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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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Alterations in metabolic hormones in tgHD rats.(A) Mean plasma amylin concentrations for WT and tgHD rats across three ages. (B) Mean plasma GIP concentrations in WT and tgHD rats across three ages. (C) Mean plasma PP concentrations in WT and tgHD rats across three ages. (D) Mean plasma PYY concentrations in WT and tgHD rats across three ages. (E) Mean plasma corticosterone concentrations in WT and tgHD rats across three ages. Values are mean ± SEM, *: p<0.05; ***: p<0.001; 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-g002: Alterations in metabolic hormones in tgHD rats.(A) Mean plasma amylin concentrations for WT and tgHD rats across three ages. (B) Mean plasma GIP concentrations in WT and tgHD rats across three ages. (C) Mean plasma PP concentrations in WT and tgHD rats across three ages. (D) Mean plasma PYY concentrations in WT and tgHD rats across three ages. (E) Mean plasma corticosterone concentrations in WT and tgHD rats across three ages. Values are mean ± SEM, *: p<0.05; ***: p<0.001; 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 measured circulating levels of numerous metabolic hormones including amylin, gastric inhibitory polypeptide (GIP), pancreatic peptide (PP), and Peptide YY (PYY). We found that amylin (Fig. 2A) and PYY (Fig. 2D) levels were significantly decreased in 3-month tgHD rats compared to WT controls (p = 0.0001 for amylin; p = 0.025 for PYY). Compared to 12-month WT rats, we observed decreasing trends in both GIP (p = 0.072) (Fig. 2B) and PP (p = 0.078) (Fig. 2C) in 12-month tgHD rats. In addition, both tgHD and WT animals displayed significant age-dependent reductions in amylin levels (p = 0.002, 12-month tgHD vs. 3-month tgHD; p<0.001, 9-month WT vs. 3-month WT; p<0.001, 12-month WT vs. 3-month WT, Fig. 2A). Compared to 3-month tgHD rats, 12-month tgHD rats exhibited significantly decreased GIP levels (Fig. 2B), whereas 9-month tgHD rats demonstrated a significant increase in PP levels (Fig. 2C). WT rats also showed profound age-related elevations in their PP levels (p = 0.02, 9-month WT vs. 3-month WT; p = 0.006, 12-month WT vs. 3-month WT, Fig. 2C). In addition to evaluating metabolic hormone levels, we also evaluated levels of corticosterone, a stress-responsive hormone. We found that only 12-month tgHD rats demonstrated a trend of reduction in systemic corticosterone (p = 0.068, vs. 12-month WT) (Fig. 2E). Additionally, we also used 2-way ANOVA to assess potential changes in plasma amylin, GIP, PP, PYY and corticosterone levels. Consistently, we observed a significant decease in amylin and PYY levels in 3-month tgHD rats, compared to 3-month WT rats (Table S1).


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)

Alterations in metabolic hormones in tgHD rats.(A) Mean plasma amylin concentrations for WT and tgHD rats across three ages. (B) Mean plasma GIP concentrations in WT and tgHD rats across three ages. (C) Mean plasma PP concentrations in WT and tgHD rats across three ages. (D) Mean plasma PYY concentrations in WT and tgHD rats across three ages. (E) Mean plasma corticosterone concentrations in WT and tgHD rats across three ages. Values are mean ± SEM, *: p<0.05; ***: p<0.001; 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-g002: Alterations in metabolic hormones in tgHD rats.(A) Mean plasma amylin concentrations for WT and tgHD rats across three ages. (B) Mean plasma GIP concentrations in WT and tgHD rats across three ages. (C) Mean plasma PP concentrations in WT and tgHD rats across three ages. (D) Mean plasma PYY concentrations in WT and tgHD rats across three ages. (E) Mean plasma corticosterone concentrations in WT and tgHD rats across three ages. Values are mean ± SEM, *: p<0.05; ***: p<0.001; 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 measured circulating levels of numerous metabolic hormones including amylin, gastric inhibitory polypeptide (GIP), pancreatic peptide (PP), and Peptide YY (PYY). We found that amylin (Fig. 2A) and PYY (Fig. 2D) levels were significantly decreased in 3-month tgHD rats compared to WT controls (p = 0.0001 for amylin; p = 0.025 for PYY). Compared to 12-month WT rats, we observed decreasing trends in both GIP (p = 0.072) (Fig. 2B) and PP (p = 0.078) (Fig. 2C) in 12-month tgHD rats. In addition, both tgHD and WT animals displayed significant age-dependent reductions in amylin levels (p = 0.002, 12-month tgHD vs. 3-month tgHD; p<0.001, 9-month WT vs. 3-month WT; p<0.001, 12-month WT vs. 3-month WT, Fig. 2A). Compared to 3-month tgHD rats, 12-month tgHD rats exhibited significantly decreased GIP levels (Fig. 2B), whereas 9-month tgHD rats demonstrated a significant increase in PP levels (Fig. 2C). WT rats also showed profound age-related elevations in their PP levels (p = 0.02, 9-month WT vs. 3-month WT; p = 0.006, 12-month WT vs. 3-month WT, Fig. 2C). In addition to evaluating metabolic hormone levels, we also evaluated levels of corticosterone, a stress-responsive hormone. We found that only 12-month tgHD rats demonstrated a trend of reduction in systemic corticosterone (p = 0.068, vs. 12-month WT) (Fig. 2E). Additionally, we also used 2-way ANOVA to assess potential changes in plasma amylin, GIP, PP, PYY and corticosterone levels. Consistently, we observed a significant decease in amylin and PYY levels in 3-month tgHD rats, compared to 3-month WT rats (Table S1).

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