Endocrine Abstracts

JOINT3950

Overweight and obesity are major public health issues. ~20% of overweight people achieve sustainable weight loss with a risk of repeated weight loss and regain. Obese patients exhibit high plasma leptin levels, but are resistant to its anorectic action. Leptin, and other adipokines, directly regulates adrenal aldosterone biosynthesis, while aldosterone has been implicated in obesity-induced suppression of adiponectin, an insulin sensitizing adipokine, suggesting a central role for aldosterone in the development of overweight-associated comorbidities. Interestingly, aldosterone levels are associated with the development of metabolic syndrome. Weight cycling is associated with fluctuations in blood pressure, heart rate and glomerular filtration, leading to increased risk of developing metabolic syndrome, type-2 diabetes, chronic kidney disease and heart failure, inducing higher mortality, particularly in women. The menopausal transition is associated with a 60% increase in the incidence of metabolic syndrome, which is associated with higher cardiovascular mortality. We hypothesize that adrenal dysfunction, in a postmenopausal context may play a role and has a lasting impact on the increased cardiometabolic risk induced by weight cycling. The aim of our study was to evaluate the impact of weight cycling on adrenal gland function and the impact on the development of cardiometabolic complications in postmenopausal conditions. We established an experimental protocol in which female mice were either ovariectomized (OVX, post-menopause) or not (non-OVX, pre-menopause) and subjected to three weight cycles of high fat diet/standard diet (Yoyo) or maintained on a standard diet throughout. At the end of each phase of the weight cycling protocol, blood samples were collected to assess various metabolic parameters and perform steroid profiling. A variety of tissues (adrenal, heart, adipose tissue…) were collected for further analyses. The yoyo diet led to a greater weight gain in OVX mice compared to non-OVX mice. After ovariectomy, mice exhibited higher fasting blood glucose and circulating leptin levels, an effect that was exacerbated in response to Yoyo diet. Additionally, OVX mice on Yoyo diet chowed impaired glucose tolerance and insulin resistance. These mice developed heart failure with preserved ejection fraction, which was prevented by the use of the mineralocorticoid receptor antagonist, finerenone. Surprisingly, OVX mice on Yoyo diet displayed an increase in adrenal gland weight, accompanied by significant morphological and functional remodeling of the adrenal cortex. The absence of estrogen leads to cardiometabolic disorders that are worsened by the Yoyo diet, as well as adrenal dysfunction, which could, in turn, contribute to the worsening of cardiometabolic comorbidities.