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 () and Susanne Mandrup ()
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Lasse K. Markussen: University of Southern Denmark
Elizabeth A. Rondini: Wayne State University
Olivia Sveidahl Johansen: Center for Adipocyte Signaling (AdipoSign)
Jesper G. S. Madsen: University of Southern Denmark
Elahu G. Sustarsic: University of Copenhagen
Ann-Britt Marcher: University of Southern Denmark
Jacob B. Hansen: University of Copenhagen
Zachary Gerhart-Hines: Center for Adipocyte Signaling (AdipoSign)
James G. Granneman: Wayne State University
Susanne Mandrup: University of Southern Denmark

Nature Communications, 2022, vol. 13, issue 1, 1-16

Abstract: 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.

Date: 2022
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DOI: 10.1038/s41467-022-31525-8

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