Cited by 206Regulation of Appetite and ObesitySleep and Wakefulness ResearchNeuroscience of respiration and sleep

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Hypoglycemia Activates Orexin Neurons and Selectively Increases Hypothalamic Orexin-B Levels

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Cai, Xue J., Evans, Martyn L., Lister, Carolyn A., Leslie, Ron A., Arch, Jonathan R. S., Wilson, Shelagh, Williams, Gareth·2001·Diabetes

DOI 10.2337/diabetes.50.1.105

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Abstract

Orexins are novel appetite-stimulating peptides expressed in the lateral hypothalamic area (LHA), and their expression is stimulated by hypoglycemia in fasted rats. We investigated activation of orexin and other neurons during insulin-induced hypoglycemia using the immediate early gene product Fos. Insulin (50 U/kg) lowered plasma glucose by >50% after 5 h and stimulated feeding sixfold compared with saline-injected controls. Hypoglycemic rats allowed to feed and normoglycemic controls both showed sparse Fos-positive (Fos+) neurons in the LHA and the paraventricular nucleus (PVN) and arcuate nucleus (ARC) and showed none in the nucleus of the solitary tract (NTS), which relays visceral feeding signals to the LHA. In the LHA, total numbers of Fos+ neurons were comparable in fed hypoglycemic and control groups (60 ± 6 vs. 52 ± 4 cells/mm2, P > 0.05), as were Fos+ neurons immunoreactive for orexin (1.4 ± 0.4 vs. 0.6 ± 0.4 cells/mm2, P > 0.05). By contrast, hypoglycemic rats that were fasted showed significantly more Fos+ nuclei in the LHA (96 ± 10 cells/mm2, P < 0.05, vs. both other groups) and Fos+ orexin neurons (8.4 ± 3.3 cells/mm2, P < 0.001, vs. both other groups). They also showed two- to threefold more Fos+ nuclei (P < 0.001) in the PVN and ARC than both fed hypoglycemic rats and controls and showed strikingly abundant Fos+ neurons in the NTS and dorsal motor nucleus of the vagus. In parallel studies, whole hypothalamic orexin-A levels were not changed in hypoglycemic rats, whether fasted or freely fed, whereas orexin-B levels were 10-fold higher in hypoglycemic fasted rats than in control and hypoglycemic fed groups. These data support our hypothesis that orexin neurons are stimulated by falling glucose levels but are readily inhibited by signals related to nutrient ingestion and suggest that they may functionally link with neuronal activity in the NTS. Orexin-A and -B may play specific roles in behavioral or neuroendocrine responses to hypoglycemia.

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Authors: Cai, X. J., Evans, M. L., Lister, C. A., Leslie, R. A., Arch, J. R. S., Wilson, S., & Williams, G.
Affiliations: From the Diabetes and Endocrinology Research Group (X.J.C., G.W.), University of Liverpool, Liverpool; and the Divisions of Neuroscience (M.L.E., R.A.L.) and Vascular Biology (C.A.L., J.R.S.A., S.W.), SmithKline Beecham Pharmaceuticals, Harlow, U.K.
University of Liverpool (GB)
ORCID: Wilson, Shelagh
Williams, Gareth
Venue: Diabetes
Publisher: American Diabetes Association
Published: 2001-01-01
Volume: 50
Issue: 1
Pages: 105-112
ISSN: 0012-1797 (ISSN-L)
1939-327X
DOI: 10.2337/diabetes.50.1.105
OpenAlex: W2155164261
Cited by: 206
References: 48
Citations by year: 2026: 1 · 2025: 3 · 2024: 1 · 2023: 1 · 2022: 5 · 2021: 8 · 2020: 5 · 2019: 6 · 2018: 7 · 2017: 9 · 2016: 4 · 2015: 7 · 2014: 8 · 2013: 7 · 2012: 8
FWCI: 5.86
Type: journal article
Language: en
Open access: bronze
doi.org
Locations: Diabetes (publishedVersion)
PubMed (publishedVersion)
Topics: Life Sciences › Neuroscience › Endocrine and Autonomic Systems › Regulation of Appetite and Obesity
Life Sciences › Neuroscience › Cognitive Neuroscience › Sleep and Wakefulness Research
Life Sciences › Neuroscience › Endocrine and Autonomic Systems › Neuroscience of respiration and sleep
Keywords: orexin, orexin-A, orexin B, lateral hypothalamus, insulin-induced hypoglycemia, Fos expression, paraventricular nucleus, arcuate nucleus, nucleus tractus solitarius, dorsal motor nucleus of the vagus, feeding behavior, fasting, glucose detection, appetite regulation, hypothalamic neurons, vagal afferents
MeSH terms: Orexins, Animals, Arcuate Nucleus of Hypothalamus, Carrier Proteins, Eating, Hyperphagia, Hypoglycemia, Hypothalamic Area, Lateral, Hypothalamus, Male, Neurons, Neuropeptides, Osmolar Concentration, Paraventricular Hypothalamic Nucleus, Vagus Nerve, Proto-Oncogene Proteins c-fos, Rats, Wistar, Solitary Nucleus, Fourth Ventricle, Intracellular Signaling Peptides and Proteins, Rats

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Hypoglycemia Activates Orexin Neurons and Selectively Increases Hypothalamic Orexin-B Levels

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