Sex-Specific Subcutaneous Adipose Tissue Transcriptome in Obesity: Insights From Monozygotic Twin Pairs Discordant for BMI.

Abstract

We investigated the impact of sex on the subcutaneous adipose tissue (AT) transcriptome and its obesity-related adaptations. We studied rare BMI-discordant monozygotic twin pairs (ΔBMI > 2.5 kg/m²; 21 female, 16 male pairs) to assess how sex affects AT and whole-body metabolism. AT RNA sequencing was analyzed using linear mixed modeling and pathway enrichment for: (1) sex differences in individual twins, adjusted for BMI, (2) sex-stratified effects of acquired obesity (ΔBMI between co-twins separately in females and males), (3) sex-specific effects of obesity (differences in the ΔBMI effect between sexes). (1) AT transcriptional profiles differed between sexes, associating with insulin sensitivity. (2) Sex-stratified obesity effects within pairs were stronger in females, with upregulated inflammation and downregulated mitochondrial oxidative phosphorylation; males showed increased inflammation and decreased histone modification. (3) The response to obesity was sex-specific: lower expression of genes in unsaturated fatty acid metabolism in obesity was seen in females only. Sex-specific obesity AT gene expression was associated with metabolic health, with a negative association between unsaturated fatty acid metabolism and insulin sensitivity in males only. Biological sex influences the AT transcriptome and its response to obesity, highlighting distinct molecular mechanisms that may contribute to sex-specific metabolic health.