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Cited by 21Adipose Tissue and MetabolismMicroRNA in disease regulationPeroxisome Proliferator-Activated Receptors

MicroRNA-33 Inhibits Adaptive Thermogenesis and Adipose Tissue Beiging

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Afonso, Milessa Silva, Verma, Narendra, van Solingen, Coen, Cyr, Yannick, Sharma, Monika, Perie, Luce, Corr, Emma M., Schlegel, Martin +6 more·2021·Arteriosclerosis, Thrombosis, and Vascular Biology
DOI 10.1161/atvbaha.120.315798PMC PMC8011606
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Abstract

Objective: Recent studies have identified key transcriptional regulators of brown adipose tissue (BAT) differentiation and function, but posttranscriptional control of this network by microRNAs remains incompletely understood. MiR-33 critically regulates genes involved in metabolic pathways, including cholesterol efflux, reverse cholesterol transport, fatty acid oxidation, and autophagy. Given its role in metabolic homeostasis, we investigated whether miR-33 participates in the regulation of BAT activity, white adipose beiging, and adaptive thermogenesis. Approach and Results: Using primary immortalized brown adipocytes and 10T1/2 cells, we show that miR-33 levels are reduced in brown fat differentiated cells compared with preadipocytes and in response to thermogenic activators. Furthermore, in mice exposed to cold, levels of miR-33 in BAT are rapidly downregulated consistent with a role for miR-33 in repressing adaptive thermogenesis. Using in silico prediction, we identified numerous putative miR-33 target genes in the thermogenic pathway conserved in mice and humans, including regulators of brown adipocyte differentiation and function and mitochondrial activity. We focused our investigation on transcriptional regulators of UCP1 (uncoupling protein 1) and of BAT-enriched genes and demonstrate that miR-33 represses Zfp516 , Dio2 , and Ppargc1a in vitro and in vivo. Treatment of mice with inhibitors of miR-33 increased expression of these miR-33 target genes in brown and subcutaneous white adipose tissue, upregulating expression of UCP1, and rendering mice resistant to cold challenge. Conclusions: Collectively, our findings demonstrate that miR-33 targets key genes involved in BAT activation and white adipose beiging and expand our understanding of how miR-33 coordinately regulates pathways involved in metabolic homeostasis.

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Crossref · 10.1161/atvbaha.120.315798

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  • Inhibition of miR-33a enhances BAT activity by upregulating UCP1-associated target genes such as Znf516, Dio2, and Ppargc1a.

    “In contrast, studies focusing solely on BAT have reported that inhibition of miR-33a enhances its activity by upregulating UCP1-associated target genes, such as Znf516, Dio2, and Ppargc1a 44) .”

    From Critical Role of microRNA-33a/b in Cardiovascular and Metabolic Disease: Molecular Mechanisms and Therapeutic Perspectives (2026) · cites this paper as [44]

    The Discussion reports that miR-33 inhibition increased BAT UCP1 expression by derepressing Ppargc1a, Zfp516, and Dio2. However, the study also examined subcutaneous white adipose tissue, so the citing sentence’s description of it as focusing solely on BAT is inaccurate. The paper calls the mouse target Zfp516, not Znf516. (LLM, conf=0.86)

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Cited by

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Authors
Afonso, M. S., Verma, N., van Solingen, C., Cyr, Y., Sharma, M., Perie, L., Corr, E. M., Schlegel, M., Shanley, L. C., Peled, D., Yoo, J. Y., Schmidt, A. M., Mueller, E., & Moore, K. J.
Affiliations
  • NYU Langone Health (US)
  • New York University (US)
  • Leon H. Charney Division of Cardiology, Department of Medicine (M.S.A., C.v.S., Y.C., M. Sharma, E.M.C., M. Schlegel, L.C.S., D.P., J.Y.Y., K.J.M.), New York University School of Medicine.
  • Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, New York University (N.V., L.P., A.M.S., E.M.).
ORCID
Venue
Arteriosclerosis, Thrombosis, and Vascular Biology
Publisher
Ovid Technologies (Wolters Kluwer Health)
Published
2021-04
Volume
41
Issue
4
Pages
1360-1373
ISSN
  • 1079-5642 (ISSN-L)
  • 1524-4636
DOI
10.1161/atvbaha.120.315798
PMC
PMC8011606
OpenAlex
W3133700052
Cited by
21
References
13
Citations by year
2026: 2 · 2025: 5 · 2024: 3 · 2023: 3 · 2022: 7 · 2021: 1
FWCI
2.20
Type
journal article
Language
en
Open access
Locations
  • Arteriosclerosis Thrombosis and Vascular Biology (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
Funders
National Heart, Lung, and Blood Institute (R01HL129433, R35HL135799, R01HL119047, T32HL098129, P01HL131481)
Topics
  • Health Sciences › Medicine › Physiology › Adipose Tissue and Metabolism
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › MicroRNA in disease regulation
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Peroxisome Proliferator-Activated Receptors
Keywords
miR-33, brown adipose tissue, adaptive thermogenesis, UCP1, DIO2, PGC-1α, cold exposure, brown adipocyte differentiation, miRNA target genes, mitochondrial activity, metabolic homeostasis
MeSH terms
Adipose Tissue, Beige, Adipocytes, Beige, Uncoupling Protein 1, Animals, Adipose Tissue, Brown, Energy Metabolism, Gene Expression Regulation, Humans, Male, Mice, Inbred C57BL, Signal Transduction, Thermogenesis, MicroRNAs, Adipogenesis, Mice, Adipose Tissue, White, Adipocytes, Brown, Adipocytes, White, Gene Regulatory Networks, HEK293 Cells

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