Sexual Dimorphism of the Fasting Adipose: Mitigation of Metabolic and Cardiovascular Dysfunction in a Non-Obese Prediabetic Rat Model

Abstract

<b>Abstract ID 15333</b> <b>Poster Board 358</b> Prediabetes is a transitional stage in the progression of Type 2 Diabetes where diabetes-related cardiovascular (CV) complications begin. Our previous work on non-obese prediabetic male rats showed that early CV and metabolic impairments were associated with confined dysfunction in the thoracic perivascular adipose tissue (PVAT) characterized by inflammation and hypoxia. There has been neither recommendations for pharmacological treatment to interrupt the hypoxic machinery in PVAT, nor clear sexual dimorphism in PVAT involvement at this stage, we therefore hypothesized that therapeutic fasting (TF) can alleviate PVAT dysfunction, metabolic and CV stress among Mild hyper-caloric (MHC)-fed rats in a sex dependent manner. Sprague-Dawley rats from both sexes (4-5weeks) were allocated into 3 groups: control diet (C), MHC diet and MHC-diet with TF, for 24 weeks. Rats were fed ad libitum in the first 12 weeks. Afterwards, the TF group were subjected to daily fasting from 7.00pm -7.00am for 12 weeks with free access to water, and to MHC-diet otherwise. Daily food intake, body weight, blood glucose, body composition (using NMR), HbA1c, serum insulin levels, echocardiographic parameters, and noninvasive blood pressure were measured. At week 24; rats were catheterized for invasive hemodynamic examination. Cardiac autonomic neuropathy was assessed by measuring baroreceptor sensitivity using the vasoactive method. After sacrifice, aortic contractility and endothelial function were measured using organ bath experiments and molecular investigation was performed on various adipose pools, in addition to cardiac and aortic tissues. To assess the role of female sex hormones 3 additional groups of females were bilaterally ovariectomized (OVX) on week 12, then the same feeding groups (C, MHC and MH-TF) were applied for the remaining 12 weeks. The same set of parameters and experiments were measured and conducted. As expected, MHC feeding induced non-obese prediabetes, signs of early cardiovascular and metabolic dysfunction with and PVAT impairment in male rats. Intact female rats resisted MHC-induced derangements, while OVX females presented an obese prediabetic phenotype, with CV and metabolic impairments and PVAT dysfunction. Moreover, on the molecular and histochemical levels, cardiac and aortic tissues as well as brainstem presented pathologies in the MHC arms presented by increased macrophage infiltration and oxidative stress in all tissues, plus an increased fibrosis in the cardiac and aortic ones. Strikingly, TF in the presence of MHC feeding and in the absence of calorie restriction, and estrogen in the case of females, seemed to substantially correct these alterations in both male and OVX rats and interrupt hypoxia in PVAT. Taken together, our work suggests a novel understanding whereby TF interferes with the hypoxia machinery in PVAT and mitigates prediabetes and related CV insults in a sex dependent manner.