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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

Subjects

Abstract

Objectives

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

Methods

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.

Results

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.

Conclusion

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.

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Acknowledgements

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.

Corresponding author

Correspondence to Aleix Gavaldà-Navarro.

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The authors declare no competing interests.

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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 46, 1652–1661 (2022). https://doi.org/10.1038/s41366-022-01169-1

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