Sex differences in adipose insulin resistance are linked to obesity, lipolysis and insulin receptor substrate 1

BACKGROUND/OBJECTIVE: Insulin resistance is more prominent in men than women. Whether this involves adipose tissue was examined. SUBJECTS/METHODS: AdipolR (in vivo adipose insulin resistance index) was measured in 2344 women and 787 men. In 259 women and 54 men, insulin-induced inhibition of lipolysis and stimulation of lipogenesis were determined in subcutaneous adipocytes; basal lipolysis was also measured. In 234 women and 115 men, RNAseq of canonical insulin signaling genes was performed in subcutaneous adipose tissue. The most discriminant transcripts were quantified by RT-qPCR in 175 women and 109 men. RESULTS: Men had higher AdipolR than women only when obesity (BMI ≥30 kg/m²) was present (p < 0.0001), a dimorphism observed across physically active/sedentary subgroups, with/without cardiometabolic disease, and with/without nicotine use (p = 0.0003 or less). In obesity, adipocyte insulin sensitivity for antilipolysis (pD2) was ~10-fold lower and maximal antilipolytic effect ~10% lower in men vs women (p = 0.005 or less). Basal lipolysis was approximately two times higher in men (p < 0.0001). Sensitivity and maximum effect of insulin on lipogenesis were similar between sexes (p = 0.26 and p = 0.18). After multiple-comparison correction, only IRS1 expression was lower in men (RNAseq p < 0.0001); IRS1 mRNA was ~60% higher in women by RT-qPCR (p < 0.0001). CONCLUSIONS: In obesity, adipose tissue insulin resistance is more pronounced in men than in women, involving less efficient insulin-mediated inhibition of adipocyte lipolysis, increased basal lipolysis, and decreased adipose expression of IRS1.