Skip to main content
  • Submit
  • About
    • Editorial Board
    • PNAS Staff
    • FAQ
    • Rights and Permissions
    • Site Map
  • Contact
  • Journal Club
  • Subscribe
    • Subscription Rates
    • Subscriptions FAQ
    • Open Access
    • Recommend PNAS to Your Librarian
  • Log in
  • My Cart

Main menu

  • Home
  • Articles
    • Current
    • Latest Articles
    • Special Features
    • Colloquia
    • Collected Articles
    • PNAS Classics
    • Archive
  • Front Matter
  • News
    • For the Press
    • Highlights from Latest Articles
    • PNAS in the News
  • Podcasts
  • Authors
    • Information for Authors
    • Purpose and Scope
    • Editorial and Journal Policies
    • Submission Procedures
    • For Reviewers
    • Author FAQ
  • Submit
  • About
    • Editorial Board
    • PNAS Staff
    • FAQ
    • Rights and Permissions
    • Site Map
  • Contact
  • Journal Club
  • Subscribe
    • Subscription Rates
    • Subscriptions FAQ
    • Open Access
    • Recommend PNAS to Your Librarian

User menu

  • Log in
  • My Cart

Search

  • Advanced search
Home
Home

Advanced Search

  • Home
  • Articles
    • Current
    • Latest Articles
    • Special Features
    • Colloquia
    • Collected Articles
    • PNAS Classics
    • Archive
  • Front Matter
  • News
    • For the Press
    • Highlights from Latest Articles
    • PNAS in the News
  • Podcasts
  • Authors
    • Information for Authors
    • Purpose and Scope
    • Editorial and Journal Policies
    • Submission Procedures
    • For Reviewers
    • Author FAQ

New Research In

Physical Sciences

Featured Portals

  • Physics
  • Chemistry
  • Sustainability Science

Articles by Topic

  • Applied Mathematics
  • Applied Physical Sciences
  • Astronomy
  • Computer Sciences
  • Earth, Atmospheric, and Planetary Sciences
  • Engineering
  • Environmental Sciences
  • Mathematics
  • Statistics

Social Sciences

Featured Portals

  • Anthropology
  • Sustainability Science

Articles by Topic

  • Economic Sciences
  • Environmental Sciences
  • Political Sciences
  • Psychological and Cognitive Sciences
  • Social Sciences

Biological Sciences

Featured Portals

  • Sustainability Science

Articles by Topic

  • Agricultural Sciences
  • Anthropology
  • Applied Biological Sciences
  • Biochemistry
  • Biophysics and Computational Biology
  • Cell Biology
  • Developmental Biology
  • Ecology
  • Environmental Sciences
  • Evolution
  • Genetics
  • Immunology and Inflammation
  • Medical Sciences
  • Microbiology
  • Neuroscience
  • Pharmacology
  • Physiology
  • Plant Biology
  • Population Biology
  • Psychological and Cognitive Sciences
  • Sustainability Science
  • Systems Biology

Orexin neurons use endocannabinoids to break obesity-induced inhibition

Alán Alpár and Tibor Harkany
PNAS June 11, 2013 110 (24) 9625-9626; https://doi.org/10.1073/pnas.1307389110
Alán Alpár
Division of Molecular Neurobiology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, SE-17177 Stockholm, Sweden
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Tibor Harkany
Division of Molecular Neurobiology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, SE-17177 Stockholm, Sweden
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
  • For correspondence: tibor.harkany@ki.se

See related content:

  • Obesity-driven synaptic remodeling affects endocannabinoid control of orexinergic neurons
    - Jun 11, 2013
  • Article
  • Figures & SI
  • Info & Metrics
  • PDF
Loading

Obesity is a pressing health problem affecting more than one-third of adults in the United States and Europe. Besides their increased risk to develop cardiovascular disease and type 2 diabetes, metabolic disturbances in overweight individuals affect sleeping behavior, promoting arousal and feeding (1). Task-dependent recruitment of diverse neuropeptidergic neurons in hypothalamic nuclei orchestrates distinct endocrine functions particularly relevant to maintain energy homeostasis (2). The interplay of neuropeptide Y (NPY)/agouti-related peptide and α-melanocyte–stimulating hormone (αMSH) neurons of the arcuate nucleus with orexin (hypocretin)-containing neurons in the lateral hypothalamus is central to the regulation of food intake and arousal. A key attribute of these hypothalamic circuits is their remarkable ability to undergo “synaptic rewiring” to maintain the body’s energy homeostasis (3, 4). In PNAS, Cristino et al. (5) provide fresh understanding of the molecular regulation of synaptic plasticity by showing how endocannabinoids control inhibitory synapses newly recruited to orexinergic neurons in obesity.

Orexin-containing neurons (up to ∼70,000 in human) (6⇓–8) are mostly located in the lateral hypothalamic nucleus, and are thought to contribute to regulating food intake, wakefulness, and arousal (3, 9). Orexin-containing cells are innervated by NPY and αMSH-containing arcuate neurons (Fig. 1A). Neuropeptides typically coexist with fast neurotransmitters (2): NPY neurons contain the inhibitory neurotransmitter GABA, and αMSH can colocalize with excitatory glutamate (10). NPY itself is an orexinergic neuropeptide robustly inducing food intake (11, 12). In contrast, αMSH is anorexigenic, decreasing feeding (13). GABAergic and glutamatergic synaptic inputs to these arcuate neurons are prone to remodeling upon genetic or dietary manipulation of leptin (4), the adipocyte-derived satiety hormone, which critically impacts energy homeostasis and body weight (14). Nevertheless, a lack of consensus exists as to the neurophysiological requirements of neuropeptide and primary fast neurotransmitter corelease from hypothalamic neurons, and their endocrine action.

Fig. 1.
  • Download figure
  • Open in new tab
  • Download powerpoint
Fig. 1.

(A) Hierarchical depiction of synaptic connections allowing information flow among neuropeptidergic neurons in the arcuate mucleus and lateral hypothalamus. Lep-Rb denotes leptin receptor expression by neurons in the arcuate nucleus. (B) Orexin-containing neurons receive predominantly excitatory synaptic inputs in lean mice. (pink: inhibitory/GABA synapse; green: excitatory/glutamate synapse; red rectangles pinpoint CB1 cannabinoid receptors). (B1) In obesity, orexin-containing neurons up-regulate DAGLα to block surplus inhibition by retrograde endocannabinoid signals.

Excitatory synapses onto orexin-containing neurons vastly outnumber inhibitory terminals (3). The number of these excitatory inputs increases upon food deprivation (3). However, synapse remodeling in the lateral hypothalamus in obesity remains unknown. Using a multiparametric approach encompassing systems neuroanatomy, neurophysiology, molecular pharmacology, and mouse genetics, Cristino et al. (5) identify an excitatory-to-inhibitory switch of synapses impacting orexin-containing neurons in genetically leptin deficient ob/ob mice (11). Here, a substantial subset of new inhibitory terminals from NPY-containing neurons replaced excitatory inputs formed by αMSH cells (Fig. 1 B and B1). Significantly, high-fat diet, evoking leptin resistance in arcuate, but not lateral hypothalamic neurons, replicated circuit remodeling. This synaptology was unequivocally driven by the lack of leptin because leptin signaling through the mammalian target of rapamycin rapidly normalized synapse composition.

Orexin, like NPY, is up-regulated upon decreased leptin availability (15). The formation of new inhibitory synapses terminating on orexin-containing neurons in ob/ob mice, which lack leptin, would suggest increased synaptic inhibition, decreasing the excitability and perhaps even reducing neuropeptide release from orexin-containing neurons. However, this is clearly not the case because orexin expression, axonal transport, and accumulation in terminals increased in ob/ob mice.

Early work by Di Marzo et al. revealed increased concentrations of hypothalamic endocannabinoids in ob/ob mice (16). Endocannabinoids, particularly 2-arachidonoyl glycerol (2-AG), are produced upon neuronal activity and released from subsynaptic dendrites to presynaptically reduce neurotransmitter release (17). Thus, and by adopting a “retrograde” mode of action, endocannabinoid signaling is a form of feedback control of synaptic neurotransmission. 2-AG is thought to be primarily produced by sn-1-diacylglycerol lipase α (DAGLα) in the adult brain (18). Cristino et al. (5) exploit this knowledge to demonstrate that the synaptic rewiring of orexin neurons in ob/ob mice coincides with their increased DAGLα expression. Because 70% of all synaptic inputs to orexin neurons, including many NPY- and αMSH-containing afferents, contain presynaptic CB1 cannabinoid receptors (CB1Rs), Cristino et al. hypothesize that orexin neurons in obese mice can successfully eliminate surplus inhibition by using 2-AG as retrograde messenger. The authors address the functional significance of synapse reorganization by showing that somatic depolarization of orexin-containing neurons, a means to induce endocannabinoid release (17), in ob/ob mice suppressed presynaptic GABA release. The lack of retrograde signaling at inhibitory synapses converging onto orexin-containing neurons in lean mice highlights the network-level significance of the glutamate-to-GABA switch.

Mice lacking monoacylglycerol lipase (MAGL), a key 2-AG–degrading enzyme (19), are lean even though presenting many-fold increased brain 2-AG levels. Similarly, synaptic afferentation of orexin neurons is unchanged in the lateral hypothalamus of MAGL−/− mice. These data clearly establish a hierarchical relationship between leptin and endocannabinoids, with leptin signaling (or the lack thereof) driving synapse remodeling. However, orexin expression was dramatically reduced by a single dose of a CB1R antagonist in ob/ob mice. This result suggests that CB1Rs on orexin-containing neurons are poised to regulate orexin expression via a hitherto unexplained mechanism.

This research, like any other comprehensive report, inspires a number of radical hypotheses, and certainly calls for further analysis. Neuropeptides coexist with fast neurotransmitters in this arcuate nucleus-lateral hypothalamus circuit (10). A key take-home message of Cristino et al. (5) and earlier studies (3, 4) is that fast neurotransmission, once reorganized, can reset the excitability of neuropeptidergic neurons. Although the relationship of neuropeptide and fast neurotransmitter action remains elusive, an appealing hypothesis is that a floating circuit code driven by the extreme plasticity of GABA/glutamate synapses (3, 4) encodes a form of “metabolic memory” to set the threshold for neuropeptide release.

High-fat diet-induced leptin resistance was found restricted to arcuate neurons, even though the leptin receptor is expressed in many neurons of the lateral hypothalamus (20). This differential response may be a result of the molecular diversity of signal transduction cascades, differences in excitability in vivo, or feedback coupling between leptin and endocannabinoid signaling systems.

The balance between excitation and inhibition on orexin neurons hinges on enhanced DAGLα synthesis in ob/ob mice. The fundamental importance of DAGLα in this monosynaptic circuitry could be tested in DAGLα null mice, where synaptic reorganization but not muted inhibition onto orexin-containing neurons would be the anticipated phenotype. More importantly, mechanistic insights in

Cristino et al. identify an excitatory-to-inhibitory switch of synapses impacting orexin-containing neurons in genetically leptin deficient ob/ob mice.

this report suggest that DAGLα inhibitors, rather than CB1R antagonists, could be used to reinstate inhibition of orexin-containing neurons. If so, this process could facilitate a sea-change in existing “CB1R-centric” views of weight control, and identify DAGLα as an equally potent molecular target. The ultimate benefit, learning from the failure of rimonabant, is that depressive/anxiety side-effects might be reduced and drug dosing made safer.

A remarkable finding is that orexin expression in various target areas of the brain was vastly enhanced, fueling the hypothesis that increased orexin release from tegmental and hypothalamic projections will exacerbate obesity. Nevertheless, orexins are primarily implicated in the regulation of arousal and sleep (21), and perhaps in reward aspects via the mesolimbic system (22). Thus, obesity-driven synaptic reorganization in the hypothalamus could also influence narcolepsy (6) and cyclic or bipolar vegetative functions, providing stepping stones to understand the molecular pathology of obesity-linked psychiatric disorders.

Exquisitely designed and executed experiments in rodents, such as the study by Cristino et al. (1), are indispensable to unravel key pathomechanisms of human diseases. Nevertheless, their human relevance, ingrained in potential evolutionary differences in the complexity of underlying neuronal circuitries, must be addressed. Does synapse remodeling on orexin neurons occur in obese humans? The discovery of equivalent patterns and mechanisms will ultimately define the clinical relevance of this study. Alas, the proof of the pudding, or rather a good burger, will be eating it.

Acknowledgments

This work was supported by the Swedish Medical Research Council and the NovoNordisk Foundation.

Footnotes

  • ↵1To whom correspondence should be addressed. E-mail: tibor.harkany{at}ki.se.
  • Author contributions: A.A. and T.H. wrote the paper.

  • The authors declare no conflict of interest.

  • See companion article on page E2229.

References

  1. ↵
    1. Taheri S,
    2. Lin L,
    3. Austin D,
    4. Young T,
    5. Mignot E
    (2004) Short sleep duration is associated with reduced leptin, elevated ghrelin, and increased body mass index. PLoS Med 1(3):e62.
    OpenUrlCrossRefPubMed
  2. ↵
    1. Hökfelt T,
    2. Johansson O,
    3. Ljungdahl A,
    4. Lundberg JM,
    5. Schultzberg M
    (1980) Peptidergic neurones. Nature 284(5756):515–521.
    OpenUrlCrossRefPubMed
  3. ↵
    1. Horvath TL,
    2. Gao XB
    (2005) Input organization and plasticity of hypocretin neurons: Possible clues to obesity’s association with insomnia. Cell Metab 1(4):279–286.
    OpenUrlCrossRefPubMed
  4. ↵
    1. Pinto S,
    2. et al.
    (2004) Rapid rewiring of arcuate nucleus feeding circuits by leptin. Science 304(5667):110–115.
    OpenUrlAbstract/FREE Full Text
  5. ↵
    1. Cristino L,
    2. et al.
    (2013) Obesity-driven synaptic remodeling affects endocannabinoid control of orexinergic neurons. Proc Natl Acad Sci USA 110:E2229–E2238.
    OpenUrlAbstract/FREE Full Text
  6. ↵
    1. Thannickal TC,
    2. et al.
    (2000) Reduced number of hypocretin neurons in human narcolepsy. Neuron 27(3):469–474.
    OpenUrlCrossRefPubMed
  7. ↵
    1. Thannickal TC,
    2. Nienhuis R,
    3. Siegel JM
    (2009) Localized loss of hypocretin (orexin) cells in narcolepsy without cataplexy. Sleep 32(8):993–998.
    OpenUrlPubMed
  8. ↵
    1. Aziz A,
    2. et al.
    (2008) Hypocretin and melanin-concentrating hormone in patients with Huntington disease. Brain Pathol 18(4):474–483.
    OpenUrlPubMed
  9. ↵
    1. Leinninger GM
    (2011) Lateral thinking about leptin: A review of leptin action via the lateral hypothalamus. Physiol Behav 104(4):572–581.
    OpenUrlCrossRefPubMed
  10. ↵
    1. Collin M,
    2. et al.
    (2003) Plasma membrane and vesicular glutamate transporter mRNAs/proteins in hypothalamic neurons that regulate body weight. Eur J Neurosci 18(5):1265–1278.
    OpenUrlCrossRefPubMed
  11. ↵
    1. Erickson JC,
    2. Hollopeter G,
    3. Palmiter RD
    (1996) Attenuation of the obesity syndrome of ob/ob mice by the loss of neuropeptide Y. Science 274(5293):1704–1707.
    OpenUrlAbstract/FREE Full Text
  12. ↵
    1. Clark JT,
    2. Kalra PS,
    3. Crowley WR,
    4. Kalra SP
    (1984) Neuropeptide Y and human pancreatic polypeptide stimulate feeding behavior in rats. Endocrinology 115(1):427–429.
    OpenUrlAbstract/FREE Full Text
  13. ↵
    1. Huszar D,
    2. et al.
    (1997) Targeted disruption of the melanocortin-4 receptor results in obesity in mice. Cell 88(1):131–141.
    OpenUrlCrossRefPubMed
  14. ↵
    1. Zhang Y,
    2. et al.
    (1994) Positional cloning of the mouse obese gene and its human homologue. Nature 372(6505):425–432.
    OpenUrlCrossRefPubMed
  15. ↵
    1. Diano S,
    2. Horvath B,
    3. Urbanski HF,
    4. Sotonyi P,
    5. Horvath TL
    (2003) Fasting activates the nonhuman primate hypocretin (orexin) system and its postsynaptic targets. Endocrinology 144(9):3774–3778.
    OpenUrlAbstract/FREE Full Text
  16. ↵
    1. Di Marzo V,
    2. et al.
    (2001) Leptin-regulated endocannabinoids are involved in maintaining food intake. Nature 410(6830):822–825.
    OpenUrlCrossRefPubMed
  17. ↵
    1. Wilson RI,
    2. Nicoll RA
    (2002) Endocannabinoid signaling in the brain. Science 296(5568):678–682.
    OpenUrlAbstract/FREE Full Text
  18. ↵
    1. Harkany T,
    2. Mackie K,
    3. Doherty P
    (2008) Wiring and firing neuronal networks: Endocannabinoids take center stage. Curr Opin Neurobiol 18(3):338–345.
    OpenUrlCrossRefPubMed
  19. ↵
    1. Dinh TP,
    2. et al.
    (2002) Brain monoglyceride lipase participating in endocannabinoid inactivation. Proc Natl Acad Sci USA 99(16):10819–10824.
    OpenUrlAbstract/FREE Full Text
  20. ↵
    1. Leinninger GM,
    2. et al.
    (2011) Leptin action via neurotensin neurons controls orexin, the mesolimbic dopamine system and energy balance. Cell Metab 14(3):313–323.
    OpenUrlCrossRefPubMed
  21. ↵
    1. Anaclet C,
    2. et al.
    (2009) Orexin/hypocretin and histamine: Distinct roles in the control of wakefulness demonstrated using knock-out mouse models. J Neurosci 29(46):14423–14438.
    OpenUrlAbstract/FREE Full Text
  22. ↵
    1. Baldo BA,
    2. Daniel RA,
    3. Berridge CW,
    4. Kelley AE
    (2003) Overlapping distributions of orexin/hypocretin- and dopamine-beta-hydroxylase immunoreactive fibers in rat brain regions mediating arousal, motivation, and stress. J Comp Neurol 464(2):220–237.
    OpenUrlCrossRefPubMed
View Abstract
PreviousNext
Back to top
Article Alerts
Email Article

Thank you for your interest in spreading the word on PNAS.

NOTE: We only request your email address so that the person you are recommending the page to knows that you wanted them to see it, and that it is not junk mail. We do not capture any email address.

Enter multiple addresses on separate lines or separate them with commas.
Orexin neurons use endocannabinoids to break obesity-induced inhibition
(Your Name) has sent you a message from PNAS
(Your Name) thought you would like to see the PNAS web site.
Citation Tools
Endocannabinoid function in orexin neurons
Alán Alpár, Tibor Harkany
Proceedings of the National Academy of Sciences Jun 2013, 110 (24) 9625-9626; DOI: 10.1073/pnas.1307389110

Citation Manager Formats

  • BibTeX
  • Bookends
  • EasyBib
  • EndNote (tagged)
  • EndNote 8 (xml)
  • Medlars
  • Mendeley
  • Papers
  • RefWorks Tagged
  • Ref Manager
  • RIS
  • Zotero
Request Permissions
Share
Endocannabinoid function in orexin neurons
Alán Alpár, Tibor Harkany
Proceedings of the National Academy of Sciences Jun 2013, 110 (24) 9625-9626; DOI: 10.1073/pnas.1307389110
del.icio.us logo Digg logo Reddit logo Twitter logo CiteULike logo Facebook logo Google logo Mendeley logo
  • Tweet Widget
  • Facebook Like
  • Mendeley logo Mendeley
Proceedings of the National Academy of Sciences: 116 (8)
Current Issue

Submit

Sign up for Article Alerts

Jump to section

  • Article
    • Acknowledgments
    • Footnotes
    • References
  • Figures & SI
  • Info & Metrics
  • PDF

You May Also be Interested in

News Feature: Cities serve as testbeds for evolutionary change
Urban living can pressure flora and fauna to adapt in intriguing ways. Biologists are starting to take advantage of this convenient laboratory of evolution.
Image credit: Kristin Winchell (Washington University in St. Louis, St. Louis).
Several aspects of the proposal, which aims to expand open access, require serious discussion and, in some cases, a rethink.
Opinion: “Plan S” falls short for society publishers—and for the researchers they serve
Several aspects of the proposal, which aims to expand open access, require serious discussion and, in some cases, a rethink.
Image credit: Dave Cutler (artist).
Featured Profile
PNAS Profile of NAS member and biochemist Hao Wu
 Nonmonogamous strawberry poison frog (Oophaga pumilio).  Image courtesy of Yusan Yang (University of Pittsburgh, Pittsburgh).
Putative signature of monogamy
A study suggests a putative gene-expression hallmark common to monogamous male vertebrates of some species, namely cichlid fishes, dendrobatid frogs, passeroid songbirds, common voles, and deer mice, and identifies 24 candidate genes potentially associated with monogamy.
Image courtesy of Yusan Yang (University of Pittsburgh, Pittsburgh).
Active lifestyles. Image courtesy of Pixabay/MabelAmber.
Meaningful life tied to healthy aging
Physical and social well-being in old age are linked to self-assessments of life worth, and a spectrum of behavioral, economic, health, and social variables may influence whether aging individuals believe they are leading meaningful lives.
Image courtesy of Pixabay/MabelAmber.

More Articles of This Classification

  • Squid genomes in a bacterial world
  • Homogeneous catalysis for the nitrogen fuel cycle
  • The future of influenza forecasts
Show more

Related Content

  • CB1 modulation of OX neurons in obesity
  • Scopus
  • PubMed
  • Google Scholar

Cited by...

  • Hypothalamic CNTF volume transmission shapes cortical noradrenergic excitability upon acute stress
  • Scopus (5)
  • Google Scholar

Similar Articles

Site Logo
Powered by HighWire
  • Submit Manuscript
  • Twitter
  • Facebook
  • RSS Feeds
  • Email Alerts

Articles

  • Current Issue
  • Latest Articles
  • Archive

PNAS Portals

  • Classics
  • Front Matter
  • Teaching Resources
  • Anthropology
  • Chemistry
  • Physics
  • Sustainability Science

Information

  • Authors
  • Editorial Board
  • Reviewers
  • Press
  • Site Map

Feedback    Privacy/Legal

Copyright © 2019 National Academy of Sciences. Online ISSN 1091-6490