Lipolysis regulates major transcriptional programs in brown adipocytes

Lasse K. Markussen, Elizabeth A. Rondini, Olivia Sveidahl Johansen, Jesper G.S. Madsen, Elahu G. Sustarsic, Ann Britt Marcher, Jacob B. Hansen, Zachary Gerhart-Hines, James G. Granneman, Susanne Mandrup*

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Abstract

β-Adrenergic signaling is a core regulator of brown adipocyte function stimulating both lipolysis and transcription of thermogenic genes, thereby expanding the capacity for oxidative metabolism. We have used pharmacological inhibitors and a direct activator of lipolysis to acutely modulate the activity of lipases, thereby enabling us to uncover lipolysis-dependent signaling pathways downstream of β-adrenergic signaling in cultured brown adipocytes. Here we show that induction of lipolysis leads to acute induction of several gene programs and is required for transcriptional regulation by β-adrenergic signals. Using machine-learning algorithms to infer causal transcription factors, we show that PPARs are key mediators of lipolysis-induced activation of genes involved in lipid metabolism and thermogenesis. Importantly, however, lipolysis also activates the unfolded protein response and regulates the core circadian transcriptional machinery independently of PPARs. Our results demonstrate that lipolysis generates important metabolic signals that exert profound pleiotropic effects on transcription and function of cultured brown adipocytes.

OriginalsprogEngelsk
Artikelnummer3956
TidsskriftNature Communications
Vol/bind13
Udgave nummer1
Antal sider16
ISSN2041-1723
DOI
StatusUdgivet - dec. 2022

Bibliografisk note

Funding Information:
We thank the members of the Mandrup lab, Granneman lab, and Gerhart-Hines lab for fruitful discussions. Work in the Mandrup laboratory was supported by grants from The Independent Research Fund Denmark (project grant: 7016-00279), The Novo Nordisk Foundation to Center for Adipocyte Signaling (ADIPOSIGN) (project grant: NNF18OC0033444), and The Danish National Research Foundation to the Center for Functional Genomics and Tissue Plasticity (ATLAS) (Project grant: 141). Work in the Granneman lab was supported by National Institutes of Health grants R01DK076629, R01DK062292, and R01DK105963. The Mandrup/Granneman collaboration was also supported by the Danish Diabetes Academy supported by the Novo Nordisk Foundation. Work in the Gerhart-Hines laboratory was supported by funding from the European Research Council under the European Union’s Horizon 2020 Research and Innovation Programme (grant agreement no. 639382).

Publisher Copyright:
© 2022, The Author(s).

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