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Regulatory Factors that Reveal Three Distinct Adipocytes: The Brown, the White and the Brite
Stockholm University, Faculty of Science, The Wenner-Gren Institute . (Cannon and Nedergaard)
2010 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Adipose tissues have long been considered to derive from a common origin. Even the functionally different brown and white adipose tissues were generalized to share a common origin. Brown adipose tissue is a highly innervated and vascularised tissue containing multilocular and multimitochondrial brown adipocytes. Brown adipose tissue expends energy through sympathetic nervous system-mediated non-shivering thermogenesis, where uncoupling protein 1 (UCP1) is the key player. In contrast, white adipose tissue consists of unilocular white adipocytes with a main role to store energy in the form of the lipid droplet.

We know today that this generalisation is exaggerated since adipocytes can derive from more than one origin and not only be brown or white. We and others have demonstrated that the brown adipocyte has a dermomyotomal origin and derives from the adipomyocyte, the precursor cell that can also become a myocyte, whereas white adipocytes are suggested to derive from pericytes, cells that are embedded within the vascular vessel walls. For a long time there has been evidence that energy-expending adipocytes reside within certain white adipose tissues, based on the fact that cold exposure, by switching on the sympathetic nervous system, leads to levels of UCP1 that are not detectable in mice housed at thermoneutrality. We demonstrated that these cells have a molecular signature that is distinct from brown and white adipocytes. Since these energy-expending cells reside within certain white adipose tissues, we chose to name them brite (brown in white) adipocytes. Moreover, we also identified regulatory factors that were specifically expressed in each adipocyte type, thus, facilitating the possibility to identify the three adipocytes: the brown, the white and the brite.

Place, publisher, year, edition, pages
Stockholm: The Wenner-Gren Institute, Stockholm University , 2010. , 89 p.
Keyword [en]
adipocyte, UCP1, brite, brown, white, Hox Zic, miRNA
National Category
Physiology
Research subject
Physiology
Identifiers
URN: urn:nbn:se:su:diva-38362ISBN: 978-91-7447-048-2 (print)OAI: oai:DiVA.org:su-38362DiVA: diva2:309926
Public defence
2010-05-12, sal E306, Arrheniuslaboratorierna, Svante Arrhenius väg 20 C, Stockholm, 10:00 (English)
Opponent
Supervisors
Note
At the time of the doctoral defense, the following papers were unpublished and had a status as follows: Paper 4: Manuscript. Paper 5: Manuscript. Available from: 2010-04-20 Created: 2010-04-09 Last updated: 2010-04-22Bibliographically approved
List of papers
1. Myogenic gene expression signature establishes that brown and white adipocytes originate from distinct cell lineages.
Open this publication in new window or tab >>Myogenic gene expression signature establishes that brown and white adipocytes originate from distinct cell lineages.
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2007 (English)In: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 104, no 11, 4401-4406 p.Article in journal (Refereed) Published
Abstract [en]

Attainment of a brown adipocyte cell phenotype in white adipocytes, with their abundant mitochondria and increased energy expenditure potential, is a legitimate strategy for combating obesity. The unique transcriptional regulators of the primary brown adipocyte phenotype are unknown, limiting our ability to promote brown adipogenesis over white. In the present work, we used microarray analysis strategies to study primary preadipocytes, and we made the striking discovery that brown preadipocytes demonstrate a myogenic transcriptional signature, whereas both brown and white primary preadipocytes demonstrate signatures distinct from those found in immortalized adipogenic models. We found a plausible SIRT1-related transcriptional signature during brown adipocyte differentiation that may contribute to silencing the myogenic signature. In contrast to brown preadipocytes or skeletal muscle cells, white preadipocytes express Tcf21, a transcription factor that has been shown to suppress myogenesis and nuclear receptor activity. In addition, we identified a number of developmental genes that are differentially expressed between brown and white preadipocytes and that have recently been implicated in human obesity. The interlinkage between the myocyte and the brown preadipocyte confirms the distinct origin for brown versus white adipose tissue and also represents a plausible explanation as to why brown adipocytes ultimately specialize in lipid catabolism rather than storage, much like oxidative skeletal muscle tissue.

Keyword
Adipocytes/*cytology, Adipose Tissue; Brown/*cytology, Animals, Basic Helix-Loop-Helix Transcription Factors/metabolism, Cell Differentiation, Cell Lineage, Gene Expression Regulation, Gene Silencing, Lipids/chemistry, Male, Mice, Muscle; Skeletal/*cytology/metabolism, Oxygen/metabolism, Principal Component Analysis, Sirtuins/metabolism
Identifiers
urn:nbn:se:su:diva-20877 (URN)10.1073/pnas.0610615104 (DOI)000244972700030 ()17360536 (PubMedID)
Available from: 2008-01-18 Created: 2008-01-18 Last updated: 2017-12-13Bibliographically approved
2. Distinct expression of muscle-specific microRNAs (myomirs) in brown adipocytes.
Open this publication in new window or tab >>Distinct expression of muscle-specific microRNAs (myomirs) in brown adipocytes.
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2009 (English)In: Journal of Cellular Physiology, ISSN 0021-9541, E-ISSN 1097-4652, Vol. 218, no 2, 444-449 p.Article in journal (Refereed) Published
Abstract [en]

MicroRNAs, a novel class of post-transcriptional gene regulators, have been demonstrated to be involved in several cellular processes regulating the expression of protein-coding genes. Here we examine murine white and brown primary cell cultures for differential expression of miRNAs. The adipogenesis-related miRNA miR-143 was highly expressed in mature white adipocytes but was low in mature brown adipocytes. Three classical "myogenic" miRNAs miR-1, miR-133a and miR-206 were absent from white adipocytes but were specifically expressed both in brown pre- and mature adipocytes, reinforcing the concept that brown adipocytes and myocytes derive from a common cell lineage that specifies energy-dissipating cells. Augmentation of adipocyte differentiation status with norepinephrine or rosiglitazone did not affect the expression of the above miRNAs, the expression levels of which were thus innately regulated. However, expression of the miRNA miR-455 was enhanced during brown adipocyte differentiation, similarly to the expression pattern of the brown adipocyte differentiation marker UCP1. In conclusion, miRNAs are differentially expressed in white and brown adipocytes and may be important in defining the common precursor cell for myocytes and brown adipocytes and thus have distinct roles in energy-storing versus energy-dissipating cells.

Identifiers
urn:nbn:se:su:diva-32905 (URN)10.1002/jcp.21621 (DOI)000262270600025 ()18937285 (PubMedID)
Available from: 2009-12-17 Created: 2009-12-17 Last updated: 2017-12-12Bibliographically approved
3. Chronic Perixosome Proliferator-activated Receptor gamma (PPARgamma) activation of epididymally derived white adipocyte cultures reveals a population of thermogenically competent, UCP1-containing adipocytes molecularly distinct from classical brown adipocytes.
Open this publication in new window or tab >>Chronic Perixosome Proliferator-activated Receptor gamma (PPARgamma) activation of epididymally derived white adipocyte cultures reveals a population of thermogenically competent, UCP1-containing adipocytes molecularly distinct from classical brown adipocytes.
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2010 (English)In: Journal of Biological Chemistry, ISSN 0021-9258, E-ISSN 1083-351X, Vol. 285, no 10, 7153-7164 p.Article in journal (Refereed) Published
Abstract [en]

The recent insight that brown adipocytes and muscle cells share a common origin and in this respect are distinct from white adipocytes has spurred questions concerning the origin and molecular characteristics of the UCP1-expressing cells observed in classical white adipose tissue depots under certain physiological or pharmacological conditions. Examining precursors from the purest white adipose tissue depot (epididymal), we report here that chronic treatment with the PPARgamma agonist rosiglitazone promotes not only the expression of PGC-1alpha and mitochondriogenesis in these cells but also a norepinephrine-augmentable UCP1 gene expression in a significant subset of the cells, providing these cells with a genuine thermogenic capacity. However, although functional thermogenic genes are expressed, the cells are devoid of transcripts for the novel transcription factors now associated with classical brown adipocytes (Zic1, Lhx8, Meox2 and characteristically PRDM16) or for myocyte-associated genes (myogenin and myomirs (muscle-specific microRNAs)) and retain white-fat characteristics such as Hoxc9 expression. Co-culture experiments verify that the UCP1-expressing cells are not proliferating classical brown adipocytes (adipomyocytes) and these cells therefore constitute a subset of adipocytes (''brite'' adipocytes) with a developmental origin and molecular characteristics distinguishing them as a separate class of cells.

National Category
Natural Sciences
Identifiers
urn:nbn:se:su:diva-33830 (URN)10.1074/jbc.M109.053942 (DOI)000275415600029 ()20028987 (PubMedID)
Available from: 2009-12-30 Created: 2009-12-30 Last updated: 2017-12-12Bibliographically approved
4. PPARa is not involved in the regulation of muscle-associated genesin brown adipose tissue.
Open this publication in new window or tab >>PPARa is not involved in the regulation of muscle-associated genesin brown adipose tissue.
(English)Manuscript (preprint) (Other academic)
Identifiers
urn:nbn:se:su:diva-38592 (URN)
Available from: 2010-04-22 Created: 2010-04-12 Last updated: 2010-04-22Bibliographically approved
5. Molecular signatures of brown, white and brite adipose tissues.
Open this publication in new window or tab >>Molecular signatures of brown, white and brite adipose tissues.
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(English)Manuscript (preprint) (Other academic)
Identifiers
urn:nbn:se:su:diva-38593 (URN)
Available from: 2010-04-22 Created: 2010-04-12 Last updated: 2010-04-22Bibliographically approved

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