The epigenetic mechanisms regulating adipose tissue development and function are poorly understood. In this study, we show that depletion of histone H3K36 methylation by H3.3K36M in preadipocytes inhibits adipogenesis by increasing H3K27me3 to prevent the induction of C/EBPα and other targets of the master adipogenic transcription factor peroxisome proliferator-activated receptor-γ (PPARγ). Depleting H3K36 methyltransferase Nsd2, but not Nsd1 or Setd2, phenocopies the effects of H3.3K36M on adipogenesis and PPARγ target expression. Consistently, expression of H3.3K36M in progenitor cells impairs brown adipose tissue (BAT) and muscle development in mice. In contrast, depletion of histone H3K36 methylation by H3.3K36M in adipocytes in vivo does not affect adipose tissue weight, but leads to profound whitening of BAT and insulin resistance in white adipose tissue (WAT). These mice are resistant to high fat diet-induced WAT expansion and show severe lipodystrophy. Together, these results suggest a critical role of Nsd2-mediated H3K36 methylation in adipose tissue development and function.