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Who is Who in the Adipose Organ: A look at the Heterogeneity of Adipocyte Biology
Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute. (Cannon / Nedergaard)ORCID iD: 0000-0001-8044-5410
2017 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

The increasing prevalence of obesity and related health complications, such as type 2 diabetes, cardiovascular disease and cancer, demands thorough investigation of the underlying processes. One of the key tissues investigated in this context is adipose tissue. It is becoming increasingly clear that adipose tissue is a very dynamic and heterogenic organ. This thesis provides an overview of various aspects of adipose biology that illustrate its heterogenic nature and describes my own scientific contributions to this field.

We typically distinguish between thermogenic, energy-expending brown adipocytes and energy-storing white adipocytes that are located in anatomically distinct adipose depots. In addition, brite (or beige) adipocytes are functionally thermogenic, but are located among white adipocytes.

Related to functional variation, adipocytes and adipose tissues display a wide range of morphological appearances. An additional property that illustrates the heterogeneity among adipose cells and depots is the variation of cellular responses to physiological cues, such as changes in diet or environmental temperature. Furthermore, the developmental origins of various adipose types display great heterogeneity, which may explain some of the functional and dynamic differences that are observed.

In line with the complexity of developmental origins, molecular markers that were initially proposed to distinguish between brown, brite/beige and white adipose subtypes have added to the notion that the composition of the adipose organ is much more complex than has long been appreciated.

My own work has contributed to the enhancement of our understanding of the heterogeneity of adipose subtypes. In particular, my findings related to marker gene expression patterns have led to increased appreciation of the complex nature of adipose gene expression patterns and the complications of translating results obtained in mice to humans. Some of my other contributions have increased the understanding of the differences and similarities in thermogenic adipose tissue functionality and dynamics. With cell culture studies, I have revealed new characteristics of pre-adipose cells from various depots that further add to the appreciation of the adipose heterogeneity.

Overall, this thesis provides an overview of important characteristics of the adipose organ, illustrating its heterogenic nature. Realization of this heterogeneity is of importance in order to properly study the adipose organ to ultimately understand how the adipose organ can be therapeutically targeted to effectively treat adipose-related diseases.

Place, publisher, year, edition, pages
Stockholm: Department of Molecular Biosciences, The Wenner-Gren Institute, Stockholm University , 2017. , 92 p.
Keyword [en]
Adipose tissue, Adipocyte, Brown, White, Brite/Beige, Physiology
National Category
Physiology
Research subject
Physiology
Identifiers
URN: urn:nbn:se:su:diva-140884ISBN: 978-91-7649-742-5 (print)ISBN: 978-91-7649-743-2 (electronic)OAI: oai:DiVA.org:su-140884DiVA: diva2:1083413
Public defence
2017-04-28, Vivi Täckholmsalen (Q211), NPQ-huset, Svante Arrheniusväg 20, 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 3: Manuscript. Paper 7: Manuscript. Paper 8: Manuscript.

Available from: 2017-04-05 Created: 2017-03-21 Last updated: 2017-04-03Bibliographically approved
List of papers
1. A stringent validation of mouse adipose tissue identity markers
Open this publication in new window or tab >>A stringent validation of mouse adipose tissue identity markers
2015 (English)In: American Journal of Physiology. Endocrinology and Metabolism, ISSN 0193-1849, E-ISSN 1522-1555, Vol. 308, no 12, E1085-E1105 p.Article in journal (Refereed) Published
Abstract [en]

The nature of brown adipose tissue in humans is presently debated: whether it is classical brown or of brite/beige nature. The dissimilar developmental origins and proposed distinct functions of the brown and brite/beige tissues make it essential to ascertain the identity of human depots with the perspective of recruiting and activating them for the treatment of obesity and type 2 diabetes. For identification of the tissues, a number of marker genes have been proposed, but the validity of the markers has not been well documented. We used established brown (interscapular), brite (inguinal), and white (epididymal) mouse adipose tissues and corresponding primary cell cultures as validators and examined the informative value of a series of suggested markers earlier used in the discussion considering the nature of human brown adipose tissue. Most of these markers unexpectedly turned out to be noninformative concerning tissue classification (Car4, Cited1, Ebf3, Eva1, Fbxo31, Fgf21, Lhx8, Hoxc8, and Hoxc9). Only Zic1 (brown), Cd137, Epsti1, Tbx1, Tmem26 (brite), and Tcf21 (white) proved to be informative in these three tissues. However, the expression of the brite markers was not maintained in cell culture. In a more extensive set of adipose depots, these validated markers provide new information about depot identity. Principal component analysis supported our single-gene conclusions. Furthermore, Zic1, Hoxc8, Hoxc9, and Tcf21 displayed anteroposterior expression patterns, indicating a relationship between anatomic localization and adipose tissue identity (and possibly function). Together, the observed expression patterns of these validated marker genes necessitates reconsideration of adipose depot identity in mice and humans.

Keyword
adipose tissue, brown, brite, beige, white
National Category
Cell Biology
Research subject
Physiology
Identifiers
urn:nbn:se:su:diva-118962 (URN)10.1152/ajpendo.00023.2015 (DOI)000356259500006 ()
Available from: 2015-07-22 Created: 2015-07-21 Last updated: 2017-03-22Bibliographically approved
2. A classical brown adipose tissue mRNA signature partly overlaps with brite in the supraclavicular region of adult humans
Open this publication in new window or tab >>A classical brown adipose tissue mRNA signature partly overlaps with brite in the supraclavicular region of adult humans
Show others...
2013 (English)In: Cell Metabolism, ISSN 1550-4131, E-ISSN 1932-7420, Vol. 17, no 5, 798-805 p.Article in journal (Refereed) Published
Abstract [en]

Human brown adipose tissue (BAT) has been detected in adults but was recently suggested to be of brite/beige origin. We collected BAT from the supraclavicular region in 21 patients undergoing surgery for suspected cancer in the neck area and assessed the gene expression of established murine markers for brown, brite/beige, and white adipocytes. We demonstrate that a classical brown expression signature, including upregulation of miR-206, miR-133b, LHX8, and ZIC1 and downregulation of HOXC8 and HOXC9, coexists with an upregulation of two newly established brite/beige markers, TBX1 and TMEM26. A similar mRNA expression profile was observed when comparing isolated human adipocytes from BAT and white adipose tissue (WAT) depots, differentiated in vitro. In conclusion, our data suggest that human BAT might consist of both classical brown and recruitable brite adipocytes, an observation important for future considerations on how to induce human BAT.

National Category
Cell Biology
Research subject
Physiology
Identifiers
urn:nbn:se:su:diva-93061 (URN)10.1016/j.cmet.2013.04.011 (DOI)000326266000020 ()23663743 (PubMedID)
Note

AuthorCount: 13;

Available from: 2013-08-30 Created: 2013-08-30 Last updated: 2017-03-22Bibliographically approved
3. Brown adipose tissue in physiologically humanized mice phenocopies human brown fat
Open this publication in new window or tab >>Brown adipose tissue in physiologically humanized mice phenocopies human brown fat
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(English)Manuscript (preprint) (Other academic)
National Category
Physiology
Research subject
Physiology
Identifiers
urn:nbn:se:su:diva-140890 (URN)
Available from: 2017-03-21 Created: 2017-03-21 Last updated: 2017-03-22Bibliographically approved
4. UCP1 in Brite/Beige Adipose Tissue Mitochondria Is Functionally Thermogenic
Open this publication in new window or tab >>UCP1 in Brite/Beige Adipose Tissue Mitochondria Is Functionally Thermogenic
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2013 (English)In: Cell reports, ISSN 2211-1247, E-ISSN 2211-1247, Vol. 5, no 5, 1196-1203 p.Article in journal (Refereed) Published
Abstract [en]

The phenomenon of white fat browning, in which certain white adipose tissue depots significantly increase gene expression for the uncoupling protein UCP1 and thus supposedly acquire thermogenic, fat-burning properties, has attracted considerable attention. Because the mRNA increases are from very low initial levels, the metabolic relevance of the change is unclear: is the UCP1 protein thermogenically competent in these brite/beige-fat mitochondria? We found that, in mitochondria isolated from the inguinal white adipose depot of cold-acclimated mice, UCP1 protein levels almost reached those in brown-fat mitochondria. The UCP1 was thermogenically functional, in that these mitochondria exhibited UCP1-dependent thermogenesis with lipid or carbohydrate substrates with canonical guanosine diphosphate (GDP) sensitivity and loss of thermogenesis in UCP1 knockout (KO) mice. Obesogenic mouse strains had a lower thermogenic potential than obesity-resistant strains. The thermogenic density (UCP1-dependent oxygen consumption per g tissue) of inguinal white adipose tissue was maximally one-fifth of interscapular brown adipose tissue, and the total quantitative contribution of all inguinal mitochondria was maximally one-third of all interscapular brown-fat mitochondria, indicating that the classical brown adipose tissue depots would still predominate in thermogenesis.

National Category
Cell Biology
Research subject
Physiology
Identifiers
urn:nbn:se:su:diva-99135 (URN)10.1016/j.celrep.2013.10.044 (DOI)000328266400005 ()
Note

AuthorCount:6;

Available from: 2014-01-13 Created: 2014-01-12 Last updated: 2017-03-22Bibliographically approved
5. UCP1 in adipose tissues: two steps to full browning
Open this publication in new window or tab >>UCP1 in adipose tissues: two steps to full browning
2017 (English)In: Biochimie, ISSN 0300-9084, E-ISSN 1638-6183, Vol. 134, 127-137 p.Article in journal (Refereed) Published
Abstract [en]

The possibility that brown adipose tissue thermogenesis can be recruited in order to combat the development of obesity has led to a high interest in the identification of "browning agents", i.e. agents that increase the amount and activity of UCP1 in brown and brite/beige adipose tissues. However, functional analysis of the browning process yields confusingly different results when the analysis is performed in one of two alternative steps. Thus, in one of the steps, using cold acclimation as a potent model browning agent, we find that if the browning process is followed in mice initially housed at 21 °C (the most common procedure), there is only weak molecular evidence for increases in UCP1 gene expression or UCP1 protein abundance in classical brown adipose tissue; however, in brite/beige adipose depots, there are large increases, apparently associating functional browning with events only in the brite/beige tissues. Contrastingly, in another step, if the process is followed starting with mice initially housed at 30 °C (thermoneutrality for mice, thus similar to normal human conditions), large increases in UCP1 gene expression and UCP1 protein abundance are observed in the classical brown adipose tissue depots; there is then practically no observable UCP1 gene expression in brite/beige tissues. This apparent conundrum can be resolved when it is realized that the classical brown adipose tissue at 21 °C is already essentially fully differentiated and thus expands extensively through proliferation upon further browning induction, rather than by further enhancing cellular differentiation. When the limiting factor for thermogenesis, i.e. the total amount of UCP1 protein per depot, is analyzed, classical brown adipose tissue is by far the predominant site for the browning process, irrespective of which of the two steps is analyzed. There are to date no published data demonstrating that alternative browning agents would selectively promote brite/beige tissues versus classical brown tissue to a higher degree than does cold acclimation. Thus, to restrict investigations to examine adipose tissue depots where only a limited part of the adaptation process occurs (i.e. the brite/beige tissues) and to use initial conditions different from the thermoneutrality normally experienced by adult humans may seriously hamper the identification of therapeutically valid browning agents. The data presented here have therefore important implications for the analysis of the potential of browning agents and the nature of human brown adipose tissue.

Keyword
Beige, Brite, Browning, Cold acclimation, UCP1
National Category
Cell Biology
Research subject
Physiology
Identifiers
urn:nbn:se:su:diva-140881 (URN)10.1016/j.biochi.2017.01.007 (DOI)000395217100016 ()28109720 (PubMedID)
Available from: 2017-03-21 Created: 2017-03-21 Last updated: 2017-05-02Bibliographically approved
6. The β3-adrenergic receptor is dispensable for browning of adipose tissues
Open this publication in new window or tab >>The β3-adrenergic receptor is dispensable for browning of adipose tissues
Show others...
2017 (English)In: American Journal of Physiology. Endocrinology and Metabolism, ISSN 0193-1849, E-ISSN 1522-1555, Vol. 312, no 6, E508-E518 p.Article in journal (Refereed) Published
Abstract [en]

Brown and brite/beige adipocytes are attractive therapeutic targets to treat metabolic diseases. To maximally utilize their functional potential, further understanding is required about their identities and their functional differences. Recent studies with β3-adrenergic receptor knockout mice reported that brite/beige adipocytes, but not classical brown adipocytes, require the β3-adrenergic receptor for cold-induced transcriptional activation of thermogenic genes. We aimed to further characterize this requirement of the β3-adrenergic receptor as a functional distinction between classical brown and brite/beige adipocytes. However, when comparing wild-type and β3-adrenergic receptor knockout mice, we observed no differences in cold-induced thermogenic gene expression (Ucp1, Pgc1a, Dio2 and Cidea) in brown or white (brite/beige) adipose tissues. Irrespective of the duration of the cold exposure or the sex of the mice, we observed no effect of the absence of the β3-adrenergic receptor. Experiments with the β3-adrenergic receptor agonist CL-316,243 verified the functional absence of β3-adrenergic signaling in these knockout mice. The β3-adrenergic receptor knockout model in the present study was maintained on a FVB/N background, whereas earlier reports used C57BL/6 and 129Sv mice. Thus, our data imply background-dependent differences in adrenergic signaling mechanisms in response to cold exposure. Nonetheless, the present data indicate that the β3-adrenergic receptor is dispensable for cold-induced transcriptional activation in both classical brown and, as opposed to earlier studies, brite/beige cells. This should be taken into account in the increasing number of studies on the induction of browning and their extrapolation to human physiology.

Keyword
β3-adrenergic receptor, adipose browning, brown adipocytes, brite/beige adipocytes, UCP
National Category
Cell Biology
Research subject
Physiology
Identifiers
urn:nbn:se:su:diva-140882 (URN)10.1152/ajpendo.00437.2016 (DOI)000404391300005 ()28223294 (PubMedID)
Available from: 2017-03-21 Created: 2017-03-21 Last updated: 2017-07-24Bibliographically approved
7. In primary brown adipose cultures, fetal and newborn bovine sera differently affect triglyceride storage and thermocompetence
Open this publication in new window or tab >>In primary brown adipose cultures, fetal and newborn bovine sera differently affect triglyceride storage and thermocompetence
(English)Manuscript (preprint) (Other academic)
National Category
Physiology
Research subject
Physiology
Identifiers
urn:nbn:se:su:diva-140885 (URN)
Available from: 2017-03-21 Created: 2017-03-21 Last updated: 2017-03-22Bibliographically approved
8. Utilization of fetal and newborn serum to uncover novel regulators of subcutaneous adipocyte differentiation
Open this publication in new window or tab >>Utilization of fetal and newborn serum to uncover novel regulators of subcutaneous adipocyte differentiation
(English)Manuscript (preprint) (Other academic)
National Category
Cell Biology
Research subject
Physiology
Identifiers
urn:nbn:se:su:diva-140886 (URN)
Available from: 2017-03-21 Created: 2017-03-21 Last updated: 2017-03-22Bibliographically approved

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