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Mammary ductal epithelium controls cold-induced adipocyte thermogenesis

Luis C. Santos, Douglas Arneson, Alexandra Alvarsson, Karthickeyan Chella Krishnan, Alessia Centzone, Sanil Patel, Shani Sadeh, In Sook Ahn, Graciel Diamante, Ingrid Cely, Atul J. Butte, Cédric Blanpain, Sarah A. Stanley, Aldons J. Lusis, Xia Yang, Prashant Rajbhandari
doi: https://doi.org/10.1101/2020.11.14.378687
Luis C. Santos
1Diabetes, Obesity, and Metabolism Institute, Icahn School of Medicine at Mount Sinai, New York, NY USA
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Douglas Arneson
2Bakar Computational Health Sciences Institute, University of California, San Francisco, CA USA
5Department of Integrative Biology and Physiology and Bioinformatics Interdepartmental Program, University of California, Los Angeles, CA USA
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Alexandra Alvarsson
1Diabetes, Obesity, and Metabolism Institute, Icahn School of Medicine at Mount Sinai, New York, NY USA
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Karthickeyan Chella Krishnan
3Department of Medicine/Division of Cardiology and Department of Human Genetics, University of California, Los Angeles, CA USA
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Alessia Centzone
4Laboratory of Stem Cells and Cancer, Université Libre de Bruxelles (ULB), Brussels, Belgium
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Sanil Patel
1Diabetes, Obesity, and Metabolism Institute, Icahn School of Medicine at Mount Sinai, New York, NY USA
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Shani Sadeh
1Diabetes, Obesity, and Metabolism Institute, Icahn School of Medicine at Mount Sinai, New York, NY USA
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In Sook Ahn
5Department of Integrative Biology and Physiology and Bioinformatics Interdepartmental Program, University of California, Los Angeles, CA USA
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Graciel Diamante
5Department of Integrative Biology and Physiology and Bioinformatics Interdepartmental Program, University of California, Los Angeles, CA USA
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Ingrid Cely
5Department of Integrative Biology and Physiology and Bioinformatics Interdepartmental Program, University of California, Los Angeles, CA USA
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Atul J. Butte
2Bakar Computational Health Sciences Institute, University of California, San Francisco, CA USA
6Department of Pediatrics, University of California, San Francisco, CA, USA
7Center for Data-Driven Insights and Innovation, University of California Health, Oakland, CA, USA
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Cédric Blanpain
5Department of Integrative Biology and Physiology and Bioinformatics Interdepartmental Program, University of California, Los Angeles, CA USA
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Sarah A. Stanley
1Diabetes, Obesity, and Metabolism Institute, Icahn School of Medicine at Mount Sinai, New York, NY USA
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Aldons J. Lusis
3Department of Medicine/Division of Cardiology and Department of Human Genetics, University of California, Los Angeles, CA USA
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Xia Yang
5Department of Integrative Biology and Physiology and Bioinformatics Interdepartmental Program, University of California, Los Angeles, CA USA
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Prashant Rajbhandari
1Diabetes, Obesity, and Metabolism Institute, Icahn School of Medicine at Mount Sinai, New York, NY USA
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  • For correspondence: prashant.rajbhandari@mssm.edu
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ABSTRACT

Sympathetic activation during cold exposure increases adipocyte thermogenesis via expression of mitochondrial protein uncoupling protein 1 (UCP1)1. The propensity of adipocytes to express UCP1 is under a critical influence of the adipose microenvironment and varies among various fat depots2–7. Here we report that cold-induced adipocyte UCP1 expression in female mouse subcutaneous white adipose tissue (scWAT) is regulated by mammary gland ductal epithelial cells in the adipose niche. Single cell RNA-sequencing (scRNA-seq) show that under cold condition glandular alveolar and hormone-sensing luminal epithelium subtypes express transcripts that encode secretory factors involved in regulating adipocyte UCP1 expression. We term mammary duct secretory factors as “mammokines”. Using whole-tissue immunofluorescence 3D visualization, we reveal previously undescribed sympathetic nerve-ductal points of contact and show that sympathetic nerve-activated mammary ducts limit adipocyte UCP1 expression via cold-induced mammokine production. Both in vivo and ex vivo ablation of mammary ductal epithelium enhances cold-induced scWAT adipocyte thermogenic gene program. The mammary duct network extends throughout most scWATs in female mice, which under cold exposure show markedly less UCP1 expression, fat oxidation, energy expenditure, and subcutaneous fat mass loss compared to male mice. These results show a previously uncharacterized role of sympathetic nerve-activated glandular epithelium in adipocyte thermogenesis. Overall, our findings suggest an evolutionary role of mammary duct luminal cells in defending glandular adiposity during cold exposure, highlight mammary gland epithelium as a highly active metabolic cell type, and implicate a broader role of mammokines in mammary gland physiology and systemic metabolism.

Competing Interest Statement

The authors have declared no competing interest.

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The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY 4.0 International license.
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Posted December 17, 2021.
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Mammary ductal epithelium controls cold-induced adipocyte thermogenesis
Luis C. Santos, Douglas Arneson, Alexandra Alvarsson, Karthickeyan Chella Krishnan, Alessia Centzone, Sanil Patel, Shani Sadeh, In Sook Ahn, Graciel Diamante, Ingrid Cely, Atul J. Butte, Cédric Blanpain, Sarah A. Stanley, Aldons J. Lusis, Xia Yang, Prashant Rajbhandari
bioRxiv 2020.11.14.378687; doi: https://doi.org/10.1101/2020.11.14.378687
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Mammary ductal epithelium controls cold-induced adipocyte thermogenesis
Luis C. Santos, Douglas Arneson, Alexandra Alvarsson, Karthickeyan Chella Krishnan, Alessia Centzone, Sanil Patel, Shani Sadeh, In Sook Ahn, Graciel Diamante, Ingrid Cely, Atul J. Butte, Cédric Blanpain, Sarah A. Stanley, Aldons J. Lusis, Xia Yang, Prashant Rajbhandari
bioRxiv 2020.11.14.378687; doi: https://doi.org/10.1101/2020.11.14.378687

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