Sympathetic Neuro-adipose Connections Mediate Leptin-Driven Lipolysis
Open accessAbstract
Leptin is a hormone produced by the adipose tissue that acts in the brain, stimulating white fat breakdown. We find that the lipolytic effect of leptin is mediated through the action of sympathetic nerve fibers that innervate the adipose tissue. Using intravital two-photon microscopy, we observe that sympathetic nerve fibers establish neuro-adipose junctions, directly "enveloping" adipocytes. Local optogenetic stimulation of sympathetic inputs induces a local lipolytic response and depletion of white adipose mass. Conversely, genetic ablation of sympathetic inputs onto fat pads blocks leptin-stimulated phosphorylation of hormone-sensitive lipase and consequent lipolysis, as do knockouts of dopamine β-hydroxylase, an enzyme required for catecholamine synthesis. Thus, neuro-adipose junctions are necessary and sufficient for the induction of lipolysis in white adipose tissue and are an efferent effector of leptin action. Direct activation of sympathetic inputs to adipose tissues may represent an alternative approach to induce fat loss, circumventing central leptin resistance. PAPERCLIP.
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
Direct innervation of WAT depots is sparser than in BAT.
“Notably, direct innervation of WAT depots is sparser than in BAT 69.”
From Inter‐organ communication: a gatekeeper for metabolic health (2019) · cites this paper as [69]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Cites
Fiji: an open-source platform for biological-image analysis
Schindelin, J., Arganda-Carreras, I., Frise, E., Kaynig, V., Longair, M., Pietzsch, T., Preibisch, S., Rueden, C., Saalfeld, S., Schmid, B., et al. (2012) · Nature Methods · doi:10.1038/nmeth.2019 · Cited by 66,890 · see citing works
Obesity is associated with macrophage accumulation in adipose tissue
Weisberg, S. P., McCann, D., Desai, M., Rosenbaum, M., Leibel, R. L., & Ferrante, A. W. (2003) · Journal of Clinical Investigation · doi:10.1172/jci200319246 · Cited by 10,041 · see citing works
Leptin and the regulation of body weight in mammals
Friedman, J. M., & Halaas, J. L. (1998) · Nature · doi:10.1038/27376 · Cited by 5,405 · see citing works
Self-citationWeight-Reducing Effects of the Plasma Protein Encoded by the <i>obese</i> Gene
Halaas, J. L., Gajiwala, K. S., Maffei, M., Cohen, S. L., Chait, B. T., Rabinowitz, D., Lallone, R. L., Burley, S. K., & Friedman, J. M. (1995) · Science · doi:10.1126/science.7624777 · Cited by 4,451 · see citing works
Self-citationDeep tissue two-photon microscopy
Helmchen, F., & Denk, W. T. (2005) · Nature Methods · doi:10.1038/nmeth818 · Cited by 4,165 · see citing works
Effects of the <i>obese</i> Gene Product on Body Weight Regulation in <i>ob</i> / <i>ob</i> Mice
Pelleymounter, M. A., Cullen, M. J., Baker, M. B., Hecht, R., Winters, D., Boone, T., & Collins, F. (1995) · Science · doi:10.1126/science.7624776 · Cited by 4,017 · see citing works
Campfield, L. A., Smith, F. J., Guisez, Y., Devos, R., & Burn, P. (1995) · Science · doi:10.1126/science.7624778 · Cited by 3,243 · see citing works
Capsaicin: cellular targets, mechanisms of action, and selectivity for thin sensory neurons.
Holzer, P. D. (1991) · Pharmacological Reviews · doi:10.1016/s0031-6997(25)06664-5 · Cited by 1,784 · see citing works
Alternatively activated macrophages produce catecholamines to sustain adaptive thermogenesis
Nguyen, K. D., Qiu, Y., Cui, X., Goh, Y. P. S., Mwangi, J., David, T., Mukundan, L., Brombacher, F., Locksley, R. M., & Chawla, A. (2011) · Nature · doi:10.1038/nature10653 · Cited by 1,038 · see citing works
Physiological response to long-term peripheral and central leptin infusion in lean and obese mice.
Halaas, J. L., Boozer, C., Blair-West, J., Fidahusein, N., Denton, D. A., & Friedman, J. M. (1997) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.94.16.8878 · Cited by 1,033 · see citing works
Self-citationBrasaemle, D. (2007) · Journal of Lipid Research · doi:10.1194/jlr.r700014-jlr200 · Cited by 997 · see citing works
Channelrhodopsin-2-assisted circuit mapping of long-range callosal projections
Petreanu, L., Huber, D., Sobczyk, A., & Svoboda, K. (2007) · Nature Neuroscience · doi:10.1038/nn1891 · Cited by 930 · see citing works
A Cre-inducible diphtheria toxin receptor mediates cell lineage ablation after toxin administration
Buch, T., Heppner, F. L., Tertilt, C., Heinen, T. J. A. J., Kremer, M., Wunderlich, F. T., Jung, S., & Waisman, A. (2005) · Nature Methods · doi:10.1038/nmeth762 · Cited by 922 · see citing works
βAR Signaling Required for Diet-Induced Thermogenesis and Obesity Resistance
Bachman, E. S., Dhillon, H., Zhang, C.-Y., Cinti, S., Bianco, A. C., Kobilka, B. K., & Lowell, B. B. (2002) · Science · doi:10.1126/science.1073160 · Cited by 782 · see citing works
White, Brown, Beige/Brite: Different Adipose Cells for Different Functions?
Giralt, M., & Villarroya, F. (2013) · Endocrinology · doi:10.1210/en.2013-1403 · Cited by 556 · see citing works
Leptin and Insulin Act on POMC Neurons to Promote the Browning of White Fat
Dodd, G. T., Decherf, S., Loh, K., Simonds, S. E., Wiede, F., Balland, E., Merry, T. L., Münzberg, H., Zhang, Z.-Y., Kahn, B. B., et al. (2015) · Cell · doi:10.1016/j.cell.2014.12.022 · Cited by 398 · see citing works
Genetic identification of C fibres that detect massage-like stroking of hairy skin in vivo
Vrontou, S., Wong, A. M., Rau, K. K., Koerber, H. R., & Anderson, D. J. (2013) · Nature · doi:10.1038/nature11810 · Cited by 289 · see citing works
Dempersmier, J. M., Sambeat, A., Gulyaeva, О. N., Paul, S. M., Hudak, C. S. S., Raposo, H. F., Kwan, H. Y., Kang, C., Wong, R. H.-F., & Sul, H. S. (2015) · Molecular Cell · doi:10.1016/j.molcel.2014.12.005 · Cited by 242 · see citing works
Sympathoadrenal system and regulation of thermogenesis
Landsberg, L., Saville, M. E., & Young, J. B. (1984) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.1984.247.2.e181 · Cited by 232 · see citing works
Leptin regulates the reward value of nutrient
Domingos, A. I., Vaynshteyn, J., Voss, H. U., Ren, X., Gradinaru, V., Zang, F., Deisseroth, K. A., de Araújo, I. E., & Friedman, J. M. (2011) · Nature Neuroscience · doi:10.1038/nn.2977 · Cited by 230 · see citing works
Self-citationAdipose Tissue: Ability to Respond to Nerve Stimulation in vitro
Correll, J. W. (1963) · Science · doi:10.1126/science.140.3565.387 · Cited by 212 · see citing works
Bartness, T. J., & Song, C. K. (2007) · Journal of Lipid Research · doi:10.1194/jlr.r700006-jlr200 · Cited by 209 · see citing works
Leptin induction of UCP1 gene expression is dependent on sympathetic innervation
Scarpace, P. J., & Matheny, M. E. (1998) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.1998.275.2.e259 · Cited by 202 · see citing works
Catecholaminergic innervation of white adipose tissue in Siberian hamsters
Youngstrom, T. G., & Bartness, T. J. (1995) · American Journal of Physiology-Regulatory, Integrative and Comparative Physiology · doi:10.1152/ajpregu.1995.268.3.r744 · Cited by 180 · see citing works
Remote Optogenetic Activation and Sensitization of Pain Pathways in Freely Moving Mice
Daou, I., Tuttle, A. H., Longo, G., Wieskopf, J. S., Bonin, R. P., Ase, A. R., Wood, J. N., De Koninck, Y., Ribeiro-da-Silva, A., Mogil, J. S., et al. (2013) · The Journal of Neuroscience · doi:10.1523/jneurosci.2424-13.2013 · Cited by 175 · see citing works
Hypothalamic melanin concentrating hormone neurons communicate the nutrient value of sugar
Domingos, A. I., Sordillo, A., Dietrich, M. O., Liu, Z.-W., Téllez, L. A., Vaynshteyn, J., Ferreira, J. G. P., Ekstrand, M. I., Horváth, T. L., de Araújo, I. E., et al. (2013) · eLife · doi:10.7554/elife.01462 · Cited by 154 · see citing works
Self-citationDing, Y. M., Jaumotte, J. D., Signore, A. P., & Zigmond, M. J. (2004) · Journal of Neurochemistry · doi:10.1111/j.1471-4159.2004.02415.x · Cited by 137 · see citing works
Brain–adipose tissue cross talk
Bartness, T. J., Song, C. K., Shi, H., Bowers, R. R., & Foster, M. T. (2005) · Proceedings of The Nutrition Society · doi:10.1079/pns2004409 · Cited by 135 · see citing works
OpenSpinMicroscopy: an open-source integrated microscopy platform
Gualda, E. J., Vale, T., Almada, P., et al. (2013) · Nature Methods · doi:10.1038/nmeth.2508 · Cited by 125 · see citing works
Giordano, A., Morroni, M., Santone, G., Marchesi, G. F., & Cinti, S. (1996) · Journal of Neurocytology · doi:10.1007/bf02284791 · Cited by 122 · see citing works
Elia, M., Stubbs, R. J., & Henry, C. J. K. (1999) · Obesity Research · doi:10.1002/j.1550-8528.1999.tb00720.x · Cited by 105 · see citing works
AWAD, S. S., Constantin‐Teodosiu, D., Macdonald, I. A., & Lobo, D. N. (2009) · Clinical Nutrition · doi:10.1016/j.clnu.2009.04.014 · Cited by 92 · see citing works
Giordano, A., Frontini, A., Murano, I., Tonello, C., Marino, M. A., Carruba, M. O., Nisoli, E., & Cinti, S. (2005) · Journal of Histochemistry & Cytochemistry · doi:10.1369/jhc.4a6566.2005 · Cited by 91 · see citing works
Acute leptin deficiency, leptin resistance, and the physiologic response to leptin withdrawal
Montez, J. M., Soukas, A. A., Asilmaz, E., Fayzikhodjaeva, G., Fantuzzi, G., & Friedman, J. M. (2005) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0409530102 · Cited by 80 · see citing works
Self-citationInsulin action during acute starvation: Evidence for selective insulin resistance in normal man
Newman, W. P., & Brodows, R. G. (1983) · Metabolism · doi:10.1016/0026-0495(83)90029-x · Cited by 78 · see citing works
Integration of sensory information via central thermoregulatory leptin targets
Rezai-Zadeh, K. P., & Münzberg, H. (2013) · Physiology & Behavior · doi:10.1016/j.physbeh.2013.02.014 · Cited by 48 · see citing works
Optical Projection Tomography of Vertebrate Embryo DevelopmentPreprint
Quintana, L., & Sharpe, J. A. (2011) · Cold Spring Harbor Protocols · doi:10.1101/pdb.top116 · Cited by 40 · see citing works
Starvation diet and very-low-calorie diets may induce insulin resistance and overt diabetes mellitus
Koffler, M., & Kisch, E. S. (1996) · Journal of Diabetes and its Complications · doi:10.1016/1056-8727(94)00077-8 · Cited by 37 · see citing works
Norepinephrine Induces Lipolysis in β1/β2/β3-Adrenoceptor Knockout Mice
Tavernier, G., Jimenez, M., Giacobino, J., Hulo, N., Lafontan, M., Muzzin, P., & Langin, D. (2005) · Molecular Pharmacology · doi:10.1124/mol.105.014670 · Cited by 37 · see citing works
Rafael, J., & Herling, A. W. (2000) · American Journal of Physiology-Regulatory, Integrative and Comparative Physiology · doi:10.1152/ajpregu.2000.278.3.r790 · Cited by 29 · see citing works
Effect of leptin on energy balance does not require the presence of intact adrenals
Arvaniti, K., Deshaies, Y., & Richard, D. (1998) · American Journal of Physiology-Regulatory, Integrative and Comparative Physiology · doi:10.1152/ajpregu.1998.275.1.r105 · Cited by 16 · see citing works
Thompson, G. E. (1986) · Quarterly Journal of Experimental Physiology · doi:10.1113/expphysiol.1986.sp003016 · Cited by 7 · see citing works
Flagged first, then by citations
Cited by
Sorted by citations
Stern, J. H., Rutkowski, J. M., & Scherer, P. E. (2016) · Cell Metabolism · doi:10.1016/j.cmet.2016.04.011 · Cited by 1,031 · see citing works
The endocrine function of adipose tissues in health and cardiometabolic disease
Scheja, L., & Heeren, J. (2019) · Nature Reviews Endocrinology · doi:10.1038/s41574-019-0230-6 · Cited by 663 · see citing works
Leptin and the endocrine control of energy balance
Friedman, J. M. (2019) · Nature Metabolism · doi:10.1038/s42255-019-0095-y · Cited by 661 · see citing works
Self-citationThe obese adipose tissue microenvironment in cancer development and progression
Quail, D. F., & Dannenberg, A. J. (2019) · Nature Reviews Endocrinology · doi:10.1038/s41574-018-0126-x · Cited by 542 · see citing works
Paired-cell sequencing enables spatial gene expression mapping of liver endothelial cells
Halpern, K. B., Shenhav, R., Massalha, H., Toth, B., Egozi, A., Massasa, E. E., Medgalia, C., David, E., Giladi, A., Moor, A. E., et al. (2018) · Nature Biotechnology · doi:10.1038/nbt.4231 · Cited by 368 · see citing works
A leptin–BDNF pathway regulating sympathetic innervation of adipose tissue
Wang, P., Loh, K. H., Wu, M., Morgan, D. A., Schneeberger, M., Yu, X., Chi, J., Kosse, C., Kim, D., Rahmouni, K., et al. (2020) · Nature · doi:10.1038/s41586-020-2527-y · Cited by 332 · see citing works
Self-citationJiang, H., Ding, X., Cao, Y., Wang, H., & Zeng, W. (2017) · Cell Metabolism · doi:10.1016/j.cmet.2017.08.016 · Cited by 204 · see citing works
Self-citationγδ T cells and adipocyte IL-17RC control fat innervation and thermogenesis
Hu, B., Jin, C., Zeng, X., Resch, J. M., Jedrychowski, M. P., Yang, Z., Desai, B. N., Banks, A. S., Lowell, B. B., Mathis, D., et al. (2020) · Nature · doi:10.1038/s41586-020-2028-z · Cited by 180 · see citing works
Inter‐organ communication: a gatekeeper for metabolic health
Castillo‐Armengol, J., Fajas, L., & Lopez‐Mejia, I. C. (2019) · The EMBO Reports · doi:10.15252/embr.201947903 · Cited by 178 · see citing works
Neuro-mesenchymal units control ILC2 and obesity via a brain–adipose circuit
Cardoso, F., Klein Wolterink, R. G. J., Godinho-Silva, C., Domingues, R. G., Ribeiro, H., da Silva, J. A., Mahú, I., Domingos, A. I., & Veiga-Fernandes, H. (2021) · Nature · doi:10.1038/s41586-021-03830-7 · Cited by 159 · see citing works
Self-citationBeyond the brain: Optogenetic control in the spinal cord and peripheral nervous system
Montgomery, K. L., Iyer, S. M., Christensen, A. J., Deisseroth, K., & Delp, S. L. (2016) · Science Translational Medicine · doi:10.1126/scitranslmed.aad7577 · Cited by 147 · see citing works
Metabolic stress drives sympathetic neuropathy within the liver
Liu, K., Yang, L., Wang, G., Liu, J., Zhao, X., Wang, Y., Li, J., & Yang, J. (2021) · Cell Metabolism · doi:10.1016/j.cmet.2021.01.012 · Cited by 146 · see citing works
Christoffersen, B. Ø., Sanchez‐Delgado, G., John, L. M., Ryan, D. H., Raun, K., & Ravussin, E. (2022) · Obesity · doi:10.1002/oby.23374 · Cited by 142 · see citing works
Obesity: A neuroimmunometabolic perspective
Larabee, C. M., Neely, O. C., & Domingos, A. I. (2020) · Nature Reviews Endocrinology · doi:10.1038/s41574-019-0283-6 · Cited by 123 · see citing works
Zhu, Y., Gao, Y., Tao, C., Shao, M., Zhao, S., Huang, W., Yao, T., Johnson, J. A., Liu, T., Cypess, A. M., et al. (2016) · Cell Metabolism · doi:10.1016/j.cmet.2016.08.005 · Cited by 100 · see citing works
Exercise-Mediated Browning of White Adipose Tissue: Its Significance, Mechanism and Effectiveness
Mu, W.-J., Zhu, J.-Y., Chen, M., & Guo, L. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms222111512 · Cited by 99 · see citing works
Neuropathy and neural plasticity in the subcutaneous white adipose depot
Blaszkiewicz, M., Willows, J. W., Dubois, A. L., Waible, S., DiBello, K., Lyons, L. L., Johnson, C. P., Paradie, E., Banks, N., Motyl, K., et al. (2019) · PLOS ONE · doi:10.1371/journal.pone.0221766 · Cited by 87 · see citing works
Hammoud, S. H., AlZaim, I., Al-Dhaheri, Y., Eid, A. H., & El-Yazbi, A. F. (2021) · Frontiers in Endocrinology · doi:10.3389/fendo.2021.707126 · Cited by 87 · see citing works
Sympathetic neuropeptide Y protects from obesity by sustaining thermogenic fat
Zhu, Y., Yao, L., Gallo-Ferraz, A. L., Bombassaro, B., Simões, M. R., Abe, I., Chen, J., Sarker, G., Ciccarelli, A., Zhou, L., et al. (2024) · Nature · doi:10.1038/s41586-024-07863-6 · Cited by 78 · see citing works
Self-citationThe hepatokine Tsukushi gates energy expenditure via brown fat sympathetic innervation
Wang, Q., Sharma, V. P., Shen, H., Xiao, Y., Zhu, Q., Xiong, X., Guo, L., Jiang, L., Ohta, K., Li, S., et al. (2019) · Nature Metabolism · doi:10.1038/s42255-018-0020-9 · Cited by 71 · see citing works
Wee, N. K. Y., Lorenz, M. R., Bekirov, Y., Jacquin, M. F., & Scheller, E. L. (2019) · Frontiers in Endocrinology · doi:10.3389/fendo.2019.00668 · Cited by 39 · see citing works
Varlamov, O., Bishop, C. V., Handu, M., Takahashi, D., Srinivasan, S., White, A., & Roberts, C. T. (2017) · Human Reproduction · doi:10.1093/humrep/dex244 · Cited by 34 · see citing works
Ma, Y., Nenkov, M., Chen, Y., & Gaßler, N. (2024) · International Journal of Molecular Sciences · doi:10.3390/ijms25158352 · Cited by 28 · see citing works
Hu, S., Wang, L., Togo, J., Yang, D., Xu, Y., Wu, Y., Douglas, A., & Speakman, J. R. (2020) · Molecular Metabolism · doi:10.1016/j.molmet.2019.11.010 · Cited by 20 · see citing works
Zhang, X., Tian, L., Majumdar, A., & Scheller, E. L. (2024) · Comprehensive Physiology · doi:10.1002/j.2040-4603.2024.tb00300.x · Cited by 18 · see citing works
- Authors
- Zeng, W., Pirzgalska, R. M., Pereira, M. M. A., Kubasova, N., Barateiro, A., Seixas, E., Lu, Y.-H., Kozlova, A., Voss, H., Martins, G. G., Friedman, J. M., & Domingos, A. I.
- Affiliations
- Howard Hughes Medical Institute (US)
- Instituto Gulbenkian de Ciência (PT)
- University of Lisbon (PT)
- Rockefeller University (US)
- Weill Cornell Medicine (US)
- Corresponding author
- Domingos, Ana I.
- ORCID
- Venue
- Cell
- Publisher
- Elsevier BV
- Published
- 2015-09
- Volume
- 163
- Issue
- 1
- Pages
- 84-94
- ISSN
- 0092-8674 (ISSN-L)
- PMC
- PMC7617198
- OpenAlex
- W2158673389
- Cited by
- 490
- References
- 42
- Citations by year
- 2026: 47 · 2025: 35 · 2024: 48 · 2023: 51 · 2022: 50 · 2021: 51 · 2020: 48 · 2019: 50 · 2018: 37 · 2017: 29 · 2016: 36 · 2015: 8
- FWCI
- 27.01
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cell (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- Wellcome Trust (208576)
- Topics
- Health Sciences › Medicine › Physiology › Adipose Tissue and Metabolism
- Life Sciences › Neuroscience › Endocrine and Autonomic Systems › Regulation of Appetite and Obesity
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Lipid metabolism and biosynthesis
- Keywords
- leptin, lipolysis, white adipose tissue, hormone-sensitive lipase, dopamine beta-hydroxylase, catecholamine synthesis, leptin resistance, fat loss, optogenetic stimulation, intravital two-photon microscopy
- MeSH terms
- Animals, Humans, Lipolysis, Phosphorylation, Receptors, Adrenergic, beta, Sympathetic Nervous System, Leptin, Mice, Adipose Tissue, White
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
