Chronic cAMP activation induces adipocyte browning through discordant biphasic remodeling of transcriptome and chromatin accessibility

dc.contributor.authorSo, Jisun
dc.contributor.authorTaleb, Solaema
dc.contributor.authorWann, Jamie
dc.contributor.authorStrobel, Olivia
dc.contributor.authorKim, Kyungchan
dc.contributor.authorRoh, Hyun Cheol
dc.contributor.departmentBiochemistry and Molecular Biology, School of Medicine
dc.date.accessioned2023-09-25T15:56:34Z
dc.date.available2023-09-25T15:56:34Z
dc.date.issued2022
dc.description.abstractObjective: Adipose tissue thermogenesis has been suggested as a new therapeutic target to promote energy metabolism for obesity and metabolic disease. Cold-inducible thermogenic adipocytes, called beige adipocytes, have attracted significant attention for their potent anti-obesity activity in adult humans. In this study, we identified the mechanisms underlying beige adipocyte recruitment, so-called adipocyte browning, by different stimuli. Methods: We generated a new adipocyte cell line with enhanced browning potentials and determined its transcriptomic and epigenomic responses following cAMP (forskolin, FSK) versus PPARγ activation (rosiglitazone). We performed time-course RNA-seq and compared the treatments and in vivo adipocyte browning. We also developed an improved protocol for Assay for Transposase Accessible Chromatin-sequencing (ATAC-seq) and defined changes in chromatin accessibility in a time course. The RNA-seq and ATAC-seq data were integrated to determine the kinetics of their coordinated regulation and to identify a transcription factor that drives these processes. We conducted functional studies using pharmacological and genetic approaches with specific inhibitors and shRNA-mediated knockdown, respectively. Results: FSK, not rosiglitazone, resulted in a biphasic transcriptomic response, resembling the kinetics of in vivo cold-induced browning. FSK promoted tissue remodeling first and subsequently shifted energy metabolism, concluding with a transcriptomic profile similar to that induced by rosiglitazone. The thermogenic effects of FSK were abolished by PPARγ antagonists, indicating PPARγ as a converging point. ATAC-seq uncovered that FSK leads to a significant chromatin remodeling that precedes or persists beyond transcriptomic changes, whereas rosiglitazone induces minimal changes. Motif analysis identified nuclear factor, interleukin 3 regulated (NFIL3) as a transcriptional regulator connecting the biphasic response of FSK-induced browning, as indicated by disrupted thermogenesis with NFIL3 knockdown. Conclusions: Our findings elucidated unique dynamics of the transcriptomic and epigenomic remodeling in adipocyte browning, providing new mechanistic insights into adipose thermogenesis and molecular targets for obesity treatment.
dc.eprint.versionFinal published version
dc.identifier.citationSo J, Taleb S, Wann J, Strobel O, Kim K, Roh HC. Chronic cAMP activation induces adipocyte browning through discordant biphasic remodeling of transcriptome and chromatin accessibility. Mol Metab. 2022;66:101619. doi:10.1016/j.molmet.2022.101619
dc.identifier.urihttps://hdl.handle.net/1805/35776
dc.language.isoen_US
dc.publisherElsevier
dc.relation.isversionof10.1016/j.molmet.2022.101619
dc.relation.journalMolecular Metabolism
dc.rightsAttribution-NonCommercial-NoDerivatives 4.0 Internationalen
dc.rights.urihttp://creativecommons.org/licenses/by-nc-nd/4.0/
dc.sourcePMC
dc.subjectBeige adipocyte
dc.subjectTranscriptome
dc.subjectEpigenome
dc.subjectNFIL3
dc.subjectCellular reprogramming
dc.subjectObesity
dc.titleChronic cAMP activation induces adipocyte browning through discordant biphasic remodeling of transcriptome and chromatin accessibility
dc.typeArticle
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