Display options
Cite
Huesing C, Zhang R, Gummadi S, et al. Organization of sympathetic innervation of interscapular brown adipose tissue in the mouse. J Comp Neurol. 2021;doi: 10.1002/cne.25281.
Huesing, C., Zhang, R., Gummadi, S., Lee, N., Qualls-Creekmore, E., Yu, S., Morrison, C. D., Burk, D., Berthoud, H. R., Neuhuber, W., & Münzberg, H. (2021). Organization of sympathetic innervation of interscapular brown adipose tissue in the mouse. The Journal of comparative neurology, . https://doi.org/10.1002/cne.25281
Huesing, Clara, et al. "Organization of sympathetic innervation of interscapular brown adipose tissue in the mouse." The Journal of comparative neurology vol. (2021). doi: https://doi.org/10.1002/cne.25281
Huesing C, Zhang R, Gummadi S, Lee N, Qualls-Creekmore E, Yu S, Morrison CD, Burk D, Berthoud HR, Neuhuber W, Münzberg H. Organization of sympathetic innervation of interscapular brown adipose tissue in the mouse. J Comp Neurol. 2021 Nov 27; doi: 10.1002/cne.25281. Epub 2021 Nov 27. PMID: 34837221.
Copy Download .nbib Format: NLM
Share it on

J Comp Neurol. 2021 Nov 27; doi: 10.1002/cne.25281. Epub 2021 Nov 27.

Organization of sympathetic innervation of interscapular brown adipose tissue in the mouse.

The Journal of comparative neurology

Clara Huesing, Rui Zhang, Sanjeev Gummadi, Nathan Lee, Emily Qualls-Creekmore, Sangho Yu, Christopher D Morrison, David Burk, Hans Rudolf Berthoud, Winfried Neuhuber, Heike Münzberg

Affiliations

  1. Neurobiology of Nutrition & Metabolism Department, Pennington Biomedical Research Center, Louisiana State University System, Baton Rouge, Louisiana, USA.
  2. Institute of Anatomy and Cell Biology, Friedrich-Alexander-University of Erlangen-Nürnberg, Bavaria, Germany.

PMID: 34837221 DOI: 10.1002/cne.25281

Abstract

The interscapular brown adipose tissue (iBAT) is under sympathetic control, and recent studies emphasized the importance of efferent sympathetic and afferent sensory or humoral feedback systems to regulate adipose tissue function and overall metabolic health. However, functional studies of the sympathetic nervous system in the mouse are limited, because details of anatomy and fine structure are lacking. Here, we used reporter mice for tyrosine hydroxylase expressing neurons (TH:tomato mice), iDISCO tissue clearance, confocal, lightsheet, and electron microscopy to clarify that (a) iBAT receives sympathetic input via dorsal rami (instead of often cited intercostal nerves); (b) dorsal rami T1-T5 correspond to the postganglionic input from sympathetic chain ganglia (stellate/T1-T5); (c) dorsal rami serve as conduits for sympathetic axons that branch off in finer nerve bundles to enter iBAT; (d) axonal varicosities show strong differential innervation of brown (dense innervation) versus white (sparse innervation) adipocytes, that surround the core iBAT in the mouse and are intermingled in human adipose tissues, (e) axonal varicosities can form neuro-adipocyte junctions with brown adipocytes. Taken together, we demonstrate that sympathetic iBAT innervation is organized by specific nerves and terminal structures that can be surgically and genetically accessed for neuromodulatory purposes.

© 2021 Wiley Periodicals LLC.

Keywords: TH-tomato reporter mice; dorsal rami; fine nerves; iDISCO; imaging; thoracic levels; tissue clearing; vascular innervation

References

  1. Anlauf, M., Eissele, R., Schafer, M. K., Eiden, L. E., Arnold, R., Pauser, U., Klöppel, G., & Weihe, E. (2003). Expression of the two isoforms of the vesicular monoamine transporter (VMAT1 and VMAT2) in the endocrine pancreas and pancreatic endocrine tumors. Journal of Histochemistry and Cytochemistry, 51(8), 1027-1040. https://doi.org/10.1177/002215540305100806 - PubMed
  2. Bargmann, W., von Hehn, G., & Lindner, E. (1968). On the cells of the brown fatty tissue and their innervation. Z Zellforsch Mikrosk Anat, 85(4), 601-613. - PubMed
  3. Baron, R., Janig, W., & With, H. (1995). Sympathetic and afferent neurones projecting into forelimb and trunk nerves and the anatomical organization of the thoracic sympathetic outflow of the rat. Journal of the Autonomic Nervous System, 53(2-3), 205-214. https://doi.org/10.1016/0165-1838(94)00171-F - PubMed
  4. Barreau, C., Labit, E., Guissard, C., Rouquette, J., Boizeau, M. L., Gani Koumassi, S., Carrière, A., Jeanson, Y., Berger-Müller, S., Dromard, C., Plouraboué, F., Casteilla, L., & Lorsignol, A. (2016). Regionalization of browning revealed by whole subcutaneous adipose tissue imaging. Obesity (Silver Spring), 24(5), 1081-1089. https://doi.org/10.1002/oby.21455 - PubMed
  5. Bartness, T. J., & Ryu, V. (2015). Neural control of white, beige and brown adipocytes. International Journal of Obesity Supplements, 5(Suppl (1),), S35-S39. https://doi.org/10.1038/ijosup.2015.9 - PubMed
  6. Bennett, M. R. (1972). Autonomic neuromuscular transmission. Monographs of the Physiological Society,(30), 1-271. - PubMed
  7. Bouret, S. G., Draper, S. J., & Simerly, R. B. (2004). Trophic action of leptin on hypothalamic neurons that regulate feeding. Science, 304(5667), 108-110. https://doi.org/10.1126/science.1095004 - PubMed
  8. Cannon, B., Nedergaard, J., Lundberg, J. M., Hokfelt, T., Terenius, L., & Goldstein, M. (1986). 'Neuropeptide tyrosine' (NPY) is co-stored with noradrenaline in vascular but not in parenchymal sympathetic nerves of brown adipose tissue. Experimental Cell Research, 164(2), 546-550. https://doi.org/10.1016/0014-4827(86)90052-2 - PubMed
  9. Chen, K. Y., Brychta, R. J., Abdul Sater, Z., Cassimatis, T. M., Cero, C., Fletcher, L. A., Israni, N. S., Johnson, J. W., Lea, H. J., Linderman, J. D., O'Mara, A. E., Zhu, K. Y., & Cypess, A. M. (2020). Opportunities and challenges in the therapeutic activation of human energy expenditure and thermogenesis to manage obesity. Journal of Biological Chemistry, 295(7), 1926-1942. https://doi.org/10.1074/jbc.REV119.007363 - PubMed
  10. Chi, J., Wu, Z., Choi, C. H. J., Nguyen, L., Tegegne, S., Ackerman, S. E., Crane, A., Marchildon, F., Tessier-Lavigne, M., & Cohen, P. (2018). Three-dimensional adipose tissue imaging reveals regional variation in beige fat biogenesis and PRDM16-dependent sympathetic neurite density. Cell Metabolism, 27(1), 226-236. https://doi.org/10.1016/j.cmet.2017.12.011 - PubMed
  11. Cypess, A. M., Lehman, S., Williams, G., Tal, I., Rodman, D., Goldfine, A. B., Kuo, F. C., Palmer, E. L., Tseng, Y. H., Doria, A., Kolodny, G. M., & Kahn, C. R. (2009). Identification and importance of brown adipose tissue in adult humans. New England Journal of Medicine, 360(15), 1509-1517. https://doi.org/10.1056/NEJMoa0810780 - PubMed
  12. Ernsberger, U., & Rohrer, H. (2018). Sympathetic tales: Subdivisons of the autonomic nervous system and the impact of developmental studies. Neural Development, 13(1), 20. https://doi.org/10.1186/s13064-018-0117-6 - PubMed
  13. Fischer, A. W., Schlein, C., Cannon, B., Heeren, J., & Nedergaard, J. (2019). Intact innervation is essential for diet-induced recruitment of brown adipose tissue. American Journal of Physiology. Endocrinology and Metabolism, 316(3), E487-E503. https://doi.org/10.1152/ajpendo.00443.2018 - PubMed
  14. Foster, D. O., Depocas, F., & Zuker, M. (1982). Heterogeneity of the sympathetic innervation of rat interscapular brown adipose tissue via intercostal nerves. Canadian Journal of Physiology and Pharmacology, 60(6), 747-754. https://doi.org/10.1139/y82-104 - PubMed
  15. Foster, M. T., & Bartness, T. J. (2006). Sympathetic but not sensory denervation stimulates white adipocyte proliferation. American Journal of Physiology. Regulatory, Integrative and Comparative Physiology, 291(6), R1630-R1637. https://doi.org/10.1152/ajpregu.00197.2006 - PubMed
  16. François, M., Torres, H., Huesing, C., Zhang, R., Saurage, C., Lee, N., Qualls-Creekmore, E., Yu, S., Morrison, C. D., Burk, D., Berthoud, H. R., & Münzberg, H. (2019). Sympathetic innervation of the interscapular brown adipose tissue in mouse. Annals of the New York Academy of Sciences, 1454(1), 3-13. https://doi.org/10.1111/nyas.14119 - PubMed
  17. Glebova, N. O., & Ginty, D. D. (2005). Growth and survival signals controlling sympathetic nervous system development. Annual Review of Neuroscience, 28, 191-222. https://doi.org/10.1146/annurev.neuro.28.061604.135659 - PubMed
  18. Grujic, D., Susulic, V. S., Harper, M. E., Himms-Hagen, J., Cunningham, B. A., Corkey, B. E., & Lowell, B. B. (1997). Beta3-adrenergic receptors on white and brown adipocytes mediate beta3-selective agonist-induced effects on energy expenditure, insulin secretion, and food intake. A study using transgenic and gene knockout mice. Journal of Biological Chemistry, 272(28), 17686-17693. https://doi.org/10.1074/jbc.272.28.17686 - PubMed
  19. Hausman, G. J., & Richardson, R. L. (1987). Adrenergic innervation of fetal pig adipose tissue. Histochemical and ultrastructural studies. Acta Anatomica, 130(4), 291-297. https://doi.org/10.1159/000146460 - PubMed
  20. Howard, M. J. (2005). Mechanisms and perspectives on differentiation of autonomic neurons. Developmental Biology, 277(2), 271-286. https://doi.org/10.1016/j.ydbio.2004.09.034 - PubMed
  21. Huesing, C., Qualls-Creekmore, E., Lee, N., François, M., Torres, H., Zhang, R., Burk, D. H., Yu, S., Morrison, C. D., Berthoud, H. R., Neuhuber, W., & Münzberg, H. (2021). Sympathetic innervation of inguinal white adipose tissue in the mouse. J Comp Neurol, 529(7), 1465-1485. https://doi.org/10.1002/cne.25031 - PubMed
  22. Jeong, J. H., Chang, J. S., & Jo, Y. H. (2018). Intracellular glycolysis in brown adipose tissue is essential for optogenetically induced nonshivering thermogenesis in mice. Scientific Reports, 8(1), 6672. https://doi.org/10.1038/s41598-018-25265-3 - PubMed
  23. Kim, S. N., Jung, Y. S., Kwon, H. J., Seong, J. K., Granneman, J. G., & Lee, Y. H. (2016). Sex differences in sympathetic innervation and browning of white adipose tissue of mice. Biology of Sex Differences, 7, 67. https://doi.org/10.1186/s13293-016-0121-7 - PubMed
  24. Luff, S. E., McLachlan, E. M., & Hirst, G. D. (1987). An ultrastructural analysis of the sympathetic neuromuscular junctions on arterioles of the submucosa of the guinea pig ileum. Journal of Comparative Neurology, 257(4), 578-594. https://doi.org/10.1002/cne.902570407 - PubMed
  25. Lyons, C. E., Razzoli, M., Larson, E., Svedberg, D., Frontini, A., Cinti, S., Vulchanova, L., Sanders, M., Thomas, M., & Bartolomucci, A. (2020). Optogenetic-induced sympathetic neuromodulation of brown adipose tissue thermogenesis. Faseb Journal, 34(2), 2765-2773. https://doi.org/10.1096/fj.201901361RR - PubMed
  26. Meurers, B. H., Zhu, C., Fernagut, P. O., Richter, F., Hsia, Y. C., Fleming, S. M., Oh, M., Elashoff, D., Dicarlo, C. D., Seaman, R. L., & Chesselet, M. F. (2009). Low dose rotenone treatment causes selective transcriptional activation of cell death related pathways in dopaminergic neurons in vivo. Neurobiology of Disease, 33(2), 182-192. https://doi.org/10.1016/j.nbd.2008.10.001 - PubMed
  27. Munzberg, H., Floyd, E., & Chang, J. S. (2021). Sympathetic innervation of white adipose tissue: To beige or not to beige? Physiology (Bethesda, Md.), 36(4), 246-255. https://doi.org/10.1152/physiol.00038.2020 - PubMed
  28. Murano, I., Barbatelli, G., Giordano, A., & Cinti, S. (2009). Noradrenergic parenchymal nerve fiber branching after cold acclimatisation correlates with brown adipocyte density in mouse adipose organ. Journal of Anatomy, 214(1), 171-178. https://doi.org/10.1111/j.1469-7580.2008.01001.x - PubMed
  29. Nguyen, N. L. T., Xue, B., & Bartness, T. J. (2018). Sensory denervation of inguinal white fat modifies sympathetic outflow to white and brown fat in Siberian hamsters. Physiology & Behavior, 190, 28-33. https://doi.org/10.1016/j.physbeh.2018.02.019 - PubMed
  30. Nisoli, E., Tonello, C., Benarese, M., Liberini, P., & Carruba, M. O. (1996). Expression of nerve growth factor in brown adipose tissue: Implications for thermogenesis and obesity. Endocrinology, 137(2), 495-503. https://doi.org/10.1210/endo.137.2.8593794 - PubMed
  31. Peeraully, M. R., Jenkins, J. R., & Trayhurn, P. (2004). NGF gene expression and secretion in white adipose tissue: Regulation in 3T3-L1 adipocytes by hormones and inflammatory cytokines. American Journal of Physiology. Endocrinology and Metabolism, 287(2), E331-339. https://doi.org/10.1152/ajpendo.00076.2004 - PubMed
  32. Rahmouni, K., Morgan, D. A., Morgan, G. M., Liu, X., Sigmund, C. D., Mark, A. L., & Haynes, W. G. (2004). Hypothalamic PI3K and MAPK differentially mediate regional sympathetic activation to insulin. Journal of Clinical Investigation, 114(5), 652-658. https://doi.org/10.1172/JCI21737 - PubMed
  33. Renier, N., Wu, Z., Simon, D. J., Yang, J., Ariel, P., & Tessier-Lavigne, M. (2014). iDISCO: a simple, rapid method to immunolabel large tissue samples for volume imaging. Cell, 159(4), 896-910. https://doi.org/10.1016/j.cell.2014.10.010 - PubMed
  34. Schreiber, R., Diwoky, C., Schoiswohl, G., Feiler, U., Wongsiriroj, N., Abdellatif, M., Kolb, D., Hoeks, J., Kershaw, E. E., Sedej, S., Schrauwen, P., Haemmerle, G., & Zechner, R. (2017). Cold-induced thermogenesis depends on ATGL-mediated lipolysis in cardiac muscle, but not brown adipose tissue. Cell Metabolism, 26(5), 753-763. https://doi.org/10.1016/j.cmet.2017.09.004 - PubMed
  35. Shi, H., Song, C. K., Giordano, A., Cinti, S., & Bartness, T. J. (2005). Sensory or sympathetic white adipose tissue denervation differentially affects depot growth and cellularity. American Journal of Physiology. Regulatory, Integrative and Comparative Physiology, 288(4), R1028-R1037. https://doi.org/10.1152/ajpregu.00648.2004 - PubMed
  36. Shin, H., Ma, Y., Chanturiya, T., Cao, Q., Wang, Y., Kadegowda, A. K. G., Jackson, R., Rumore, D., Xue, B., Shi, H., Gavrilova, O., & Yu, L. (2017). Lipolysis in brown adipocytes is not essential for cold-induced thermogenesis in mice. Cell Metabolism, 26(5), 764-777. https://doi.org/10.1016/j.cmet.2017.09.002 - PubMed
  37. Thiede-Stan, N. K., & Schwab, M. E. (2015). Attractive and repulsive factors act through multi-subunit receptor complexes to regulate nerve fiber growth. Journal of Cell Science, 128(14), 2403-2414. https://doi.org/10.1242/jcs.165555 - PubMed
  38. Torres, H., Huesing, C., Burk, D. H., Molinas, A. J. R., Neuhuber, W. L., Berthoud, H. R., Münzberg, H., Derbenev, A. V., & Zsombok, A. (2021). Sympathetic innervation of the mouse kidney and liver arising from prevertebral ganglia. American Journal of Physiology. Regulatory, Integrative and Comparative Physiology, 321, R328-R337. https://doi.org/10.1152/ajpregu.00079.2021 - PubMed
  39. Tseng, Y. Y., Gruzdeva, N., Li, A., Chuang, J. Z., & Sung, C. H. (2010). Identification of the Tctex-1 regulatory element that directs expression to neural stem/progenitor cells in developing and adult brain. Journal of Comparative Neurology, 518(16), 3327-3342. https://doi.org/10.1002/cne.22402 - PubMed
  40. Umahara, Y. (1968). Light and electron microscopic studies on the brown adipose tissue in the bat. Archivum Histologicum Japonicum. Nippon Soshikigaku Kiroku, 29(5), 459-509. https://doi.org/10.1679/aohc1950.29.459 - PubMed
  41. van Marken Lichtenbelt, W. D., Vanhommerig, J. W., Smulders, N. M., Drossaerts, J. M., Kemerink, G. J., Bouvy, N. D., Schrauwen, P., & Teule, G. J.. (2009). Cold-activated brown adipose tissue in healthy men. New England Journal of Medicine, 360(15), 1500-1508. https://doi.org/10.1056/NEJMoa0808718 - PubMed
  42. Vaughan, C. H., Zarebidaki, E., Ehlen, J. C., & Bartness, T. J. (2014). Analysis and measurement of the sympathetic and sensory innervation of white and brown adipose tissue. Methods in Enzymology, 537, 199-225. https://doi.org/10.1016/B978-0-12-411619-1.00011-2 - PubMed
  43. Wang, P., Loh, K. H., Wu, M., Morgan, D. A., Schneeberger, M., Yu, X., Chi, J., Kosse, C., Kim, D., Rahmouni, K., Cohen, P., & Friedman, J. (2020). A leptin-BDNF pathway regulating sympathetic innervation of adipose tissue. Nature, 583(7818), 839-844. https://doi.org/10.1038/s41586-020-2527-y - PubMed
  44. Wiedmann, N. M., Stefanidis, A., & Oldfield, B. J. (2017). Characterization of the central neural projections to brown, white, and beige adipose tissue. Faseb Journal, 31(11), 4879-4890. https://doi.org/10.1096/fj.201700433R - PubMed
  45. Yu, S., Cheng, H., François, M., Qualls-Creekmore, E., Huesing, C., He, Y., Jiang, Y., Gao, H., Xu, Y., Zsombok, A., Derbenev, A. V., Nillni, E. A., Burk, D. H., Morrison, C. D., Berthoud, H. R., & Münzberg, H. (2018). Preoptic leptin signaling modulates energy balance independent of body temperature regulation. Elife, 7. e33505. https://doi.org/10.7554/eLife.33505 - PubMed
  46. Zeng, W., Pirzgalska, R. M., Pereira, M. M., Kubasova, N., Barateiro, A., Seixas, E., Lu, Y. H., Kozlova, A., Voss, H., Martins, G. G., Friedman, J. M., & Domingos, A. I. (2015). Sympathetic neuro-adipose connections mediate leptin-driven lipolysis. Cell, 163(1), 84-94. https://doi.org/10.1016/j.cell.2015.08.055 - PubMed
  47. Zeng, X., Ye, M., Resch, J. M., Jedrychowski, M. P., Hu, B., Lowell, B. B., Ginty, D. D., & Spiegelman, B. M. (2019). Innervation of thermogenic adipose tissue via a calsyntenin 3beta-S100b axis. Nature, 569(7755), 229-235. https://doi.org/10.1038/s41586-019-1156-9 - PubMed
  48. Zhang, Y., Kerman, I. A., Laque, A., Nguyen, P., Faouzi, M., Louis, G. W., Jones, J. C., Rhodes, C., & Münzberg, H. (2011). Leptin-receptor-expressing neurons in the dorsomedial hypothalamus and median preoptic area regulate sympathetic brown adipose tissue circuits. Journal of Neuroscience, 31(5), 1873-1884. https://doi.org/10.1523/JNEUROSCI.3223-10.2011 - PubMed
  49. Zingaretti, M. C., Crosta, F., Vitali, A., Guerrieri, M., Frontini, A., Cannon, B., Nedergaard, J., & Cinti, S. (2009). The presence of UCP1 demonstrates that metabolically active adipose tissue in the neck of adult humans truly represents brown adipose tissue. Faseb Journal, 23(9), 3113-3120. https://doi.org/10.1096/fj.09-133546 - PubMed

Publication Types

Grant support