Characterizing left ventricular diastolic function, exercise capacity and the adrenal cortex after yoyo diet-induced weight-cycling in mice with or without ovariectomy-induced post-menopausal condition

Studies report that only ∼20% of overweight people achieve sustainable weight loss with the risk to incur weight cycling. The over-shoot theory relates to an increased risk to develop metabolic syndrome (metS) and associated cardiovascular dysfunctions with successive phases of weight gain. In women, the prevalence of metS and heart failure with preserved ejection fraction (HFpEF) increases after menopause. To characterize the cardiac and adrenal consequences of yoyo-dieting in female mice with or without ovariectomy-induced post-menopausal condition. After ovariectomy (OVX) or not, mice were subjected to 3 cycles of a 60% high fat diet (HFD, 4-week duration) followed by a standard diet (SD) (increasing duration of 4, 6 and 10 weeks). Non-OVX control mice (CTL) were fed a SD. To assess the development of HFpEF, left ventricular (LV) function was characterized by ultrasound and invasive hemodynamics. Exercise capacity was evaluated on a treadmill. The morphology of the adrenal gland was described using HES staining, Sirius Red and immunofluorescence. Adrenal function and the vascular network were assessed using RT-qPCR to quantify mRNA expression for genes involved respectively in steroidogenesis and angiogenesis. At the end of the protocol, Yoyo mice had incomplete weight recovery and an insulin tolerance test indicated decreased sensitivity to the hormone. Moreover, there was an increase in LV-end-diastolic-pressure-volume-relation in OVX-Yoyo mice compared to CTL mice, indicating decreased compliance. In addition, the absence of difference in systolic fractional shortening (i.e., ejection fraction) and a lower exercise capacity in OVX-Yoyo mice compared to CTL demonstrated HFpEF. These OVX-Yoyo mice had major disorganization and remodeling in the adrenal gland with the apparition of dysplasia and fibrosis throughout the cortex. The vascular architecture was also affected, with lower expression of Vegf-a. Despite higher adrenal weight, there was no difference in cell proliferation. Whereas CYP11B2 expression, coding for the aldosterone synthase was not affected, the mRNA expression of CYP11B1, involved in glucocorticoids biosynthesis, was lower in OVX-Yoyo mice. Female mice in post-menopausal condition and subjected to yoyo-dieting showed an increased risk of developing HFpEF as well as major morphological and functional differences in the adrenal cortex.