Altered Hypothalamic Protein Expression in a Rat Model of Huntington's Disease

Chadwick

Journal of Biological Chemistry

et al. 2015

Self Cite

Background: Etiology of Huntington disease (HD) is related to the overproduction of mutant huntingtin (mHTT) protein.Results: Amitriptyline improved motor symptoms via decreasing mHTT protein expression, improving neurotrophin signaling, and enhancing mitochondrial functions in HD mice. Conclusion: Amitriptyline demonstrated beneficial effects in HD mice. Significance: Amitriptyline has therapeutic potential in treating HD.

Section: Discussionmentioning

confidence: 99%

Amitriptyline Improves Motor Function via Enhanced Neurotrophin Signaling and Mitochondrial Functions in the Murine N171-82Q Huntington Disease Model

Chadwick

Journal of Biological Chemistry

et al. 2015

Self Cite

“…A comprehensive lab animal metabolic monitoring system (CLAMS; Columbus Instruments, Columbus, OH) was employed to collect data concerning mouse ambulatory activity (x, z axis motion counts), energy expenditure (kL/hr), O 2 consumption (mL/Kg/hr), CO 2 production (mL/Kg/hr) and respiratory exchange ratio (RER = Vco 2 /Vo 2 ), as described previously [37], [38]. Energy expenditure was calculated from the gas exchange data [energy expenditure = (3.815+1.232 ×RER) ×V O2 ] and expressed as kJ/kg/h.…”

Section: Methodsmentioning

confidence: 99%

“…Both fasting and non-fasting glucose levels were measured using the EasyGluco blood glucose monitoring system as described previously (US Diagnostics, Inc., New York, NY) [37], [39]. For fasting glucose measurements, mice were food deprived 12 hours prior to blood collection.…”

Section: Methodsmentioning

confidence: 99%

Altered Lipid and Salt Taste Responsivity in Ghrelin and GOAT Null Mice

et al. 2013

Self Cite

Taste perception plays an important role in regulating food preference, eating behavior and energy homeostasis. Taste perception is modulated by a variety of factors, including gastric hormones such as ghrelin. Ghrelin can regulate growth hormone release, food intake, adiposity, and energy metabolism. Octanoylation of ghrelin by ghrelin O-acyltransferase (GOAT) is a specific post-translational modification which is essential for many biological activities of ghrelin. Ghrelin and GOAT are both widely expressed in many organs including the gustatory system. In the current study, overall metabolic profiles were assessed in wild-type (WT), ghrelin knockout (ghrelin−/−), and GOAT knockout (GOAT−/−) mice. Ghrelin−/− mice exhibited decreased food intake, increased plasma triglycerides and increased ketone bodies compared to WT mice while demonstrating WT-like body weight, fat composition and glucose control. In contrast GOAT−/− mice exhibited reduced body weight, adiposity, resting glucose and insulin levels compared to WT mice. Brief access taste behavioral tests were performed to determine taste responsivity in WT, ghrelin−/− and GOAT−/− mice. Ghrelin and GOAT null mice possessed reduced lipid taste responsivity. Furthermore, we found that salty taste responsivity was attenuated in ghrelin−/− mice, yet potentiated in GOAT−/− mice compared to WT mice. Expression of the potential lipid taste regulators Cd36 and Gpr120 were reduced in the taste buds of ghrelin and GOAT null mice, while the salt-sensitive ENaC subunit was increased in GOAT−/− mice compared with WT mice. The altered expression of Cd36, Gpr120 and ENaC may be responsible for the altered lipid and salt taste perception in ghrelin−/− and GOAT−/− mice. The data presented in the current study potentially implicates ghrelin signaling activity in the modulation of both lipid and salt taste modalities.

“…Transgenic HD rats contains a truncated huntingtin cDNA fragment with 51 CAG repeats under the control of the native rat huntingtin promoter (13,21). These rats show alterations in the expression of several hypothalamic proteins, such as glial fibrillary acidic protein, and also changes in circulating levels of leptin, insulin and ghrelin (21). The Q175 mouse model of HD has a spontaneous expansion of the CAG repeats in the original CAG140 knock-in line.…”

Section: Genetic Rodent Models Of Hdmentioning

confidence: 99%

Hypothalamic Alterations in Huntington's Disease Patients: Comparison with Genetic Rodent Models

Wamelen

Aziz

Roos

et al. 2014

J Neuroendocrinology

Unintended weight loss, sleep and circadian disturbances and autonomic dysfunction are prevalent features of Huntington's disease (HD), an autosomal dominantly inherited neurodegenerative disorder caused by an expanded CAG repeat sequence in the HTT gene. These features form a substantial contribution to disease burden in HD patients and appear to be accompanied by a number of neuroendocrine and metabolic changes, pointing towards hypothalamic pathology as a likely underlying mechanism. Neuronal inclusion bodies of mutant huntingtin, which are hallmarks of the disease, occur throughout the hypothalamus, and indicate local mutant huntingtin expression that could interfere with hypothalamic neuropeptide production. Also, several genetic rodent models of HD show features that could be related to hypothalamic pathology, such as weight loss and circadian rhythm disturbances. In these rodents, several hypothalamic neuropeptide populations are affected. In the present review, we summarise the changes in genetic rodent models of HD for individual hypothalamic nuclei, compare these observations to the hypothalamic changes that occur in HD patients, and make an inventory of the work that still needs to be done. Surprisingly, there is only limited overlap in the hypothalamic changes reported in HD patients and genetic rodent models. At present, the only similarity between the hypothalamic alterations in HD patients and genetic rodent models is a decrease in the number of orexin-expressing neurones in the lateral hypothalamus. Possible reasons for these discrepancies, as well as potential consequences for the development of novel therapeutic strategies, are discussed.