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Adipocyte and Cell Biology

The armadillo-repeat containing X-linked protein 3, ARMCX3, is a negative regulator of the browning of adipose tissue associated with obesity




To determine the role of armadillo repeat-containing X-linked protein 3 (ARMCX3) in the thermogenic plasticity of adipose tissue.


Adipose tissues were characterized in Armcx3-KO male mice. Armcx3 gene expression was analyzed in adipose tissue from mice exposed to thermogenic inducers (cold, β3-adenergic stimulus) and in differentiating brown and beige cells in culture. Analyses encompassed circulating metabolite and hormonal profiling, tissue characterization, histology, gene expression patterns, and immunoblot assays. Armcx3 gene expression was assessed in subcutaneous adipose tissue from lean individuals and individuals with obesity and was correlated with expression of marker genes of adipose browning. The effects of adenoviral-mediated overexpression of ARMCX3 on differentiating brown adipocyte gene expression and respiratory activity were determined.


Male mice lacking ARMCX3 showed significant induction of white adipose tissue browning. In humans, ARMCX3 expression in subcutaneous adipose tissue was inversely correlated with the expression of marker genes of thermogenic activity, including CIDEA, mitochondrial transcripts, and creatine kinase-B. Armcx3 expression in adipose tissues was repressed by thermogenic activation (cold or β3-adrenergic stimulation) and was upregulated by obesity in mice and humans. Experimentally-induced increases in Armcx3 caused down-regulation of thermogenesis-related genes and reduced mitochondrial oxidative activity of adipocytes in culture, whereas siRNA-mediated Armcx3 knocking-down enhanced expression of thermogenesis-related genes.


ARMCX3 is a novel player in the control of thermogenic adipose tissue plasticity that acts to repress acquisition of the browning phenotype and shows a direct association with indicators of obesity in mice and humans.

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Fig. 1: Armcx3-KO mice are protected against HFD-induced obesity.
Fig. 2: Lack of Armcx3 promotes browning of subcutaneous WAT in mice.
Fig. 3: ARMCX3 expression in adipose tissues is upregulated in mouse and human obesity, and is negatively correlated with the expression of marker genes of browning.
Fig. 4: Induction of browning in vivo and differentiation of brown/beige adipocytes “in vitro” repress Armcx3 expression.
Fig. 5: Armcx3 overexpression impairs the differentiation and respiratory capacity of brown adipocytes.

Data availability

All data generated or analysed during this study are included in this published article and its supplementary information files.


  1. Giralt M, Villarroya F. White, brown, beige/brite: different adipose cells for different functions? Endocrinology. 2013;154:2992–3000.

    CAS  Article  Google Scholar 

  2. Cannon B, Nedergaard J. Brown adipose tissue: function and physiological significance. Physiol Rev. 2004;84:277–359.

    CAS  Article  Google Scholar 

  3. Shabalina IG, Petrovic N, deJong JMA, Kalinovich AV, Cannon B, Nedergaard J. UCP1 in Brite/Beige adipose tissue mitochondria is functionally thermogenic. Cell Rep. 2013;5:1196–203.

    CAS  Article  Google Scholar 

  4. Kazak L, Chouchani ET, Jedrychowski MP, Erickson BK, Shinoda K, Cohen P, et al. A creatine-driven substrate cycle enhances energy expenditure and thermogenesis in beige fat. Cell. 2015;163:643–55.

    CAS  Article  Google Scholar 

  5. Xue B, Rim JS, Hogan JC, Coulter AA, Koza RA, Kozak LP. Genetic variability affects the development of brown adipocytes in white fat but not in interscapular brown fat. J Lipid Res. 2007;48:41–51.

    CAS  Article  Google Scholar 

  6. Cohen P, Kajimura S. The cellular and functional complexity of thermogenic fat. Nat Rev Mol Cell Biol. 2021;22:393–409.

    CAS  Article  Google Scholar 

  7. Huang Y, Jiang Z, Gao X, Luo P, Jiang X. ARMC subfamily: structures, functions, evolutions, interactions, and diseases. Front Mol Biosci. 2021;8:1190.

    Google Scholar 

  8. López-Doménech G, Serrat R, Mirra S, D’Aniello S, Somorjai I, Abad A, et al. The Eutherian Armcx genes regulate mitochondrial trafficking in neurons and interact with Miro and Trak2. Nat Commun. 2012;3.

  9. Serrat R, López-Doménech G, Mirra S, Quevedo M, Garcia-Fernàndez J, Ulloa F, et al. The non-canonical Wnt/PKC pathway regulates mitochondrial dynamics through degradation of the arm-like domain-containing protein Alex3. PLoS One. 2013;8.

  10. Mirra S, Gavaldà-Navarro A, Manso Y, Higuera M, Serrat R, Salcedo MT, et al. ARMCX3 mediates susceptibility to hepatic tumorigenesis promoted by dietary lipotoxicity. Cancers. 2021;13:1–22.

    Article  Google Scholar 

  11. Chen Y, Wu Z, Zhao S, Xiang R. Chemical chaperones reduce ER stress and adipose tissue inflammation in high fat diet-induced mouse model of obesity. Sci Rep. 2016;6:27486.

    CAS  Article  Google Scholar 

  12. Wang H, Willershäuser M, Karlas A, Gorpas D, Reber J, Ntziachristos V, et al. A dual Ucp1 reporter mouse model for imaging and quantitation of brown and brite fat recruitment. Mol Metab. 2019;20:14–27.

    CAS  Article  Google Scholar 

  13. Gonzalez-Hurtado E, Lee J, Choi J, Wolfgang MJ. Fatty acid oxidation is required for active and quiescent brown adipose tissue maintenance and thermogenic programing. Mol Metab. 2018;7:45–56.

    CAS  Article  Google Scholar 

  14. Oeckl J, Bast-Habersbrunner A, Fromme T, Klingenspor M, Li Y. Isolation, culture, and functional analysis of murine thermogenic adipocytes. STAR Protoc. 2020;1:100118.

    Article  Google Scholar 

  15. Clookey SL, Welly RJ, Shay D, Woodford ML, Fritsche KL, Rector RS, et al. Beta 3 adrenergic receptor activation rescues metabolic dysfunction in female estrogen receptor alpha-null mice. Front Physiol. 2019;10.

  16. Mirra S, Ulloa F, Gutierrez-Vallejo I, Martì E, Soriano E, Function of Armcx3 and Armc10/SVH genes in the regulation of progenitor proliferation and neural differentiation in the chicken spinal cord. Front Cell Neurosci. 2016;10.

  17. de Winter TJJ, Nusse R, Running Against the Wnt: How Wnt/β-Catenin suppresses adipogenesis. Front Cell Dev Biol. 2021;9.

  18. Longo KA, Wright WS, Kang S, Gerin I, Chiang SH, Lucas PC, et al. Wnt10b inhibits development of white and brown adipose tissues. J Biol Chem. 2004;279:35503–9.

    CAS  Article  Google Scholar 

  19. Gulyaeva O, Nguyen H, Sambeat A, Heydari K, Sul HS. Sox9-Meis1 inactivation is required for adipogenesis, advancing Pref-1 + to PDGFRα + Cells. Cell Rep. 2018;25:1002–17.e4.

    CAS  Article  Google Scholar 

  20. Whittle AJ, Jiang M, Peirce V, Relat J, Virtue S, Ebinuma H, et al. Soluble LR11/SorLA represses thermogenesis in adipose tissue and correlates with BMI in humans. Nat Commun. 2015;6.

  21. Peyrou M, Cereijo R, Quesada-López T, Campderrós L, Gavaldà-Navarro A, Liñares-Pose L, et al. The kallikrein-kinin pathway as a mechanism for auto-control of brown adipose tissue activity. Nat Commun. 2020;11.

  22. Rhee M, Kim JW, Lee MW, Yoon KH, Lee SH, Preadipocyte factor 1 regulates adipose tissue browning via TNF-α-converting enzyme-mediated cleavage. Metab - Clin Exp. 2019;101.

  23. Armengol J, Villena JA, Hondares E, Carmona MC, Sul HS, Iglesias R, et al. Pref-1 in brown adipose tissue: specific involvement in brown adipocyte differentiation and regulatory role of C/EBPδ. Biochem J. 2012;443:799–810.

    CAS  Article  Google Scholar 

  24. Alipoor E, Hosseinzadeh-Attar MJ, Rezaei M, Jazayeri S, Chapman M. White adipose tissue browning in critical illness: A review of the evidence, mechanisms and future perspectives. Obes Rev. 2020;21:e13085.

    Article  Google Scholar 

  25. Cereijo R, Quesada-López T, Gavaldà-Navarro A, Tarascó J, Pellitero S, Reyes M. et al. The chemokine CXCL14 is negatively associated with obesity and concomitant type-2 diabetes in humans. Int J Obes. 2021;45:706–10.

    CAS  Article  Google Scholar 

  26. Campderrós L, Moure R, Cairó M, Gavaldà-Navarro A, Quesada-López T, Cereijo R, et al. Brown adipocytes secrete GDF15 in response to thermogenic activation. Obesity. 2019;27:1606–16.

    Article  Google Scholar 

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The authors acknowledge A. Peró and M. Morales for technical support. This work was funded by the Ministerio de Ciencia e Innovación/Agencia Estatal de Investigación (10.13039/501100011033 and PID2020-114112RB-I00 to FV; SAF2016-76340R and PID2019-106764RB-C21 to ES), María de Maeztu Excellence program to ES, Instituto de Salud Carlos III (CIBERNED) to ES, Marató de TV3 Foundation (grant 201337-30-31-32) to ES, and Ministerio de Economía, Industria y Competitividad (PI17/01455) to D.S-I.

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AG-N, SM and YM conducted and analyzed the experiments. AG-N, DS-I, MG and FV obtained and analyzed data from human subjects. AG-N, MG, ES and FV conceived the study and interpreted the data. AG-N and FV wrote the manuscript. All authors critically reviewed and edited the manuscript.

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Correspondence to Aleix Gavaldà-Navarro.

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Gavaldà-Navarro, A., Mirra, S., Manso, Y. et al. The armadillo-repeat containing X-linked protein 3, ARMCX3, is a negative regulator of the browning of adipose tissue associated with obesity. Int J Obes (2022).

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