Physical Sciences Division
Published January 9, 2025 | Version v1
Journal article Open

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

Creators

  • 1. Harvard University
  • 2. University of Chicago
  • 3. National University of Singapore
  • 4. Helmholtz Institute for Metabolic, Obesity and Vascular Research

Description

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.

Data availability

m6A-sequencing and RNA-sequencing datasets from mouse brown adipose tissue, white adipose tissue, differentiated human brown adipocytes, and differentiated human white adipocytes have been deposited with the National Center for Biotechnology Information Gene Expression Omnibus under accession code GSE250137. Source data are provided in this paper. All data supporting the findings described in this manuscript are available in the article and in the Supplementary Information and from the corresponding author upon request. Source data are provided with this paper.

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Additional details

Identifiers

DOI
10.1038/s41467-024-55694-w
Other
oai:uchicago.tind.io:14385

Funding

National Institutes of Health
R01 DK67536
National Institutes of Health
RC2 DK139552
National Institutes of Health
UC4 DK116278
National Institutes of Health
RM1 HG008935
American Diabetes Association
Mary K. Iacocca Junior Postdoctoral Fellowship
National Institutes of Health
K99 DK135927
Hiroo Kaneda Scholarship, Japan
SUNSTAR Research Fellowship
American Heart Association
903968
Medical School, Harvard University
Eleanor and Miles Shore Program Award
National Institutes of Health
R01 DK102898
National Institutes of Health
R01 DK132469
Deutsche Forschungsgemeinschaft
CRC 1052

UChicago Information

Division(s)
Physical Sciences Division
Department(s)
Chemistry