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Cited by 49Adipose Tissue and MetabolismMicroRNA in disease regulationNeuroscience of respiration and sleep

microRNA-33 maintains adaptive thermogenesis via enhanced sympathetic nerve activity

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Horie, Takahiro, Nakao, Tetsushi, Miyasaka, Yui, Nishino, Tomohiro, Matsumura, Shigenobu, Nakazeki, Fumiko, Ide, Yuya, Kimura, Masahiro +25 more·2021·Nature Communications
DOI 10.1038/s41467-021-21107-5PMC PMC7886914
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Abstract

Adaptive thermogenesis is essential for survival, and therefore is tightly regulated by a central neural circuit. Here, we show that microRNA (miR)-33 in the brain is indispensable for adaptive thermogenesis. Cold stress increases miR-33 levels in the hypothalamus and miR-33−/− mice are unable to maintain body temperature in cold environments due to reduced sympathetic nerve activity and impaired brown adipose tissue (BAT) thermogenesis. Analysis of miR-33 f/f dopamine-β-hydroxylase (DBH)-Cre mice indicates the importance of miR-33 in Dbh-positive cells. Mechanistically, miR-33 deficiency upregulates gamma-aminobutyric acid (GABA)A receptor subunit genes such as Gabrb2 and Gabra4. Knock-down of these genes in Dbh-positive neurons rescues the impaired cold-induced thermogenesis in miR-33 f/fDBH-Cre mice. Conversely, increased gene dosage of miR-33 in mice enhances thermogenesis. Thus, miR-33 in the brain contributes to maintenance of BAT thermogenesis and whole-body metabolism via enhanced sympathetic nerve tone through suppressing GABAergic inhibitory neurotransmission. This miR-33-mediated neural mechanism may serve as a physiological adaptive defense mechanism for several stresses including cold stress.

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  • miR-33a deficiency decreases sympathetic nervous activity through the activation of GABAergic inhibitory neurons, mediated by the enhanced expression of GABAA receptor subunits such as GABRB2 and GABRA4, which leads to reduced adaptive thermogenesis primarily in brown adipose tissue (BAT) and contributes to obesity.

    “MiR-33a deficiency decreases sympathetic nervous activity through the activation of GABAergic inhibitory neurons, mediated by the enhanced expression of GABAA receptor subunits, such as GABRB2 and GABRA4, which leads to reduced adaptive thermogenesis primarily in brown adipose tissue (BAT) and contributes to obesity 43) .”

    From Critical Role of microRNA-33a/b in Cardiovascular and Metabolic Disease: Molecular Mechanisms and Therapeutic Perspectives (2026) · cites this paper as [43]

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References 62 · Cited by 49

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  1. [2]Peirce V Carobbio S Vidal-Puig A The different shades of fat Nature 2014 510 76 83 10.1038/nature13477 24899307 · DOI
  2. [3]van Marken Lichtenbelt WD Cold-activated brown adipose tissue in healthy men N. Engl. J. Med. 2009 360 1500 1508 10.1056/NEJMoa0808718 19357405 · DOI · Paper page
  3. [4]Cypess AM Identification and importance of brown adipose tissue in adult humans N. Engl. J. Med. 2009 360 1509 1517 10.1056/NEJMoa0810780 19357406 PMC2859951 · DOI · Paper page
  4. [5]Virtanen KA Functional brown adipose tissue in healthy adults N. Engl. J. Med. 2009 360 1518 1525 10.1056/NEJMoa0808949 19357407 · DOI · Paper page
  5. [6]Morrison SF Nakamura K Central mechanisms for thermoregulation Annu. Rev. Physiol. 2019 81 285 308 10.1146/annurev-physiol-020518-114546 30256726 · DOI
  6. [7]Morrison SF Madden CJ Tupone D Central neural regulation of brown adipose tissue thermogenesis and energy expenditure Cell Metab. 2014 19 741 756 10.1016/j.cmet.2014.02.007 24630813 PMC4016184 · DOI
  7. [8]Bartel DP MicroRNAs: genomics, biogenesis, mechanism, and function Cell 2004 116 281 297 10.1016/S0092-8674(04)00045-5 14744438 · DOI
  8. [9]Goody D Pfeifer A MicroRNAs in brown and beige fat Biochim. Biophys. Acta Mol. Cell Biol. Lipids 2019 1864 29 36 10.1016/j.bbalip.2018.05.003 29758288 · DOI · Paper page
  9. [11]Rayner KJ MiR-33 contributes to the regulation of cholesterol homeostasis Science 2010 328 1570 1573 10.1126/science.1189862 20466885 PMC3114628 · DOI · Paper page
  10. [12]Horie T MicroRNA-33 encoded by an intron of sterol regulatory element-binding protein 2 (Srebp2) regulates HDL in vivo Proc. Natl Acad. Sci. USA 2010 107 17321 17326 10.1073/pnas.1008499107 20855588 PMC2951399 · DOI · Paper page
  11. [14]Horie T MicroRNA-33 deficiency reduces the progression of atherosclerotic plaque in ApoE-/- mice J. Am. Heart Assoc. 2012 1 e003376 10.1161/JAHA.112.003376 23316322 PMC3540673 · DOI · Paper page
  12. [15]Nakao T Genetic ablation of microRNA-33 attenuates inflammation and abdominal aortic aneurysm formation via several anti-inflammatory pathways Arterioscler. Thromb. Vasc. Biol. 2017 37 2161 2170 10.1161/ATVBAHA.117.309768 28882868 · DOI · Paper page
  13. [17]Nishino T SREBF1/microRNA-33b axis exhibits potent effect on unstable atherosclerotic plaque formation in vivo Arterioscler. Thromb. Vasc. Biol. 2018 38 2460 2473 10.1161/ATVBAHA.118.311409 30354203 · DOI · Paper page
  14. [18]Rayner KJ Inhibition of miR-33a/b in non-human primates raises plasma HDL and lowers VLDL triglycerides Nature 2011 478 404 407 10.1038/nature10486 22012398 PMC3235584 · DOI · Paper page
  15. [19]Rottiers V Pharmacological inhibition of a microRNA family in nonhuman primates by a seed-targeting 8-mer antimiR Sci. Transl. Med. 2013 5 212ra162 10.1126/scitranslmed.3006840 24259050 PMC4033576 · DOI · Paper page
  16. [23]von Essen G Lindsund E Cannon B Nedergaard J Adaptive facultative diet-induced thermogenesis in wild-type but not in UCP1-ablated mice Am. J. Physiol. Endocrinol. Metab. 2017 313 E515 E527 10.1152/ajpendo.00097.2017 28679625 · DOI
  17. [25]Tsukita S Hepatic glucokinase modulates obesity predisposition by regulating BAT thermogenesis via neural signals Cell Metab. 2012 16 825 832 10.1016/j.cmet.2012.11.006 23217261 · DOI
  18. [27]Harms M Seale P Brown and beige fat: development, function and therapeutic potential Nat. Med. 2013 19 1252 1263 10.1038/nm.3361 24100998 · DOI · Paper page
  19. [28]Vaughan CH Zarebidaki E Ehlen JC Bartness TJ Analysis and measurement of the sympathetic and sensory innervation of white and brown adipose tissue Methods Enzymol. 2014 537 199 225 10.1016/B978-0-12-411619-1.00011-2 24480348 PMC4004027 · DOI
  20. [29]Nakamura K Identification of sympathetic premotor neurons in medullary raphe regions mediating fever and other thermoregulatory functions J. Neurosci. 2004 24 5370 5380 10.1523/JNEUROSCI.1219-04.2004 15190110 PMC6729310 · DOI
  21. [30]Rzechorzek NM Connick P Patani R Selvaraj BT Chandran S Hypothermic preconditioning of human cortical neurons requires proteostatic priming EBioMedicine 2015 2 528 535 10.1016/j.ebiom.2015.04.004 26287272 PMC4534756 · DOI
  22. [31]Sun Y Endoplasmic reticulum stress affects lipid metabolism in atherosclerosis via CHOP activation and over-expression of miR-33 Cell Physiol. Biochem. 2018 48 1995 2010 10.1159/000492522 30092598 · DOI
  23. [32]Feng X Lin YL Wei LN Behavioral stress reduces RIP140 expression in astrocyte and increases brain lipid accumulation Brain Behav. Immun. 2015 46 270 279 10.1016/j.bbi.2015.02.008 25697398 PMC4414809 · DOI
  24. [33]Ramirez S Claret M Hypothalamic ER stress: a bridge between leptin resistance and obesity FEBS Lett. 2015 589 1678 1687 10.1016/j.febslet.2015.04.025 25913783 · DOI
  25. [34]Matsushita N Kobayashi K Miyazaki J Kobayashi K Fate of transient catecholaminergic cell types revealed by site-specific recombination in transgenic mice J. Neurosci. Res. 2004 78 7 15 10.1002/jnr.20229 15372500 · DOI
  26. [35]Jovasevic V GABAergic mechanisms regulated by miR-33 encode state-dependent fear Nat. Neurosci. 2015 18 1265 1271 10.1038/nn.4084 26280760 PMC4880671 · DOI · Paper page
  27. [36]Nakazeki F MiR-33a is a therapeutic target in SPG4-related hereditary spastic paraplegia human neurons Clin. Sci. 2019 133 583 595 10.1042/CS20180980 30777884 · DOI
  28. [38]Kim, J. Y., Grunke, S. D., Levites, Y., Golde, T. E. & Jankowsky, J. L. Intracerebroventricular viral injection of the neonatal mouse brain for persistent and widespread neuronal transduction. J. Vis. Exp. 10.3791/51863 (2014). PMC4199253 25286085 · DOI
  29. [40]Calarco, C. A. et al. Molecular and cellular characterization of nicotinic acetylcholine receptor subtypes in the arcuate nucleus of the mouse hypothalamus. Eur. J. Neurosci.10.1111/ejn.13966 (2018). PMC6251769 29791746 · DOI · Paper page
  30. [41]Nakamura Y Nakamura K Central regulation of brown adipose tissue thermogenesis and energy homeostasis dependent on food availability Pflug. Arch. 2018 470 823 837 10.1007/s00424-017-2090-z PMC5942360 29209779 · DOI
  31. [42]Cano G Anatomical substrates for the central control of sympathetic outflow to interscapular adipose tissue during cold exposure J. Comp. Neurol. 2003 460 303 326 10.1002/cne.10643 12692852 · DOI
  32. [43]Kataoka N Hioki H Kaneko T Nakamura K Psychological stress activates a dorsomedial hypothalamus-medullary raphe circuit driving brown adipose tissue thermogenesis and hyperthermia Cell Metab. 2014 20 346 358 10.1016/j.cmet.2014.05.018 24981837 · DOI
  33. [44]Nakamura K Morrison SF Central efferent pathways for cold-defensive and febrile shivering J. Physiol. 2011 589 3641 3658 10.1113/jphysiol.2011.210047 21610139 PMC3167123 · DOI · Paper page
  34. [45]Madden CJ Morrison SF Excitatory amino acid receptors in the dorsomedial hypothalamus mediate prostaglandin-evoked thermogenesis in brown adipose tissue Am. J. Physiol. Regul. Integr. Comp. Physiol. 2004 286 R320 R325 10.1152/ajpregu.00515.2003 14563660 · DOI
  35. [46]Colgan SM Tang D Werstuck GH Austin RC Endoplasmic reticulum stress causes the activation of sterol regulatory element binding protein-2 Int. J. Biochem. Cell Biol. 2007 39 1843 1851 10.1016/j.biocel.2007.05.002 17604677 · DOI
  36. [47]Sato R Sterol-dependent transcriptional regulation of sterol regulatory element-binding protein-2 J. Biol. Chem. 1996 271 26461 26464 10.1074/jbc.271.43.26461 8900111 · DOI
  37. [48]Rottiers V Naar AM MicroRNAs in metabolism and metabolic disorders Nat. Rev. Mol. Cell Biol. 2012 13 239 250 10.1038/nrm3313 22436747 PMC4021399 · DOI · Paper page
  38. [49]Ono K MicroRNA-33a/b in lipid metabolism—novel “thrifty” models Circ. J. 2015 79 278 284 10.1253/circj.CJ-14-1252 25744742 · DOI
  39. [51]Dutta P Myocardial infarction accelerates atherosclerosis Nature 2012 487 325 329 10.1038/nature11260 22763456 PMC3401326 · DOI
  40. [54]Malpas SC Sympathetic nervous system overactivity and its role in the development of cardiovascular disease Physiol. Rev. 2010 90 513 557 10.1152/physrev.00007.2009 20393193 · DOI
  41. [55]Koyama S Identification of differential roles of microRNA-33a and -33b during atherosclerosis progression with genetically modified mice J. Am. Heart Assoc. 2019 8 e012609 10.1161/JAHA.119.012609 31242815 PMC6662357 · DOI · Paper page
  42. [56]Damiano F Alemanno S Gnoni GV Siculella L Translational control of the sterol-regulatory transcription factor SREBP-1 mRNA in response to serum starvation or ER stress is mediated by an internal ribosome entry site Biochem. J. 2010 429 603 612 10.1042/BJ20091827 20513236 · DOI
  43. [57]Nakamura Y Yanagawa Y Morrison SF Nakamura K Medullary reticular neurons mediate neuropeptide Y-induced metabolic inhibition and mastication Cell Metab. 2017 25 322 334 10.1016/j.cmet.2016.12.002 28065829 PMC5299028 · DOI
  44. [58]Nishiga M MicroRNA-33 controls adaptive fibrotic response in the remodeling heart by preserving lipid raft cholesterol Circ. Res. 2017 120 835 847 10.1161/CIRCRESAHA.116.309528 27920122 · DOI
  45. [59]Hiraoka Y Critical roles of nardilysin in the maintenance of body temperature homoeostasis Nat. Commun. 2014 5 3224 10.1038/ncomms4224 24492630 PMC3926010 · DOI
  46. [60]Kwong SC Jamil AHA Rhodes A Taib NA Chung I Metabolic role of fatty acid binding protein 7 in mediating triple-negative breast cancer cell death via PPAR-alpha signaling J. Lipid Res. 2019 60 1807 1817 10.1194/jlr.M092379 31484694 PMC6824484 · DOI
  47. [61]Takahashi K Induction of pluripotent stem cells from adult human fibroblasts by defined factors Cell 2007 131 861 872 10.1016/j.cell.2007.11.019 18035408 · DOI · Paper page

Authors
Horie, T., Nakao, T., Miyasaka, Y., Nishino, T., Matsumura, S., Nakazeki, F., Ide, Y., Kimura, M., Tsuji, S., Rodriguez, R. R., Watanabe, T., Yamasaki, T., Xu, S., Otani, C., Miyagawa, S., Matsushita, K., Sowa, N., Omori, A., Tanaka, J., Nishimura, C., Nishiga, M., Kuwabara, Y., Baba, O., Watanabe, S., Nishi, H., Nakashima, Y., Picciotto, M. R., Inoue, H., Watanabe, D., Nakamura, K., Sasaki, T., Kimura, T., & Ono, K.
Affiliations
  • Kyoto University (JP)
  • Yale University (US)
  • Nagoya University (JP)
Corresponding author
  • Horie, Takahiro
  • Ono, Koh
ORCID
Venue
Nature Communications
Publisher
Springer Science and Business Media LLC
Published
2021-02-16
Volume
12
Issue
1
Pages
843-843
ISSN
2041-1723 (ISSN-L)
DOI
10.1038/s41467-021-21107-5
PMC
PMC7886914
OpenAlex
W3132727719
Cited by
49
References
62
Citations by year
2026: 5 · 2025: 7 · 2024: 9 · 2023: 7 · 2022: 7 · 2021: 14
FWCI
5.80
Type
journal article
Language
en
Open access
Licence
Locations
  • Nature Communications (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • Institutional Repositories DataBase (IRDB) (submittedVersion, cc-by)
  • RePEc: Research Papers in Economics (submittedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
  • Kyoto University Research Information Repository (Kyoto University) (submittedVersion, cc-by)
Funders
  • MEXT | Japan Society for the Promotion of Science (17H05599, 20H03675)
  • Japan Agency for Medical Research and Development (JP19fk0210112)
Topics
  • Health Sciences › Medicine › Physiology › Adipose Tissue and Metabolism
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › MicroRNA in disease regulation
  • Life Sciences › Neuroscience › Endocrine and Autonomic Systems › Neuroscience of respiration and sleep
Keywords
microRNA-33, adaptive thermogenesis, brown adipose tissue, sympathetic activity, cold stress, hypothalamus, GABAergic inhibition, GABAA receptor subunits, GABRB2, GABRA4, thermoregulation, whole-body metabolism
MeSH terms
Animals, Body Temperature, Body Weight, Brain, Adipose Tissue, Brown, Cell Line, Cold Temperature, Humans, Male, Mice, Obese, Oxygen Consumption, Phenotype, Receptors, GABA-A, Sympathetic Nervous System, Integrases, Protein Subunits, Thermogenesis, MicroRNAs, Mice, Diet, High-Fat, Endoplasmic Reticulum Stress

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