Divergent roles of m6A in orchestrating brown and white adipocyte transcriptomes and systemic metabolism

Ling Xiao; Dario F De Jesus; Cheng-Wei Ju; Jiang-Bo Wei; Jiang Hu; Ava DiStefano-Forti; Valeria Salerno Gonzales; Tadataka Tsuji; Siying Wei; Matthias Blüher; Yu-Hua Tseng; Chuan He; Rohit N Kulkarni

doi:10.1038/s41467-024-55694-w

Divergent roles of m⁶A in orchestrating brown and white adipocyte transcriptomes and systemic metabolism

Nat Commun. 2025 Jan 9;16(1):533. doi: 10.1038/s41467-024-55694-w.

Authors

Affiliations

¹ Section of Islet Cell and Regenerative Biology, Joslin Diabetes Center; Department of Medicine, BIDMC; Harvard Stem Cell Institute, Harvard Medical School, Boston, MA, USA.
² Department of Chemistry, Howard Hughes Medical Institute, The University of Chicago, Chicago, USA.
³ Department of Chemistry, National University of Singapore, Singapore, Singapore.
⁴ Section on Integrative Physiology and Metabolism, Joslin Diabetes Center; Department of Medicine, BIDMC, Harvard Medical School; Harvard Stem Cell Institute, Boston, MA, USA.
⁵ Section of Islet Cell and Regenerative Biology, and CRISPR Screen Core Laboratory, Joslin Diabetes Center; Department of Medicine, BIDMC; Harvard Medical School, Boston, MA, USA.
⁶ Helmholtz Institute for Metabolic, Obesity and Vascular Research, HI, Leipzig, Germany.
⁷ Section of Islet Cell and Regenerative Biology, Joslin Diabetes Center; Department of Medicine, BIDMC; Harvard Stem Cell Institute, Harvard Medical School, Boston, MA, USA. [email protected].

^# Contributed equally.

PMID: 39788955
DOI: 10.1038/s41467-024-55694-w

Abstract

N⁶-methyladenosine (m⁶A) is among the most abundant mRNA modifications, yet its cell-type-specific regulatory roles remain unclear. Here we show that m⁶A methyltransferase-like 14 (METTL14) differentially regulates transcriptome in brown versus white adipose tissue (BAT and WAT), leading to divergent metabolic outcomes. In humans and mice with insulin resistance, METTL14 expression differs significantly from BAT and WAT in the context of its correlation with insulin sensitivity. Mettl14-knockout in BAT promotes prostaglandin secretion, improving systemic insulin sensitivity. Conversely, Mettl14-knockout in WAT triggers adipocyte apoptosis and systemic insulin resistance. m⁶A-seq and RNA-seq integration revealed upregulated prostaglandin biosynthesis pathways in BAT and apoptotic pathways in WAT with Mettl14 deficiency. Stable METTL14-knockout hBAs/hWAs show METTL14-mediated m⁶A promotes mRNA decay of PTGES2 and CBR1 in hBAs and TRAIL and TNFR1 in hWAs. These data shed light on the ability of m⁶A to impact metabolism in a cell-type-specific manner with implications for influencing the pathophysiology of metabolic diseases.

MeSH terms

Adenosine* / analogs & derivatives
Adenosine* / metabolism
Adipocytes, Brown / metabolism
Adipocytes, White* / metabolism
Adipose Tissue, Brown / metabolism
Adipose Tissue, White / metabolism
Animals
Apoptosis* / genetics
Humans
Insulin Resistance* / genetics
Male
Methyltransferases* / genetics
Methyltransferases* / metabolism
Mice
Mice, Inbred C57BL
Mice, Knockout*
RNA Stability
RNA, Messenger / genetics
RNA, Messenger / metabolism
Receptors, Tumor Necrosis Factor, Type I / genetics
Receptors, Tumor Necrosis Factor, Type I / metabolism
TNF-Related Apoptosis-Inducing Ligand / genetics
TNF-Related Apoptosis-Inducing Ligand / metabolism
Transcriptome*

Substances

Adenosine
N-methyladenosine
Methyltransferases
Mettl14 protein, mouse
METTL14 protein, human
TNF-Related Apoptosis-Inducing Ligand
Receptors, Tumor Necrosis Factor, Type I
RNA, Messenger

Abstract

MeSH terms

Substances

Grants and funding