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ThermoMouse: An In Vivo Model to Identify Modulators of UCP1 Expression in Brown Adipose Tissue
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2014 (English)In: Cell reports, ISSN 2211-1247, E-ISSN 2211-1247, Vol. 9, no 5, p. 1584-1593Article in journal (Refereed) Published
Abstract [en]

Obesity develops when energy intake chronically exceeds energy expenditure. Because brown adipose tissue (BAT) dissipates energy in the form of heat, increasing energy expenditure by augmenting BAT-mediated thermogenesis may represent an approach to counter obesity and its complications. The ability of BAT to dissipate energy is dependent on expression of mitochondrial uncoupling protein 1 (UCP1). To facilitate the identification of pharmacological modulators of BAT UCP1 levels, which may have potential as antiobesity medications, we developed a transgenic model in which luciferase activity faithfully mimics endogenous UCP1 expression and its response to physiologic stimuli. Phenotypic screening of a library using cells derived from this model yielded a small molecule that increases UCP1 expression in brown fat cells and mice. Upon adrenergic stimulation, compound-treated mice showed increased energy expenditure. These tools offer an opportunity to identify pharmacologic modulators of UCP1 expression and uncover regulatory pathways that impact BAT-mediated thermogenesis.

Place, publisher, year, edition, pages
2014. Vol. 9, no 5, p. 1584-1593
Keywords [en]
UCP1, brown adipose tissue, mouse model, screening, Luciferase
National Category
Biochemistry and Molecular Biology
Research subject
Molecular Cellbiology
Identifiers
URN: urn:nbn:se:su:diva-163375DOI: 10.1016/j.celrep.2014.10.066OAI: oai:DiVA.org:su-163375DiVA, id: diva2:1274253
Funder
Swedish Research CouncilAvailable from: 2018-12-28 Created: 2018-12-28 Last updated: 2019-01-21Bibliographically approved
In thesis
1. Modulators of UCP1-dependent thermogenesis: Glucocorticoids, diet and novel research models
Open this publication in new window or tab >>Modulators of UCP1-dependent thermogenesis: Glucocorticoids, diet and novel research models
2019 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

The activation and recruitment of brown adipose tissue (BAT) thermogenesis has been put forward as a promising strategy to reduce the disease burden of obesity and obesity-related diseases. Heat production by BAT can be attributed to the tissue-specific mitochondrial uncoupling protein 1 (UCP1). Upon activation, UCP1 uncouples substrate oxidation from ATP production, thereby dissipating energy solely as heat and thus facilitating the ‘wasting’ of energy. To date, cold exposure is the strongest known BAT activator. However, to harness the energy wasting potential of BAT as a weight-reducing agent, the search for alternative factors that alter the activation or recruitment state of BAT is ongoing. The goal of this thesis is to obtain a better understanding of compounds and processes that modulate UCP1-dependent thermogenesis. 

We investigate glucocorticoids for their potential to alter the UCP1-dependent thermogenic capacity of mice. We provide the novel insight that glucocorticoid supplementation reduces total BAT UCP1 protein levels, but only in mice housed at thermoneutrality. This reduction occurs at the transcriptional level by direct binding of the liganded glucocorticoid receptor to Ucp1regulatory regions. We also demonstrate that the glucocorticoid-induced reduction in BAT thermogenesis does not contribute to the development of glucocorticoid-induced obesity.

Further, we show that high-fat diet- and cafeteria diet-feeding induces the activation and recruitment of BAT UCP1 protein in the obesity-resistant 129S mouse strain. We demonstrate the importance of this diet-induced modulation of BAT thermogenic capacity by reporting an increased metabolic efficiency in UCP1-ablated mice compared to wild-type mice. 

We finally present two novel models that can be used for the identification of novel modulators of BAT thermogenesis, namely a brown adipocyte clonal cell line derived from adult human BAT, and a UCP1-luciferase reporter mouse which facilitates real-time tracking of endogenous Ucp1expression. Using these models, we identify the genes Mtus1and Kcnk3, and the compound WWL113, as novel modulators of UCP1-dependent thermogenesis. 

Place, publisher, year, edition, pages
Stockholm: Department of Molecular Biosciences, The Wenner-Gren Institute, Stockholm University, 2019
Keywords
brown adipose tissue, UCP1, glucocorticoids, diet-induced thermogenesis, obesity, physiology
National Category
Biochemistry and Molecular Biology
Research subject
Molecular Bioscience
Identifiers
urn:nbn:se:su:diva-163376 (URN)978-91-7797-580-9 (ISBN)978-91-7797-581-6 (ISBN)
Public defence
2019-03-01, Vivi Täckholmsalen (Q-salen), NPQ-huset, Svante Arrhenius Väg 20, Stockholm, 10:00 (English)
Opponent
Supervisors
Funder
The Royal Swedish Academy of Sciences
Note

At the time of the doctoral defense, the following papers were unpublished and had a status as follows: Paper 1: Manuscript. Paper 2: Manuscript. Paper 5: Manuscript.

Available from: 2019-02-06 Created: 2019-01-10 Last updated: 2019-01-31Bibliographically approved

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