The m6A reader YTHDF1 modulates adipocyte mitochondrial remodeling and diet-induced adiposity through translational control of NOD1.

The excessive expansion of white adipose tissue (WAT) that characterizes obesity is a major global health concern. N6-methyladenosine (m6A) modification and its readers regulate metabolic homeostasis, but how m6A-dependent translational control shapes mitochondrial remodeling in white adipocytes during obesity remains unclear. In this study, we examined the function of the m6A reader YTHDF1 in diet-induced adiposity using whole-body and adipocyte-specific Ythdf1 knockout mice, together with primary adipocyte models. Under high-fat diet (HFD) feeding, both Ythdf1-/- and Ythdf1AKO mice developed greater obesity with WAT hypertrophy and metabolic dysfunction. YTHDF1 was enriched in adipocyte precursor cells and downregulated during adipogenesis and in WAT from obese mice. RNA sequencing of differentiating adipocytes revealed that Ythdf1 deficiency rewired energy metabolism, with enrichment of tricarboxylic acid cycle and oxidative phosphorylation pathways, increased mitochondrial remodeling, and enhanced lipid accumulation. Mechanistically, functional studies combined with RIP-qPCR, reporter assays and polysome profiling supported Nod1 as an m6A-responsive translational target of YTHDF1 in adipocytes, sustaining NOD1 protein abundance in WAT. Ythdf1 deletion reduced NOD1 protein abundance and enhanced mitochondrial- and lipid-associated readouts, whereas NOD1 overexpression attenuated these phenotypes in Ythdf1-deficient adipocytes. SERCA1 protein abundance was also altered upon Ythdf1/Nod1 perturbation, suggesting a possible association between the YTHDF1-NOD1 pathway and SERCA1-related calcium handling in adipocytes. Together, these findings identify YTHDF1 as an m6A reader that limits diet-induced adiposity and adipocyte mitochondrial remodeling, at least partly through maintaining NOD1 protein abundance, with SERCA1 emerging as a candidate molecule associated with Ythdf1/Nod1 perturbation.