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In the absence of UCP1-mediated diet-induced thermogenesis, obesity is augmented even in the obesity-resistant 129S mouse strain
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.
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(English)Manuscript (preprint) (Other academic)
Abstract [en]

The attractive tenet that recruitment and activation of brown adipose tissue (BAT) and Uncoupling Protein 1 (UCP1) could counteract the development of obesity and its comorbidities in humans has been experimentally corroborated mainly by experiments demonstrating that UCP1-ablated mice on a C57Bl/6 background (housed exempt from thermal stress) become more obese when fed a high-fat diet. However, concerns may be raised that this outcome of UCP1 ablation is restricted to this very special inbred and particularly obesity-prone mouse strain. We have therefore examined to which degree UCP1 ablation has similar metabolic effects in a mouse strain known tobe obesity resistant: the 129S strain. For this, male 129S2/sv or 129SV/Pas mice and corresponding UCP1-KO mice were fed chow, or a high-fat or a cafeteria diet for 4 weeks. The absence of UCP1 augmented obesity (weight gain, body fat mass, % body fat, fat depot size) in high-fat diet- and cafeteria-fed mice, with a similar or lower food intake, indicating that, when present, UCP1 indeed decreases metabolic efficiency. The increased obesity was due to a decrease in energy expenditure. The consumption of a high-fat or cafeteria diet increased total BAT UCP1 protein levels in wild-type mice, and correspondingly, high-fat diet and cafeteria diet-fed mice demonstrated increased norepinephrine-induced oxygen consumption. There was a positive correlation between body fat and total BAT UCP1 protein content. No evidence for diet-induced adrenergic thermogenesis was found in UCP1-ablated mice. Thus, the obesity-reducing effect of UCP1 is not restricted to a particular, and perhaps not representative, mouse strain. 

National Category
Biochemistry and Molecular Biology
Research subject
Molecular Bioscience
Identifiers
URN: urn:nbn:se:su:diva-163422OAI: oai:DiVA.org:su-163422DiVA, id: diva2:1276852
Funder
The Royal Swedish Academy of SciencesAvailable from: 2019-01-09 Created: 2019-01-09 Last updated: 2019-01-24Bibliographically 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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