Overweight and obesity are major public health issues. Central obesity is associated with the risk of developing a metabolic syndrome. However, less than 20% of overweight people achieve sustainable weight loss, leading to repeated cycles of weight loss and regain, which are particularly associated with an increased risk of developing metabolic syndrome. Moreover, in postmenopausal women, estrogen deficiency promotes metabolic and endothelial dysfunction, further predisposing them to metabolic syndrome and its cardiovascular complications. Furthermore, leptin, an adipokine whose levels are higher in obese patients, especially in women, directly stimulates aldosterone production, suggesting that the adrenal glands could be a comorbidity factor in metabolic diseases. During estrogen deficiency, such as in menopause, there is an increase in Luteinizing Hormone (LH), due to the loss of negative feedback by sex steroid. In experimental studies, menopause increases aldosterone levels, an effect alleviated by estrogen treatment, while other studies have shown a decrease in aldosterone levels in postmenopausal women.

All these observations support a strong physiological and/or pathological link between the sex steroids’ status (pre- or post-menopausal) and aldosterone synthesis and secretion. In turn, excess aldosterone could lead to cardiovascular and metabolic alterations

Our objective is to assess the role of the adrenal gland in postmenopausal cardiometabolic complications associated with cyclic weight variations.

For this purpose, female mice, both ovariectomized and non-ovariectomized, were subjected to three cycles of a high-fat diet/standard diet (yo-yo diet) or to a standard diet for 33 weeks. Functional and molecular explorations were performed at the end of each phase.

The yo-yo diet induced greater weight gain in ovariectomized mice compared to non-ovariectomized mice. Post-ovariectomy, the mice exhibited higher fasting blood glucose levels and circulating leptin levels, an effect that was more pronounced when the mice were subjected to the yo-yo diet. Ovariectomized mice on the yo-yo diet developed heart failure with preserved ejection fraction, which was prevented by the use of a mineralocorticoid receptor antagonist. Interestingly, ovariectomized mice on the yo-yo diet showed an increase in adrenal gland weight, accompanied by significant morphological and functional remodeling of the adrenal cortex.

The absence of estrogens leads to cardiometabolic disorders that are worsened by a yo-yo diet but also to adrenal dysfunction, which could in turn contribute to the worsening of cardiometabolic functions.