Sex-dependent differential chromatin state changes in adipocytes across different fat depots during obesity

Abstract

Adipose tissue exhibits a high degree of plasticity and undergoes significant cellular remodeling in response to nutritional availability. While adipose tissue remodeling displays sexual dimorphism, its underlying molecular mechanisms remain poorly understood. In this study, we investigate the role of epigenetic modifications and gene expression in sexual dimorphism of adipose tissue in mice during obesity. We perform CUT&Tag (Cleavage Under Targets and Tagmentation) technique in conjunction with RNA-sequencing with female adipocytes from different fat depots and compare them to male mice. We find significant changes in H3K27ac, H3K27me3, H3K9me3 and RNA-seq after high fat diet (HFD) feeding. The changes are functionally characterized by a reduction in cellular metabolism and an elevation in cytoskeletal organization. Interestingly, these changes commonly occur in both visceral and subcutaneous fat depots with minor differences in females, which distinguishes them from males that exhibit differential responses between depots. Surprisingly, the chromatin states and expression profiles of female subcutaneous fat depots closely resemble those of male visceral adipose tissues during obesity. These results suggest that distinct responses across fat depots in male and females may contribute to different susceptibilities to metabolic diseases between the sexes. These findings enhance our understanding of the molecular mechanisms underlying adipocyte dysfunction during obesity and highlights the interplay between sex, adipose tissue depots, and metabolic responses.