Weight cycling is associated with fluctuations in blood pressure, heart rate and kidney filtration, leading to increased risk of diabetes, vascular damage, renal and cardiovascular disease, inducing higher mortality, particularly in women.

In mice with pre- or post-menopausal condition 4weeks after ovariectomy (Ovx), we induced weight cycling (WC) along two phases of high-fat-sucrose (HFS) diet interspersed with calorie restriction under a standard diet phase (SD) (each phase lasting 4weeks). In addition, finerenone (Fine) treatment (1.5mg/kg/day, gavage) was administered during the SD phase only, in order to restrict the development of a harmful memory and its rebound consequences on the successive phase of overweight.

Global metabolism was assessed by oral glucose and insulin tolerance tests. Functional study of the left ventricle (LV) was carried out using ultrasound and invasive hemodynamics.

During the protocol, ultrasound showed no decrease in fraction shortening, i.e. ejection fraction. At the end of the first phase of HFS diet, there was overweight in all mice and decreased glucose tolerance in Ovx mice only, which was recovered after 4weeks of calorie restriction under SD, although no mice returned to their starting weight before HFS diet. At the end of the second HFS diet phase, Ovx mice were bigger than non-Ovx mice, and all weight-cycler mice had increased fasting blood glucose, impaired glucose tolerance and impaired insulin tolerance. In addition, all weight-cycler mice had HFpEF with impaired LV compliance. Previous finerenone treatment, limited to the calorie restriction SD phase, allowed restricting the rebound effect on weight regain, allowed improving glucose tolerance in non-Ovx mice, and allowed improving insulin sensitivity in both non-Ovx and Ovx mice. Remarkably, finerenone allowed preventing the development of HFpEF in WC mice (LV compliance, mmHg/RVU: Ctrl 1.67±0.50, WC 6.69±0.67*, WC+Fine 4.06±0.96$; Ctrl+Ovx 4.36±0.44, WC+Ovx 8.28±1.18*, WC+Ovx+Fine 1.85±0.29 $;* vs. Ctrl, $ vs. untreated).

Data show that during WC in female mice, with 2 phases of HFS diet-induced weight gain, finerenone treatment limited to an interspersed calorie restriction phase limits body mass regain, ameliorates global metabolism over the overweight resurgence and prevents the development of HFpEF. Moreover, finerenone remains efficient even in post-menopausal context associated with a worsening of the phenotype.