Cardiovascular regulatory actions of the hypocretins in brain

Samson, Willis K.; Gosnell, Blake A.; Chang, Jaw Kang; Resch, Zachary T.; Murphy, Tonya C.

doi:10.1016/s0006-8993(99)01457-2

Cited by 281 publications

(174 citation statements)

References 14 publications

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“…Signalling in body-weight homeostasis -B at lower doses than stimulate feeding increases blood pressure, autonomic efferent nerve activity and luteinizing hormone secretion in steroid-treated ovariectomized rats (Pu et al 1998;Samson et al 1999;A. Niijima and K Nagai, unpublished results).…”

Section: Other Possible Functions Of Orexinsmentioning

confidence: 99%

The hypothalamus and the regulation of energy homeostasis: lifting the lid on a black box

2000

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The hypothalamus is the focus of many peripheral signals and neural pathways that control energy homeostasis and body weight. Emphasis has moved away from anatomical concepts of ‘feeding’ and ‘satiety’ centres to the specific neurotransmitters that modulate feeding behaviour and energy expenditure. We have chosen three examples to illustrate the physiological roles of hypothalamic neurotransmitters and their potential as targets for the development of new drugs to treat obesity and other nutritional disorders. Neuropeptide Y (NPY) is expressed by neurones of the hypothalamic arcuate nucleus (ARC) that project to important appetite-regulating nuclei, including the paraventricular nucleus (PVN). NPY injected into the PVN is the most potent central appetite stimulant known, and also inhibits thermogenesis; repeated administration rapidly induces obesity. The ARC NPY neurones are stimulated by starvation, probably mediated by falls in circulating leptin and insulin (which both inhibit these neurones), and contribute to the increased hunger in this and other conditions of energy deficit. They therefore act homeostatically to correct negative energy balance. ARC NPY neurones also mediate hyperphagia and obesity in the ob/ob and db/db mice and fa/fa rat, in which leptin inhibition is lost through mutations affecting leptin or its receptor. Antagonists of the Y5 receptor (currently thought to be the NPY ‘feeding’ receptor) have anti-obesity effects. Melanocortin-4 receptors (MC4-R) are expressed in various hypothalamic regions, including the ventromedial nucleus and ARC. Activation of MC4-R by agonists such as α-melanocyte-stimulating hormone (a cleavage product of pro-opiomelanocortin which is expressed in ARC neurones) inhibits feeding and causes weight loss. Conversely, MC4-R antagonists such as ‘agouti’ protein and agouti gene-related peptide (AGRP) stimulate feeding and cause obesity. Ectopic expression of agouti in the hypothalamus leads to obesity in the AVY mouse, while AGRP is co-expressed by NPY neurones in the ARC. Synthetic MC4-R agonists may ultimately find use as anti-obesity drugs in human subjects Orexins-A and -B, derived from prepro-orexin, are expressed in specific neurones of the lateral hypothalamic area (LHA). Orexin-A injected centrally stimulates eating and prepro-orexin mRNA is up regulated by fasting and hypoglycaemia. The LHA is important in receiving sensory signals from the gut and liver, and in sensing glucose, and orexin neurones may be involved in stimulating feeding in response to falls in plasma glucose.

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Section: Other Possible Functions Of Orexinsmentioning

confidence: 99%

The hypothalamus and the regulation of energy homeostasis: lifting the lid on a black box

2000

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“…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. Interestingly, intracerebroventricular injection of hypocretin has potent stimulatory effects on sympathetic outflow (Samson et al, 1999;Shirasaka et al 1999) and cortisol release but decreases prolactin and growth hormone release (Hagan et al 1999). Central administration of hypocretin-1 was also shown to increase metabolic rate (Lubkin and Stricker-Krongrad 1998).…”

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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“…Hypocretins promote arousal and alertness by suppressing REM sleep and lowering the arousal threshold (Sutcliffe and de Lecea, 2002). Hypocretins also stimulate energy expenditure (Yoshimichi et al, 2001), as well as sympathetic nervous system activity (Samson et al, 1999;Shirasaka et al, 1999;Chen et al, 2000;Samson et al, 2002). Indeed, intracerebroventricular administration of hcrt-1 increases feeding behavior, locomotor activity (Hagan et al, 1999;Samson et al, 1999), and body temperature (Yoshimichi et al, 2001).…”

Section: Introductionmentioning

confidence: 99%

“…Hypocretins also stimulate energy expenditure (Yoshimichi et al, 2001), as well as sympathetic nervous system activity (Samson et al, 1999;Shirasaka et al, 1999;Chen et al, 2000;Samson et al, 2002). Indeed, intracerebroventricular administration of hcrt-1 increases feeding behavior, locomotor activity (Hagan et al, 1999;Samson et al, 1999), and body temperature (Yoshimichi et al, 2001). In addition, hypocretin-1 also stimulates gastric secretion in a dose-dependent manner (Takahashi et al, 1999) and increases arterial blood pressure, heart rate (Samson et al, 1999), cerebral blood flow, and renal sympathetic nerve activity (Shirasaka et al, 1999).…”

Section: Introductionmentioning

confidence: 99%

Interaction between the Corticotropin-Releasing Factor System and Hypocretins (Orexins): A Novel Circuit Mediating Stress Response

Winsky‐Sommerer¹,

Yamanaka²,

Diano³

et al. 2004

J. Neurosci.

418

316

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The hypothalamic neuropeptides hypocretins (orexins) play a crucial role in the stability of arousal and alertness. We tested whether the hypocretinergic system is a critical component of the stress response activated by the corticotropin-releasing factor (CRF). Our results show that CRF-immunoreactive terminals make direct contact with hypocretin-expressing neurons in the lateral hypothalamus and that numerous hypocretinergic neurons express the CRF-R1/2 receptors. We also demonstrate that application of CRF to hypothalamic slices containing identified hypocretin neurons depolarizes membrane potential and increases firing rate in a subpopulation of hypocretinergic cells. CRF-induced depolarization was tetrodotoxin insensitive and was blocked by the peptidergic CRF-R1 antagonist astressin. Moreover, activation of hypocretinergic neurons in response to acute stress was severely impaired in CRF-R1 knock-out mice. Together, our data provide evidence of a direct neuroanatomical and physiological input from CRF peptidergic system onto hypocretin neurons. We propose that, after stressor stimuli, CRF stimulates the release of hypocretins and that this circuit contributes to activation and maintenance of arousal associated with the stress response.

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Cardiovascular regulatory actions of the hypocretins in brain

Cited by 281 publications

References 14 publications

The hypothalamus and the regulation of energy homeostasis: lifting the lid on a black box

The hypothalamus and the regulation of energy homeostasis: lifting the lid on a black box

A Commentary on the Neurobiology of the Hypocretin/Orexin System

Interaction between the Corticotropin-Releasing Factor System and Hypocretins (Orexins): A Novel Circuit Mediating Stress Response

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