Letter | Published:

Bidirectional electromagnetic control of the hypothalamus regulates feeding and metabolism

Nature volume 531, pages 647650 (31 March 2016) | Download Citation


Targeted, temporally regulated neural modulation is invaluable in determining the physiological roles of specific neural populations or circuits. Here we describe a system for non-invasive, temporal activation or inhibition of neuronal activity in vivo and its use to study central nervous system control of glucose homeostasis and feeding in mice. We are able to induce neuronal activation remotely using radio waves or magnetic fields via Cre-dependent expression of a GFP-tagged ferritin fusion protein tethered to the cation-conducting transient receptor potential vanilloid 1 (TRPV1) by a camelid anti-GFP antibody (anti-GFP–TRPV1)1. Neuronal inhibition via the same stimuli is achieved by mutating the TRPV1 pore, rendering the channel chloride-permeable. These constructs were targeted to glucose-sensing neurons in the ventromedial hypothalamus in glucokinase–Cre mice, which express Cre in glucose-sensing neurons2. Acute activation of glucose-sensing neurons in this region increases plasma glucose and glucagon, lowers insulin levels and stimulates feeding, while inhibition reduces blood glucose, raises insulin levels and suppresses feeding. These results suggest that pancreatic hormones function as an effector mechanism of central nervous system circuits controlling blood glucose and behaviour. The method we employ obviates the need for permanent implants and could potentially be applied to study other neural processes or used to regulate other, even dispersed, cell types.

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  1. 1.

    , , , & Remote regulation of glucose homeostasis in mice using genetically encoded nanoparticles. Nature Med. 21, 92–98 (2015)

  2. 2.

    et al. Profiling of glucose-sensing neurons reveals that GHRH neurons are activated by hypoglycemia. Cell Metab. 18, 596–607 (2013)

  3. 3.

    , & Enhancement of feeding produced by stimulation of the ventromedial hypothalamus. J. Comp. Physiol. Psychol. 86, 414–419 (1974)

  4. 4.

    , , & Effect of ventromedial hypothalamic lesions on the secretion of somatostatin, insulin, and glucagon by the perfused rat pancreas. Metabolism 29, 986–990 (1980)

  5. 5.

    , & Reciprocal influences of the ventromedial and lateral hypothalamic nuclei on blood glucose level and liver glycogen content. Nature 210, 1178–1179 (1966)

  6. 6.

    et al. Cooperation between brain and islet in glucose homeostasis and diabetes. Nature 503, 59–66 (2013)

  7. 7.

    , , , & Physiological and molecular characteristics of rat hypothalamic ventromedial nucleus glucosensing neurons. Diabetes 53, 549–559 (2004)

  8. 8.

    , & AGRP neurons are sufficient to orchestrate feeding behavior rapidly and without training. Nature Neurosci. 14, 351–355 (2011)

  9. 9.

    et al. Control of stress-induced persistent anxiety by an extra-amygdala septohypothalamic circuit. Cell 156, 522–536 (2014)

  10. 10.

    , & Regulation of glucose production by the liver. Annu. Rev. Nutr. 19, 379–406 (1999)

  11. 11.

    , & CREB phosphorylation and dephosphorylation: a Ca2+- and stimulus duration-dependent switch for hippocampal gene expression. Cell 87, 1203–1214 (1996)

  12. 12.

    , , & Calcium regulation of gene expression in neuronal cells. J. Neurobiol. 25, 294–303 (1994)

  13. 13.

    & How does DBS work? Suppl. Clin. Neurophysiol. 57, 733–736 (2004)

  14. 14.

    , & The transmembrane segment S6 determines cation versus anion selectivity of TRPM2 and TRPM8. J. Biol. Chem. 282, 27598–27609 (2007)

  15. 15.

    & Animal responses to 2-deoxy-d-glucose administration. Proc. Soc. Exp. Biol. Med. 99, 124–127 (1958)

  16. 16.

    , & Genetically programmed superparamagnetic behavior of mammalian cells. J. Biotechnol. 162, 237–245 (2012)

  17. 17.

    , & Metabolic and neurochemical correlates of glucoprivic feeding. Brain Res. Bull. 14, 617–624 (1985)

  18. 18.

    et al. Hypothalamic ATP-sensitive K+ channels play a key role in sensing hypoglycemia and triggering counterregulatory epinephrine and glucagon responses. Diabetes 53, 2542–2551 (2004)

  19. 19.

    , , , & AMP-activated protein kinase and nitric oxide regulate the glucose sensitivity of ventromedial hypothalamic glucose-inhibited neurons. Am. J. Physiol. Cell Physiol. 297, C750–C758 (2009)

  20. 20.

    et al. Brain uncoupling protein 2: uncoupled neuronal mitochondria predict thermal synapses in homeostatic centers. J. Neurosci. 19, 10417–10427 (1999)

  21. 21.

    , , , & Wireless magnetothermal deep brain stimulation. Science 347, 1477–1480 (2015)

  22. 22.

    et al. Radio-wave heating of iron oxide nanoparticles can regulate plasma glucose in mice. Science 336, 604–608 (2012)

  23. 23.

    , , , & Evolving the lock to fit the key to create a family of G protein-coupled receptors potently activated by an inert ligand. Proc. Natl Acad. Sci. USA 104, 5163–5168 (2007)

  24. 24.

    et al. Remote control of neuronal activity in transgenic mice expressing evolved G protein-coupled receptors. Neuron 63, 27–39 (2009)

  25. 25.

    et al. New insights into the function of M4 muscarinic acetylcholine receptors gained using a novel allosteric modulator and a DREADD (designer receptor exclusively activated by a designer drug). Mol. Pharmacol. 74, 1119–1131 (2008)

  26. 26.

    , & Long-term evaluation of changes in operative technique and hardware-related complications with deep brain stimulation. Neuromodulation 18, 670–677 (2015)

  27. 27.

    et al. The capsaicin receptor: a heat-activated ion channel in the pain pathway. Nature 389, 816–824 (1997)

  28. 28.

    & Expression and purification of epitope-tagged multisubunit protein complexes from mammalian cells. Curr. Protoc. Mol. Biol . Chapter 16, Unit 16.13 (2002)

  29. 29.

    , , & Olfactomedin 1 interacts with the Nogo A receptor complex to regulate axon growth. J. Biol. Chem. 287, 37171–37184 (2012)

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We would like to thank A. North, P. Ariel and K. Thomas for help with confocal imaging, D. Acehan and K. Uryu for performing EM studies and S. Korres for assistance with the manuscript. This work was funded by Howard Hughes Medical Institute, the JPB Foundation, the National Institutes of Health (GM095654 and MH105941) and a Rensselaer Fellowship (to J.S.) under an NIH predoctoral training grant (GM067545). Support for this project was provided by a grant from the Robertson Foundation.

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  1. Laboratory of Molecular Genetics, Rockefeller University, New York, New York 10065, USA

    • Sarah A. Stanley
    • , Leah Kelly
    • , Kaamashri N. Latcha
    • , Sarah F. Schmidt
    • , Xiaofei Yu
    • , Alexander R. Nectow
    •  & Jeffrey M. Friedman
  2. Department of Chemical & Biological Engineering, Center for Biotechnology & Interdisciplinary Studies, Rensselaer Polytechnic Institute, Troy, New York 12180, USA

    • Jeremy Sauer
    •  & Jonathan S. Dordick
  3. Department of Radiology, Weill Cornell Medical College, New York, New York 10065, USA

    • Jonathan P. Dyke
  4. Howard Hughes Medical Institute, New York, New York 10065, USA

    • Jeffrey M. Friedman


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J.M.F. conceived the project and supervised the studies. S.A.S. and L.K. designed and performed the experiments. K.L. and S.F.S. provided technical assistance. A.N. assisted with optogenetic studies, J.S. assisted with magnet activation studies and X.Y. assisted with cell culture studies. J.D. provided technical advice for in vivo magnet activation studies. J.S.D. provided technical advice. S.A.S., L.K. and J.M.F. wrote the manuscript.

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The authors declare no competing financial interests.

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Correspondence to Jeffrey M. Friedman.

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