Excess dietary zinc drives a Cushing's-like syndrome in ovariectomized mice – Implications for postmenopausal obesity

Postmenopausal women have an increased risk of obesity, but the underlying cause is not clear. We unexpectedly found that excess dietary zinc induced severe obesity and a Cushing's-like syndrome without increased food intake in ovariectomized (Ovx) but not in sham-operated mice. Zinc accumulated in the adrenal glands and inhibited adrenal 17,20-lyase activity and steroid synthesis. As adrenal steroids are the only source of estrogen in Ovx mice, estrogen deficiency induced adrenal hyperplasia, glucocorticoid overproduction, and consequent development of a Cushing's-like syndrome. Adrenal steroid supplementation prevented the effects of zinc. Plasma zinc was positively correlated with cortisol level and negatively correlated with the levels of adrenal steroids and estrogen in obese postmenopausal women. The finding of a link between dietary zinc, estrogen deficiency, and postmenopausal obesity, implies that postmenopausal obesity might be prevented by supplementation with a adrenal steroid and avoiding excess dietary zinc. • Excess zinc inhibited adrenal 17,20-lyase activity and adrenal steroid production. • Excess zinc stimulated adrenal hyperplasia and excessive glucocorticoids in Ovx mice. • Plasma zinc correlated with cortisol, estrogen, and obesity in postmenopausal women. • Steroid supplementation prevented the zinc-induced a Cushing's-like syndrome in Ovx mice.