Objective The aim of this study was to examine the effects of sex and menopausal status on depot‐specific estrogen signaling in white adipose tissue (AT) in age‐matched men and women with morbid obesity. Methods A total of 28 premenopausal women, 16 postmenopausal women, and 27 age‐matched men undergoing bariatric surgery were compared for omental (OM) AT (OMAT) and abdominal subcutaneous (SQ) AT (SQAT) genes and proteins. Results With the exception of fasting nonesterified fatty acids being higher in women (P < 0.01), no differences were found in other indicators of glucose and lipid metabolism. In OMAT, estrogen receptor (ER) beta (ERβ) levels were higher in older women than in younger women and older men (sex‐age interaction, P < 0.01), and aromatase expression was higher in older men than in older women (P < 0.05). In SQAT, women had lower expression of ERβ than men (P < 0.05). Protein content of ER alpha and ERβ was highly correlated with the mitochondrial protein uncoupling protein 1 across sexes and ages (P < 0.001). Age increased SQ inflammatory gene expression in both sexes. Conclusions In morbid obesity, sex and age affect AT ERs, lipid metabolism, mitochondrial uncoupling protein 1, and inflammatory expression in an AT depot–dependent manner. The SQAT immunometabolic profile is heavily influenced by age and menopause status, more so than OMAT.

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