma lipid levels including triglycerides, total cholesterol, high density lipoprotein (HDL), and low-density lipoprotein (LDL). The triglyceride levels of 3-month tgHD rats were significantly reduced compared to WT animals (p = 0.0025, vs. 3-month WT). However, this difference was abolished in both 9-month and 12-month tgHD rats. In addition, WT rats, but not tgHD rats, exhibited age-related significant decreases in plasma triglycerides (p = 0.046, 9-month WT vs. 3-month WT; p = 0.008, 12-month WT vs. 3month WT, Fig. 3A). The tgHD rats and WT rats shared similar total cholesterol levels, except for the 3-month tgHD rats, which showed a trend of reduction (p = 0.056, vs. 3-month WT). Longitudinally, compared to 3-month tgHD rats, both 9-month and 12-month tgHD rats possessed markedly increased levels of total cholesterol (p = 0.0005, 9-month tgHD vs. 3-month tgHD; p = 0.0378, 12-month tgHD vs. 3month tgHD, Fig. 3B). For plasma lipoproteins, a significant decrease was detected in HDL of 3-month tgHD rats compared to age-matched WTs (p = 0.032, Fig. 3C). No statistical difference between tgHD and WT animals was observed with respect to LDL levels (Fig. 3D). Similarly, there was no difference between tgHD and WT animals with respect to the ratio of HDL to LDL (Fig. 3E). Both 12-month tgHD and WT rats had lower HDL levels than their 3-month counterparts. Longitudinally, in terms of LDL and HDL/LDL, both tgHD rats and WT rats showed similar age-dependent changes (Fig. 3E). Using 2-way ANOVA analysis, again, we obtained similar plasma lipid results (Table S1). Triglyceride levels in 3-month old tgHD rats were significantly reduced compared to the age-matched WT animals. Longitudinally, compared to the 3-month old tgHD rats, both 9-month and 12-month tgHD rats possessed markedly increased levels of total cholesterol. Additionally, 3-month old tgHD rats also demonstrated markedly lower LDL levels, compared to 9-month or 12-month tgHD rats. In terms of the ratio of HDL/LDL, tgHD rats demonstrated an obvious age-dependent reduction.


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)

Changes in plasma lipid levels in tgHD rats.(A) Mean plasma triglyceride levels for WT and tgHD rats across three ages. (B) Mean plasma total cholesterol levels in WT and tgHD rats across three ages. (C) Mean plasma HDL levels in WT and tgHD rats across three ages. (D) Mean plasma LDL levels in WT and tgHD rats across three ages. (E) Mean ratio of HDL/LDL in WT and tgHD rats across three ages. Values are mean ± SEM, * : p<0.05; * * : p<0.01; tgHD vs. WT, #: p<0.05; ##: p<0.01; ###: p<0.001; 9-month or 12 month tgHD vs. 3-month tgHD, n = 5 per group.
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC3475691&req=5

pone-0047240-g003: Changes in plasma lipid levels in tgHD rats.(A) Mean plasma triglyceride levels for WT and tgHD rats across three ages. (B) Mean plasma total cholesterol levels in WT and tgHD rats across three ages. (C) Mean plasma HDL levels in WT and tgHD rats across three ages. (D) Mean plasma LDL levels in WT and tgHD rats across three ages. (E) Mean ratio of HDL/LDL in WT and tgHD rats across three ages. Values are mean ± SEM, * : p<0.05; * * : p<0.01; tgHD vs. WT, #: p<0.05; ##: p<0.01; ###: p<0.001; 9-month or 12 month tgHD vs. 3-month tgHD, n = 5 per group.
Mentions: We next analyzed plasma lipid levels including triglycerides, total cholesterol, high density lipoprotein (HDL), and low-density lipoprotein (LDL). The triglyceride levels of 3-month tgHD rats were significantly reduced compared to WT animals (p = 0.0025, vs. 3-month WT). However, this difference was abolished in both 9-month and 12-month tgHD rats. In addition, WT rats, but not tgHD rats, exhibited age-related significant decreases in plasma triglycerides (p = 0.046, 9-month WT vs. 3-month WT; p = 0.008, 12-month WT vs. 3month WT, Fig. 3A). The tgHD rats and WT rats shared similar total cholesterol levels, except for the 3-month tgHD rats, which showed a trend of reduction (p = 0.056, vs. 3-month WT). Longitudinally, compared to 3-month tgHD rats, both 9-month and 12-month tgHD rats possessed markedly increased levels of total cholesterol (p = 0.0005, 9-month tgHD vs. 3-month tgHD; p = 0.0378, 12-month tgHD vs. 3month tgHD, Fig. 3B). For plasma lipoproteins, a significant decrease was detected in HDL of 3-month tgHD rats compared to age-matched WTs (p = 0.032, Fig. 3C). No statistical difference between tgHD and WT animals was observed with respect to LDL levels (Fig. 3D). Similarly, there was no difference between tgHD and WT animals with respect to the ratio of HDL to LDL (Fig. 3E). Both 12-month tgHD and WT rats had lower HDL levels than their 3-month counterparts. Longitudinally, in terms of LDL and HDL/LDL, both tgHD rats and WT rats showed similar age-dependent changes (Fig. 3E). Using 2-way ANOVA analysis, again, we obtained similar plasma lipid results (Table S1). Triglyceride levels in 3-month old tgHD rats were significantly reduced compared to the age-matched WT animals. Longitudinally, compared to the 3-month old tgHD rats, both 9-month and 12-month tgHD rats possessed markedly increased levels of total cholesterol. Additionally, 3-month old tgHD rats also demonstrated markedly lower LDL levels, compared to 9-month or 12-month tgHD rats. In terms of the ratio of HDL/LDL, tgHD rats demonstrated an obvious age-dependent reduction.

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