Abstract
Metabolic and psychiatric disturbances occur early on in the clinical manifestation of Huntington’s disease (HD), a neurodegenerative disorder caused by an expanded CAG repeat in the huntingtin (HTT) gene. Hypothalamus has emerged as an important site of pathology and alterations in this area and its neuroendocrine circuits may play a role in causing early non-motor symptoms and signs in HD. Leptin is a hormone that controls energy homeostasis by signaling through leptin receptors in the hypothalamus. Disturbed leptin action is implicated in both obesity and depression and altered circulating levels of leptin have been reported in both clinical HD and rodent models of the disease. Pathological leptin signaling may therefore be involved in causing the metabolic and psychiatric disturbances of HD. Here we tested the hypothesis that expression of mutant HTT in leptin receptor carrying neurons plays a role in the development of the non-motor phenotype in the BACHD mouse model. Our results show that inactivation of mutant HTT in leptin receptor-expressing neurons in the BACHD mouse using cross-breeding based on a cre-loxP system did not have an effect on the metabolic phenotype or anxiety-like behavior. The data suggest that mutant HTT disrupts critical hypothalamic pathways by other mechanisms than interfering with intracellular leptin signaling.
Highlights
Huntington’s disease (HD) is a fatal neurodegenerative disorder caused by a CAG repeat expansion in the huntingtin (HTT) gene [1]
BACHD mice were here crossbred with LepR-cre mice in order to inactivate mutant HTT in leptin receptor expressing neurons in the offspring in order to assess its effect on the metabolic and behavioral phenotype
Defect leptin signaling has been implicated in the pathological process in both metabolic and psychiatric disturbances and altered levels of leptin have been reported in clinical HD [6,14,16,20]
Summary
Huntington’s disease (HD) is a fatal neurodegenerative disorder caused by a CAG repeat expansion in the huntingtin (HTT) gene [1]. It is well known that psychiatric and cognitive disturbances as well altered sleep and metabolism often begin several years before motor onset but the underlying neuropathological mechanisms behind these symptoms are still not known [4,5,6,7,8,9,10]. Since hypothalamus is the main regulator of metabolism, sleep and emotions, pathological alterations in this area and neuroendocrine circuits may play a role in causing these early non-motor symptoms and signs in HD. Leptin is a peptide secreted into the blood by adipose tissue and that enters the brain via a saturable transport mechanism It exerts its control of energy homeostasis by binding to leptin receptors in the hypothalamus, but leptin receptors are expressed in other brain areas implicated in mood and emotion, such as the amygdala, hippocampus and cortex [16,17,18]. Impaired leptin action in the central nervous system (CNS) has been implicated in both obesity and depression and a potential link between these conditions have been suggested [16,19,20]
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