METTL14-mediated m6A differentially orchestrates brown and white adipose tissue transcriptomes to regulate systemic metabolism

Human brown and white adipocytes (hBAT and hWAT) display markedly distinct m6A landscapes; besides, in insulin-resistant humans and mice, methyltransferase like 14 (METTL14) expression differs significantly between BAT and WAT in the context of its correlation with insulin sensitivity. We therefore employed independent BAT- and WAT-specific METTL14 knockout models to unveil the cell-type specificity of m6A mRNA methylation. Mettl14 knockout via Ucp1-cre or Adipoq-cre drivers in BAT and WAT, respectively, yields divergent metabolic outcomes in mouse. Mettl14fl/fl mice on a C57BL/6N background (De Jesus et al. 2019) were crossed with Ucp1cre strain (stock no.024670, the Jackson Laboratory) or Adipoqcre strain (stock no.028020, the Jackson Laboratory) mice, which do not harbor the nicotinamide nucleotide transhydrogenase (Nnt) mutation, to generate the knockouts. For studies on diet-induced obesity and long-term insulin resistance, M14fl/fl,M14fl/fl-Ucp1cre, and M14fl/fl-Adipoqcre mice were fed either 10% fat LFD or a conventional 60% fat HFD for 14 weeks, starting at 6 weeks of age. To examine tissue-specific insulin sensitivity, mice were fasted for 16 hours.