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Ucp1 transcription is regulated by glucocorticoid receptor binding at Ucp1 regulatory regions
Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
Visa övriga samt affilieringar
(Engelska)Manuskript (preprint) (Övrigt vetenskapligt)
Abstract [en]

Glucocorticoids suppress Ucp1gene expression in brown adipocytes (BA) and brite/beige adipocytes (WA) in a cell-autonomous manner. The intracellular mechanism through which this suppression is mediated is not known. In in vitrodifferentiated primary cultures of murine brown and brite pre-adipocytes, the presence of dexamethasone (DEX) significantly reduced adrenergically-induced Ucp1mRNA levels, but upregulated the expression of other adrenergically-regulated genes. Additionally, DEX treatment increased NE-induced cAMP accumulation in BA. We thus conclude that the glucocorticoid-induced downregulation of Ucp1transcription occurs independently of a glucocorticoid-induced upregulation of the adrenergic signaling pathway. Using chromatin immunoprecipitation in combination with DNA sequencing in brown adipose tissue isolated from C57Bl/6 and BALB/c mice, we identified 6 glucocorticoid receptor binding sites in Ucp1active enhancer regions marked by H3K27ac. Luciferase reporter gene assays in the BA WT1 cell line indicated that the liganded GR binds to a regulatory region 0-4 kb upstream of the Ucp1transcription start site and thereby suppresses transcription. Thus, our study has identified a direct regulation of Ucp1transcription by the glucocorticoid receptor that occurs independently of the effects of glucocorticoids on adrenergic signaling. 

Nyckelord [en]
Glucocorticoids, UCP1, transcription, adrenergic signaling, brown adipocyte, glucocorticoid response element
Nationell ämneskategori
Biokemi och molekylärbiologi
Forskningsämne
molekylärbiologi
Identifikatorer
URN: urn:nbn:se:su:diva-163988OAI: oai:DiVA.org:su-163988DiVA, id: diva2:1277537
Forskningsfinansiär
Kungliga VetenskapsakademienTillgänglig från: 2019-01-10 Skapad: 2019-01-10 Senast uppdaterad: 2022-02-26Bibliografiskt granskad
Ingår i avhandling
1. Modulators of UCP1-dependent thermogenesis: Glucocorticoids, diet and novel research models
Öppna denna publikation i ny flik eller fönster >>Modulators of UCP1-dependent thermogenesis: Glucocorticoids, diet and novel research models
2019 (Engelska)Doktorsavhandling, sammanläggning (Övrigt vetenskapligt)
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. 

Ort, förlag, år, upplaga, sidor
Stockholm: Department of Molecular Biosciences, The Wenner-Gren Institute, Stockholm University, 2019
Nyckelord
brown adipose tissue, UCP1, glucocorticoids, diet-induced thermogenesis, obesity, physiology
Nationell ämneskategori
Biokemi och molekylärbiologi
Forskningsämne
molekylär biovetenskap
Identifikatorer
urn:nbn:se:su:diva-163376 (URN)978-91-7797-580-9 (ISBN)978-91-7797-581-6 (ISBN)
Disputation
2019-03-01, Vivi Täckholmsalen (Q-salen), NPQ-huset, Svante Arrhenius Väg 20, Stockholm, 10:00 (Engelska)
Opponent
Handledare
Forskningsfinansiär
Kungliga Vetenskapsakademien
Anmärkning

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.

Tillgänglig från: 2019-02-06 Skapad: 2019-01-10 Senast uppdaterad: 2022-02-26Bibliografiskt granskad

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Luijten, InekeGao, YunCannon, BarbaraNedergaard, Jan

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Luijten, InekeGao, YunCannon, BarbaraNedergaard, Jan
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Institutionen för molekylär biovetenskap, Wenner-Grens institut
Biokemi och molekylärbiologi

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