Hypothalamic orexin expression: modulation by blood glucose and feeding.

Cai, Xue; Widdowson, Peter; Harrold, Joanne A.; Wilson, Shelagh; Buckingham, Robin E.; Arch, Jonathan R.S.; Tadayyon, M.; Clapham, John C.; Wilding, John; Williams, Gareth

doi:10.2337/diabetes.48.11.2132

Cited by 279 publications

(187 citation statements)

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“…In addition, there was no significant correlation between BMI and orexin-A in a cohort of normal subjects (data not shown). Although it is possible that changes in orexin-A release from the gut could be due to a marked erosion of the gastrointestinal mucosae during fasting, these findings are consistent with the findings in rats that orexin appeared to participate in a short-term regulation of energy homeostasis in response to falls in glucose which was terminated after food ingestion (32). It is also possible that there is some direct effect of circulating orexin-A on the peripheral gut tissues, as orexin excited secretomotor neurons in the guinea pig submucosal plexus, and increased motility (21).…”

Section: Discussionsupporting

confidence: 79%

Orexin-A and leptin change inversely in fasting non-obese subjects

Kobashi

Matsumoto

Nishikata

et al. 2001

European Journal of Endocrinology

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Objective: Leptin, neuropeptide-Y (NPY) and orexin are peptides regulating energy metabolism and appetite control. NPY and orexin are mainly found in the central nervous system and they have also recently been found in the peripheral nervous system. We investigated how fasting affects changes in circulating concentrations of these peptides and their association with nutritional and metabolic parameters in humans. Design and methods: Ten non-obese female patients with psychosomatic disorders fasted for 7 or 10 days. Blood samples were collected at 0800 h before fasting, on the 3rd and 7th days during the fast (with an additional sample taken on the 10th day when the fasting continued for 10 days) and on the 3rd and 7th days of refeeding. We measured blood concentrations of orexin-A, NPY, leptin, adrenocorticotropin, cortisol, insulin, C-peptide, glucose, and b-hydroxybutyrate. Results: Body mass index and plasma leptin concentrations concomitantly and significantly decreased during fasting, whereas serum orexin-A concentrations significantly increased and were negatively correlated with plasma leptin concentrations. Plasma NPY concentrations decreased slightly but were not significantly different from the prefasting values, and no significant relationship with leptin or orexin-A was found. Orexin-A and leptin concentrations showed a significant inverse correlation with serum glucose, insulin, C-peptide, and b-hydroxybutyrate concentrations. Only changes in plasma leptin concentrations showed a significant negative correlation with serum cortisol concentrations. All the measured indices which changed during fasting returned to the prefasting concentrations by the 7th day of refeeding. Conclusion: Peripheral orexin-A and leptin concentrations inversely change during fasting, which is significantly correlated with energy metabolism in humans.

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Section: Discussionsupporting

confidence: 79%

Orexin-A and leptin change inversely in fasting non-obese subjects

Kobashi

Matsumoto

Nishikata

et al. 2001

European Journal of Endocrinology

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“…Prepro-orexin mRNA is reduced in leptin signalling-deficient ob/ob and db/db mice, and 7 d leptin treatment decreased orexin-A levels in the rat LHA-PeF; on the other hand, hypothalamic orexin-A content was unchanged in both fasted and overfed rats, and in lean or obese Zucker rats (Beck & Richy, 1999;Taheri et al 1999;Yamamoto et al 1999). Moreover, our own studies (Cai et al 1999) did not show any significant changes in prepro-orexin mRNA levels over a range of conditions in which circulating leptin levels alter dramatically (underfeeding, dietary obesity, insulin-deficient diabetes), or in food restriction with or without leptin treatment that prevented the usual fall in leptin levels.…”

Section: Orexins Feeding and Energy Balancementioning

confidence: 84%

“…However, evidence is emerging to indicate that the orexins may stimulate feeding under specific circumstances of increased hunger. We (Cai et al 1999) and others have found that prepro-orexin mRNA is elevated only under conditions of increased appetite when plasma glucose falls and food is absent from the gut, i.e. prolonged fasting or hypoglycaemia when food is witheld.…”

Section: Orexins Feeding and Energy Balancementioning

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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“…Prepro-orexin expression increases during fasting and acute hypoglycemia (8,15,16), and recent work suggests that a subset of orexin neurons are stimulated by falls in blood glucose (15)(16)(17). During acute hypoglycemia, 14% of orexin neurons display the early activation marker Fos, whereas 9% of all Fos-positive LHA neurons contain orexin (15). Hypoglycemia-induced activation of orexin and nonorexin LHA cells is abolished by feeding (17).…”

mentioning

confidence: 99%

“…Orexin A stimulates feeding acutely when injected intracerebroventricularly (8,12) or into the LHA (13), but chronic administration does not induce sustained hyperphagia or obesity; this suggests a role in short-term feeding regulation (8,11,14). Prepro-orexin expression increases during fasting and acute hypoglycemia (8,15,16), and recent work suggests that a subset of orexin neurons are stimulated by falls in blood glucose (15)(16)(17). During acute hypoglycemia, 14% of orexin neurons display the early activation marker Fos, whereas 9% of all Fos-positive LHA neurons contain orexin (15).…”

mentioning

confidence: 99%

Orexin A Preferentially Excites Glucose-Sensitive Neurons in the Lateral Hypothalamus of the Rat In Vitro

Liu

Morris²,

Spiller³

et al. 2001

Diabetes

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Falls in blood glucose induce hunger and initiate feeding. The lateral hypothalamic area (LHA) contains glucose-sensitive neurons (GSNs) and orexin neurons, both of which are stimulated by falling blood glucose and are implicated in hypoglycemia-induced feeding. We combined intracellular electrophysiological recording with fluorescein labeling of GSNs to determine their neuroanatomic and functional relationships with orexin neurons. Orexin A (1 mol/l) caused a 500% increase (P < 0.01) in spontaneous firing rate and rapid and lasting depolarization that was tetrodotoxin-resistant and thus a direct postsynaptic effect. Orexin A altered the intrinsic neuronal properties of GSNs, consistent with increased excitability. Confocal microscopy showed that GSNs were intimately related to orexin neurons: orexin-immunoreactive axons were frequently entwined around GSN dendrites, establishing close and putatively synaptic contacts. Orexin-cell axons also passed in close proximity to glucose-responsive neurons, which are inhibited by low glucose, but orexin A caused smaller depolarization than on GSNs and only a 200% increase in spontaneous firing rate (P < 0.05 vs. GSN). We conclude that GSNs are specific target neurons for orexin A and suggest that they may mediate, at least in part, the acute appetite-stimulating effect of orexin A. Orexin neurons may regulate GSNs so as to control the onset and termination of hypoglycemiainduced feeding. Diabetes 50:2431-2437, 2001 R educed availability of glucose, the brain's main metabolic fuel, causes intense hunger (1). The lateral hypothalamic area (LHA) is crucial to the hyperphagia induced by hypoglycemia and glucoprivation, as this feeding response is abolished by LHA lesions (1). The LHA neuronal systems that drive glucoprivic feeding are unknown, but promising candidates include the glucose-sensing neurons and orexin (hypocretin) neurons that are prominent in this region.Glucose-sensing neurons, which alter their firing behavior in response to changes in ambient glucose concentration, are found in the hypothalamus and in several other central nervous system regions (2). Glucose-sensitive neurons (GSNs) are inhibited by rising glucose concentrations but excited when glucose falls, whereas glucose-responsive neurons (GRNs) are stimulated as glucose rises and are inhibited by hypoglycemia (3,4). GSNs are particularly abundant in the LHA, where they account for 30 -40% of all neurons (3,5). These cells are stimulated directly by low glucose in vitro (3,6) but are also regulated indirectly in vivo, being inhibited by rising glucose levels in the hindbrain and viscera and by gastric distension (1,7). These indirect signals are presumed to be relayed to the LHA from the nucleus of the solitary tract (NTS) in the medulla, which contains glucose-sensing neurons and also receives vagal afferents from visceral glucose sensors and gastric stretch receptors (7). In view of these properties, lateral hypothalamic GSNs are assumed to participate in triggering and controlling glucoprivic feeding...

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Hypothalamic orexin expression: modulation by blood glucose and feeding.

Cited by 279 publications

References 0 publications

Orexin-A and leptin change inversely in fasting non-obese subjects

Orexin-A and leptin change inversely in fasting non-obese subjects

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

Orexin A Preferentially Excites Glucose-Sensitive Neurons in the Lateral Hypothalamus of the Rat In Vitro

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