Genetic Ablation of Orexin Neurons in Mice Results in Narcolepsy, Hypophagia, and Obesity

Hara, Junko; Beuckmann, Carsten T.; Nambu, Tadahiro; Willie, Jon T.; Chemelli, Richard M.; Sinton, Christopher M.; Sugiyama, Fumihiro; Yagami, Ken Ichi; Goto, Katsutoshi; Yanagisawa, Masashi; Sakurai, Takeshi

doi:10.1016/s0896-6273(01)00293-8

Cited by 1,305 publications

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“…First, rather than only stimulating food intake, downstream effects of hypocretins on energy consumption might be more important to the regulation of body homeostasis. In fact, hypocretin knockout mice have normal body weight and ataxin-3 mutants with absent hypocretin containing-cells have increased body weight (Hara et al 2001), an effect inconsistent with a decreased orexinogenic signal. Obesity is generally believed to reflect decreased metabolic activity and energy expenditure in hypocretin deficient animals, an effect that would be quantitatively more important than hypophagia.…”

Section: Food Intake Energy Metabolism and Neurohormonal Control Of mentioning

confidence: 99%

A Commentary on the Neurobiology of the Hypocretin/Orexin System

Mignot¹

2001

Neuropsychopharmacology

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Rarely in the history of medicine has scientific discovery moved so quickly from the report of a neurotransmitter system to a disease pathophysiology (Mignot 2001). In 1998, two groups independently identified the same neuropeptide system and called the molecules "hypocretins" and "orexins" respectively (de Lecea et al. 1998;Sakurai et al. 1998). One of the most striking findings of these initial studies was the discrete localization of hypocretin-containing cells within a very discrete region of the lateral hypothalamus. This led one group to call this peptide system "hypocretin", a term derived from hypo thalamus and se cretin (a weak-and contested-homology with secretin was noted by these authors). The established role of the perifornical region in the regulation of appetite, together with the observation that intracerebroventricular injections of the peptides induced food intake in rats, led the other group to coin the term "orexin" (orexis ϭ appetite) for this system.The discovery in 1999 that canine narcolepsy was caused by mutations in the Hypocretin receptor 2 (Hcrtr2) gene is shifting the research emphasis from appetite control to sleep regulation (Lin et al. 1999). This finding was followed by the observation that hypocretin knockout mice have sleep and behavioral abnormalities reminiscent of narcolepsy (Chemelli et al. 1999). Other studies have indicated dense projections to all monoaminergic cell groups and wake-promoting effects of hypocretins when administered centrally (Hagan et al. 1999). More recently, clinical studies have shown that most patients with narcolepsy have undetectable hypocretins in the CSF and a striking decrease in hypocretin immunoreactivity and transcript levels in the perifornical hypothalamus Thannickal et al. 2000). The most fre- quent cause of human narcolepsy is now known to be hypocretin deficiency, most probably as the result of an autoimmune attack against hypocretin-containing cells. In this commentary, I will briefly review the current knowledge regarding this system, speculate on its possible function in sleep regulation and discuss the potential importance of this system for neuropsychiatry. HYPOCRETIN/OREXINS: NEURONATOMY AND RECEPTOR SYSTEMSThe description of this system has been the object of multiple recent reviews ( Kilduff and Peyron 2000;Sutcliffe and de Lecea 2000;Hungs and Mignot 2001;Overeem et al. 2001;Willie et al. 2001) and will only be briefly outlined. Two biologically active peptides encoded by a single two-exon precursor gene, the preprohypocretin (Hcrt) locus, have been described. The precursor gene contains a signal peptide sequence, followed by a first active peptide, hypocretin-1 (or orexin-A), a second active peptide, hypocretin-2 (or orexin-B) and a C-terminal section of unknown biological activity. Endopeptidic cleavage occurs at typical dibasic residue sequences located between the hypocretin peptides and at the C-terminal of the hypocretin-2 sequence. The hypocretin-1 and hypocretin-2 regions but not the C-terminal region of the precursor ...

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Section: Food Intake Energy Metabolism and Neurohormonal Control Of mentioning

confidence: 99%

A Commentary on the Neurobiology of the Hypocretin/Orexin System

Mignot¹

2001

Neuropsychopharmacology

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“…In humans, narcolepsy is accompanied by energy imbalance, such as decreased energy intake and increased BMI, resulting in an increase in the incidence of type 2 diabetes [12][13][14][15]. Mice deficient in orexin neurons also exhibit late-onset obesity, despite eating less [16], and on a high-fat diet, become heavier than wildtype mice [17]. Thus, orexin neurons appear to provide a crucial link between arousal and energy balance [1,11,18].…”

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confidence: 99%

Age-related insulin resistance in hypothalamus and peripheral tissues of orexin knockout mice

et al. 2008

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Aims/hypothesis Orexin/hypocretin is a hypothalamic neuropeptide that regulates motivated behaviours, such as feeding and arousal, and, importantly, is also involved in energy homeostasis. The aim of this study was to reveal the role of orexin in the regulation of insulin sensitivity for glucose metabolism. Methods Orexin knockout mice fasted overnight underwent oral glucose tolerance testing and insulin tolerance testing. The impact of orexin deficiency on insulin signalling was studied by Western blotting to measure levels of Akt phosphorylation and its upstream and downstream molecules in the hypothalamus, muscle and liver in orexin knockout mice. Results We found that orexin deficiency caused the agerelated development of impaired glucose tolerance and insulin resistance in both male mice without obesity and female mice with mild obesity, fed a normal chow diet. When maintained on a high-fat diet, these abnormalities became more pronounced exclusively in female orexin knockout mice that developed severe obesity. Insulin signalling through Akt was disrupted in peripheral tissues of middle-aged (9-month-old) but not young adult (2-to-3-month-old) orexin knockout mice fed a normal chow diet. Moreover, basal levels of hypothalamic Akt phosphorylation were abnormally elevated in orexin knockout mice at every age studied, and insulin stimulation failed to increase the level of phosphorylation. Similar abnormalities were observed with respect to GSK3β phosphorylation in the hypothalamus and peripheral tissues of middle-aged orexin knockout mice. Conclusions/interpretation Our results demonstrate a novel role for orexin in hypothalamic insulin signalling, which is likely to be responsible for preventing the development of peripheral insulin resistance with age.

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“…An important difference in the effects on feeding between orexin and other orexigenic factors, such as NPY and melanin-concentrating hormone (MCH), is that orexin increases both food intake and energy expenditure MM&TS 10 (Lubkin and Stricker-Krongrad, 1998;Hara et al, 2001), while other feeding peptides generally decrease energy expenditure (Spiegelman and Flier, 2001): the latter response is more adaptive to conserving energy under food scarcity. Increased energy expenditure by orexin administration seems to be caused by increased wakefulness and locomotor activity, as well as an increase in sympathetic outflow.…”

Section: Integrative Physiology Of Orexin Systemmentioning

confidence: 99%

“…Indeed, orexin deficiency decreases sympathetic tone (Kayaba et al, 2003;Zhang et al, 2006), resulting in reduced energy expenditure. This may explain why human and mouse narcolepsy are associated with an increase of body weight despite hypophagia (Lammers et al, 1996;Schuld et al, 2000;Hara et al, 2001). Additionally, a recent work suggested that orexin enhances leptin-sensitivity through an OX2R-mediated mechanism (Funato et al, 2009).…”

Section: Integrative Physiology Of Orexin Systemmentioning

confidence: 99%

Overview of orexin/hypocretin system

Mieda

Sakurai

2012

Progress in Brain Research

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A series of recent studies has established the orexin/hypocretin system as a critical regulator of sleep/wake states. Its deficiency results in the sleep disorder narcolepsy in humans, dogs, and rodents. These findings have brought about the possibility of novel therapies for sleep disorders including narcolepsy and insomnia. Moreover, accumulating evidence indicates that the orexin/hypocretin system regulates sleep and wakefulness through interactions with neuronal systems that regulate emotion, reward, and energy homeostasis. Here, we briefly summarize the progress of orexin/hypocretin studies and future perspectives.

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Genetic Ablation of Orexin Neurons in Mice Results in Narcolepsy, Hypophagia, and Obesity

Cited by 1,305 publications

References 32 publications

A Commentary on the Neurobiology of the Hypocretin/Orexin System

A Commentary on the Neurobiology of the Hypocretin/Orexin System

Age-related insulin resistance in hypothalamus and peripheral tissues of orexin knockout mice

Overview of orexin/hypocretin system

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