Overweight and obesity are significant public health concerns. Merely 20% of overweight individuals achieve sustainable weight loss, leading to repeated cycles of weight loss and gain that are associated with an increased risk of developing metabolic syndrome. Furthermore, menopausal transition correlates with a 60% elevation in metabolic syndrome incidence, which is associated with increased cardiovascular mortality.

Our objective is to investigate the role of the adrenal gland in postmenopausal cardiometabolic complications associated with weight cycling.

Female mice, either ovariectomized (OVX) or sham-operated, were subjected to three cycles of high-fat diet/standard diet (yo-yo diet) or standard diet only for 33 weeks. Functional and molecular analyses were conducted upon completion of each dietary phase.

Compared to sham mice, weight cycling induced greater weight gain in OVX mice, which also exhibited elevated fasting blood glucose and circulating leptin levels. Furthermore, OVX mice under weight cycling showed impaired glucose tolerance and insulin resistance. These mice developed heart failure with preserved ejection fraction, which was prevented by mineralocorticoid receptor antagonist treatment. Histological analysis revealed increased heart weight (Fig. 1a) and enlarged cardiomyocyte cross-sectional area (CSA) in OVX mice after three dietary cycles (Fig. 1b). Notably, ovariectomized mice subjected to weight cycling showed increased adrenal gland mass accompanied by significant morphological and functional remodeling of the adrenal cortex.

OVX induces cardiometabolic disorders that are amplified by weight cycling, and leads to adrenal dysfunction which may, in turn, contribute to the deterioration of cardiometabolic functions.