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Characteristics and mechanisms of hypothalamic neuronal fatty acid sensing
Open accessAbstract
We assessed the mechanisms by which specialized hypothalamic ventromedial nucleus (VMN) neurons utilize both glucose and long-chain fatty acids as signaling molecules to alter their activity as a potential means of regulating energy homeostasis. Fura-2 calcium (Ca 2+) and membrane potential dye imaging, together with pharmacological agents, were used to assess the mechanisms by which oleic acid (OA) alters the activity of dissociated VMN neurons from 3- to 4-wk-old rats. OA excited up to 43% and inhibited up to 29% of all VMN neurons independently of glucose concentrations. In those neurons excited by both 2.5 mM glucose and OA, OA had a concentration-dependent effective excitatory concentration (EC 50) of 13.1 nM. Neurons inhibited by both 2.5 mM glucose and OA had an effective inhibitory concentration (IC 50) of 93 nM. At 0.5 mM glucose, OA had markedly different effects on these same neurons. Inhibition of carnitine palmitoyltransferase, reactive oxygen species formation, long-chain acetyl-CoA synthetase and ATP-sensitive K+channel activity or activation of uncoupling protein 2 (UCP2) accounted for only ∼20% of OA's excitatory effects and ∼40% of its inhibitory effects. Inhibition of CD36, a fatty acid transporter that can alter cell function independently of intracellular fatty acid metabolism, reduced the effects of OA by up to 45%. Thus OA affects VMN neuronal activity through multiple pathways. In glucosensing neurons, its effects are glucose dependent. This glucose-OA interaction provides a potential mechanism whereby such “metabolic sensing” neurons can respond to differences in the metabolic states associated with fasting and feeding.
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“However, basal levels of FAO enzymes and FA transport proteins (such as FATP-1, FATP-4, and FAT/CD36) are expressed in hypothalamic neurons ([93](#B93), [95](#B95)).”
From Mitochondrial fatty acid oxidation in obesity (2013) · cites this paper as [95]
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“and the capacity of hypothalamic neurons to sense glucose and FFA simultaneously and to integrate other nutritional and hormonal inputs ([95](#B95), [99](#B99))”
From Mitochondrial fatty acid oxidation in obesity (2013) · cites this paper as [95]
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“Similarly, inhibition of FAS activity by central administration of the pharmacological FAS inhibitor C75 has been shown to reduce food intake (73) and to elevate malonyl-CoA levels (74).”
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“Nonetheless, the direct correlation observed between fasting and FFA levels (156) and the capacity of hypothalamic neurons to sense glucose and FFA simultaneously and to integrate other nutritional and hormonal inputs (95, 99) seem to throw light on how important FAO really is in hypothalamic nuclei.”
Metadata
- Authors
- Le Foll, C., Irani, B. G., Magnan, C., Dunn-Meynell, A. A., & Levin, B. E.
- ORCID
- Levin, Barry E.
- Venue
- American Journal of Physiology-Regulatory, Integrative and Comparative Physiology
- Publisher
- American Physiological Society
- Published
- 2009-09
- Volume
- 297
- Issue
- 3
- Pages
- R655-R664
- ISSN
- 0363-6119 (ISSN-L)
- 1522-1490
- PMC
- PMC2739790
- OpenAlex
- W2067285665
- Cited by
- 159
- References
- 57
- Citations by year
- 2026: 4 · 2025: 5 · 2024: 7 · 2023: 7 · 2022: 4 · 2021: 7 · 2020: 6 · 2019: 6 · 2018: 3 · 2017: 15 · 2016: 13 · 2015: 15 · 2014: 18 · 2013: 17 · 2012: 9
- FWCI
- 4.79
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- American Journal of Physiology-Regulatory, Integrative and Comparative Physiology (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institute of Diabetes and Digestive and Kidney Diseases (DK 53181, R01DK053181)
- Topics
- Life Sciences › Neuroscience › Endocrine and Autonomic Systems › Regulation of Appetite and Obesity
- Life Sciences › Neuroscience › Endocrine and Autonomic Systems › Neuroscience of respiration and sleep
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Peroxisome Proliferator-Activated Receptors
- Keywords
- ventromedial hypothalamus, oleic acid, fatty acid sensing, glucose detection, energy homeostasis, neuronal excitation and inhibition, CD36, fatty acid transporters, carnitine palmitoyltransferase, reactive oxygen species, ATP-sensitive potassium channels, UCP2, fasting and feeding
- MeSH terms
- Uncoupling Protein 2, Animals, Carnitine O-Palmitoyltransferase, Coenzyme A Ligases, Energy Metabolism, Enzyme Inhibitors, Glucose, Homeostasis, Ion Channels, Male, Membrane Potentials, Microscopy, Fluorescence, Neural Inhibition, Neurons, Time Factors, Ventromedial Hypothalamic Nucleus, Free Radical Scavengers, Rats, Sprague-Dawley, Reactive Oxygen Species, CD36 Antigens, Oleic Acid, Calcium Signaling, Mitochondrial Proteins, Potassium Channel Blockers, Rats, KATP Channels
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