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Glucocorticoid-induced obesity develops independently of UCP1
Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.ORCID iD: 0000-0002-2915-6450
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(English)Manuscript (preprint) (Other academic)
Abstract [en]

An excess of glucocorticoids is associated with the development of obesity, as is evident from the accumulation of visceral fat in patients suffering from Cushing’s Syndrome. Activated brown adipose tissue (BAT) reduces metabolic efficiency; correspondingly an inactivation of BAT has been proposed to cause glucocorticoid-induced obesity. Here we determine the extent to which changes in BAT function as a result of glucocorticoid treatment contribute to the simultaneous development of obesity. In mice housed at 21 °C and treated with corticosterone for 2 weeks (CORT), we unexpectedly found no change in total BAT uncoupling protein 1 (UCP1) protein levels or in non-shivering thermogenic capacity. In mice housed at thermoneutrality, a humanized condition, we did observe a reduction in total UCP1 protein levels in BAT in response to CORT, which was reflected in reduced brown adipocyte cellular and mitochondrial UCP1-dependent respiration. However, glucocorticoid-induced obesity developed to the same extent in animals housed at 21 °C and 30 °C, while total BAT UCP1 protein levels differed 100-fold between the two groups. In wild-type and UCP1 knock-out mice housed at 30 °C and treated with CORT, obesity also developed to the same extent. Thus, contrary to what has previously been suggested, our results show that the development of glucocorticoid-induced obesity is unrelated to the presence of UCP1.

Keywords [en]
uncoupling protein 1, corticosterone, obesity, thermogenesis, energy balance, brown adipose tissue, thermoneutrality, cold exposure
National Category
Biochemistry and Molecular Biology
Research subject
Molecular Bioscience
Identifiers
URN: urn:nbn:se:su:diva-163421OAI: oai:DiVA.org:su-163421DiVA, id: diva2:1274718
Funder
Swedish Research CouncilAvailable from: 2019-01-02 Created: 2019-01-02 Last updated: 2022-02-26Bibliographically 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: 2022-02-26Bibliographically approved

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Luijten, InekeBrooks, KatieBoulet, NathalieShabalina, IrinaFischer, AlexanderCannon, BarbaraNedergaard, Jan

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Luijten, InekeBrooks, KatieBoulet, NathalieShabalina, IrinaFischer, AlexanderCannon, BarbaraNedergaard, Jan
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