Adipocyte hypertrophy and lipid dynamics underlie mammary gland remodeling after lactation

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Abstract

Adipocytes undergo pronounced changes in size and behavior to support diverse tissue functions, but the mechanisms that control these changes are not well understood. Mammary gland-associated white adipose tissue (mgWAT) regresses in support of milk fat production during lactation and expands during the subsequent involution of milk-producing epithelial cells, providing one of the most marked physiological examples of adipose growth. We examined cellular mechanisms and functional implications of adipocyte and lipid dynamics in the mouse mammary gland (MG). Using in vivo analysis of adipocyte precursors and genetic tracing of mature adipocytes, we find mature adipocyte hypertrophy to be a primary mechanism of mgWAT expansion during involution. Lipid tracking and lipidomics demonstrate that adipocytes fill with epithelial-derived milk lipid. Furthermore, ablation of mgWAT during involution reveals an essential role for adipocytes in milk trafficking from, and proper restructuring of, the mammary epithelium. This work advances our understanding of MG remodeling and tissue-specific roles for adipocytes.

Abstract

During mammary gland involution, the organ undergoes extensive remodeling. Here, the authors explore the role of mammary gland adipose tissue (mgWAT) in this process and demonstrate that adipocyte hypertrophy and lipid trafficking underlie mgWAT expansion and epithelial regression.

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Most cited references 55

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Distinct fibroblast lineages determine dermal architecture in skin development and repair

Ryan R. Driskell, Beate M Lichtenberger, Esther Hoste … (2013)

Fibroblasts are the major mesenchymal cell type in connective tissue and deposit the collagen and elastic fibers of the extracellular matrix (ECM) 1 . Even within a single tissue fibroblasts exhibit remarkable functional diversity, but it is not known whether this reflects the existence of a differentiation hierarchy or is a response to different environmental factors. Here we show, using transplantation assays and lineage tracing, that the fibroblasts of skin connective tissue arise from two distinct lineages. One forms the upper dermis, including the dermal papilla that regulates hair growth and the arrector pili muscle (APM), which controls piloerection. The other forms the lower dermis, including the reticular fibroblasts that synthesise the bulk of the fibrillar ECM, and the pre-adipocytes and adipocytes of the hypodermis. The upper lineage is required for hair follicle formation. In wounded adult skin, the initial wave of dermal repair is mediated by the lower lineage and upper dermal fibroblasts are recruited only during re-epithelialisation. Epidermal beta-catenin activation stimulates expansion of the upper dermal lineage, rendering wounds permissive for hair follicle formation. Our findings explain why wounding is linked to formation of ECM-rich scar tissue that lacks hair follicles 2-4 . They also form a platform for discovering fibroblast lineages in other tissues and for examining fibroblast changes in ageing and disease.

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Thematic review series: adipocyte biology. The perilipin family of structural lipid droplet proteins: stabilization of lipid droplets and control of lipolysis.

Dawn L. Brasaemle (2007)

The majority of eukaryotic cells synthesize neutral lipids and package them into cytosolic lipid droplets. In vertebrates, triacylglycerol-rich lipid droplets of adipocytes provide a major energy storage depot for the body, whereas cholesteryl ester-rich droplets of many other cells provide building materials for local membrane synthesis and repair. These lipid droplets are coated with one or more of five members of the perilipin family of proteins: adipophilin, TIP47, OXPAT/MLDP, S3-12, and perilipin. Members of this family share varying levels of sequence similarity, lipid droplet association, and functions in stabilizing lipid droplets. The most highly studied member of the family, perilipin, is the most abundant protein on the surfaces of adipocyte lipid droplets, and the major substrate for cAMP-dependent protein kinase [protein kinase A (PKA)] in lipolytically stimulated adipocytes. Perilipin serves important functions in the regulation of basal and hormonally stimulated lipolysis. Under basal conditions, perilipin restricts the access of cytosolic lipases to lipid droplets and thus promotes triacylglycerol storage. In times of energy deficit, perilipin is phosphorylated by PKA and facilitates maximal lipolysis by hormone-sensitive lipase and adipose triglyceride lipase. A model is discussed whereby perilipin serves as a dynamic scaffold to coordinate the access of enzymes to the lipid droplet in a manner that is responsive to the metabolic status of the adipocyte.

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Characterization of the adipocyte cellular lineage in vivo

Ryan Berry, Matthew S Rodeheffer (2013)

Mature adipocytes are generated through the proliferation and differentiation of precursor cells. Our prior studies identified adipocyte progenitors in white adipose tissue (WAT) as Lin−:CD29+:CD34+:Sca-1+:CD24+ (CD24+) cells that are capable of generating functional WAT 1 . Here, we employ several Cre recombinase mouse models to identify the adipocyte cellular lineage in vivo. While it has been proposed that white adipocytes are derived from endothelial 2 and hematopoietic 3, 4 lineages, we find that neither of these lineages label white adipocytes. However, platelet-derived growth factor receptor α (PdgfRα)-Cre trace labels all white adipocytes. Analysis of WAT from PdgfRα-Cre reporter mice identifies CD24+ and Lin−:CD29+:CD34+:Sca-1+:CD24− (CD24−) cells as adipocyte precursors. We show that CD24+ cells generate the CD24− population in vivo and the CD24− cells express late markers of adipogenesis. From these data we propose a model where the CD24+ adipocyte progenitors become further committed to the adipocyte lineage as CD24 expression is lost, generating CD24− preadipocytes. This characterization of the adipocyte cellular lineage will facilitate study of the mechanisms that regulate WAT formation in vivo and WAT mass expansion in obesity.

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Author and article information

Contributors

Valerie Horsley: valerie.horsley@yale.edu

Journal

Journal ID (nlm-ta): Nat Commun

Journal ID (iso-abbrev): Nat Commun

Title: Nature Communications

Publisher: Nature Publishing Group UK (London )

ISSN (Electronic): 2041-1723

Publication date (Electronic): 4 September 2018

Publication date PMC-release: 4 September 2018

Publication date Collection: 2018

Volume: 9

Electronic Location Identifier: 3592

Affiliations

[1 ]ISNI 0000000419368710, GRID grid.47100.32, Department of Molecular, Cellular and Developmental Biology, , Yale University, ; 219 Prospect St., New Haven, CT 06520 USA

[2 ]ISNI 0000 0001 0703 675X, GRID grid.430503.1, Division of Endocrinology, Metabolism, and Diabetes, , University of Colorado, ; Mail Stop F-8305; RC1 North, 12800 E. 19th Avenue P18-5107, Aurora, CO 80045 USA

[3 ]ISNI 0000 0001 2348 0746, GRID grid.4989.c, WELBIO, Interdisciplinary Research Institute (IRIBHM), , Université Libre de Bruxelles (ULB), ; 808, route de Lennik, BatC, C6-130, 1070 Brussels, Belgium

[4 ]ISNI 0000 0004 0421 8357, GRID grid.410425.6, Department of Population Sciences and Bekman Institute, , City of Hope, ; 1500 East Duarte Rd., Duarte, CA 91010 USA

[5 ]ISNI 0000000419368710, GRID grid.47100.32, Section of Plastic and Reconstructive Surgery, Department of Surgery, , Yale University, ; 333 Ceder St., New Haven, CT 06510 USA

[6 ]ISNI 0000000419368710, GRID grid.47100.32, Section of Endocrinology and Metabolism, Department of Internal Medicine, , Yale University, ; 333 Ceder St., New Haven, CT 06510 USA

[7 ]ISNI 0000000419368710, GRID grid.47100.32, Department of Comparative Medicine, , Yale University, ; 333 Ceder St., New Haven, CT 06510 USA

[8 ]ISNI 0000000419368710, GRID grid.47100.32, Department of Dermatology, , Yale University, ; 333 Ceder St., New Haven, CT 06510 USA

Author information

Rachel K. Zwick http://orcid.org/0000-0003-2012-5890

Brandon Holtrup http://orcid.org/0000-0002-8883-0177

Article

Publisher ID: 5911

DOI: 10.1038/s41467-018-05911-0

PMC ID: 6123393

PubMed ID: 30181538

SO-VID: 10f191f2-21d3-4335-af7f-62ef723efc99

License:

Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

History

Date received : 30 January 2018

Date accepted : 30 July 2018

Funding

Funded by: FundRef https://doi.org/10.13039/100009633, U.S. Department of Health & Human Services | NIH | Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD);

Award ID: F32 HD082956

Award ID: K12 HD057022

Award ID: R01 HD076248

Award Recipient : Valerie Horsley

Funded by: FundRef https://doi.org/10.13039/100000057, U.S. Department of Health & Human Services | NIH | National Institute of General Medical Sciences (NIGMS);

Award ID: T32 GM007499

Award Recipient : Valerie Horsley

Funded by: FundRef https://doi.org/10.13039/100000069, U.S. Department of Health & Human Services | NIH | National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS);

Award ID: R01 AR060296

Award Recipient : Valerie Horsley

Funded by: FundRef https://doi.org/10.13039/100000062, U.S. Department of Health & Human Services | NIH | National Institute of Diabetes and Digestive and Kidney Diseases (National Institute of Diabetes & Digestive & Kidney Diseases);

Award ID: K01 DK109079

Award ID: R01 DK090489

Award Recipient : Valerie Horsley

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Adipocyte hypertrophy and lipid dynamics underlie mammary gland remodeling after lactation

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Abstract

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Journal of Circulating Biomarkers

Most cited references 55

Distinct fibroblast lineages determine dermal architecture in skin development and repair

Thematic review series: adipocyte biology. The perilipin family of structural lipid droplet proteins: stabilization of lipid droplets and control of lipolysis.

Characterization of the adipocyte cellular lineage in vivo

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Cited by 27

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