Therapeutic fasting mitigates metabolic and cardiovascular dysfunction in a prediabetic rat model: Possible role of adipose inflammation

Abstract

The risk of cardiovascular complications in type 2 diabetes increases as early as in the prediabetic stage. Our previous studies showed that perivascular adipose tissue inflammation contributes to vascular and cardiac autonomic dysfunction in prediabetic rats. Intermittent fasting has been extensively studied in the management of metabolic diseases. Here, we aim to examine the impact of therapeutic fasting (TF) on the metabolic and cardiovascular stress among prediabetic rats. Male SD rats (4–5weeks) were randomly allocated into 3 dietary groups; control diet (C), high‐calorie (HC) diet and HC‐diet with TF, for 24 weeks. Rats were fed ad libitum in the first 12 weeks. Afterwards, the TF group was subjected to daily fasting from 7.00pm – 7.00am (during the dark period) for 12 weeks with free access to water, and to HC‐diet during the light phase. Daily food intake, body weight (BW), blood glucose (fasting FBG and random RBG), body composition (BC) (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 (CAN) was assessed by measuring baroreceptor sensitivity (BRS) using the vasoactive method. After sacrifice, aortic contractility and endothelial function were assessed using organ bath experiments. Daily calorie intake was higher in the HC group compared to control with no difference in body weight, blood glucose level, HbA1c, and glucose tolerance. Similar to our previous observations, HC feeding led to an increased fat/lean ratio, increased serum insulin level, insulin resistance, increased vascular reactivity, and reduced endothelium‐dependent relaxation. Despite a lack of effect on daily calorie intake, the previous parameters were reversed by TF. As well, SBP was higher in the HC‐fed rats (137.7 vs. 119 mm Hg), which was reversed in TF rats. This could be explained based on the observed increase in vascular sensitivity to phenylephrine‐induced contraction (pEC50 5.95 vs. 5.53) and a reduced acetylcholine mediated endothelium‐dependent relaxation in HC rats. Both observations were normalized in TF rats. Moreover, HC‐fed rats showed parasympathetic CAN manifesting as reduced BRS (DMAP vs. DHR slope decreased to −0.15 from −0.4) that was reversed in TF. Our results indicate that HC feeding induced vascular and cardiac autonomic dysfunction secondary to perivascular adipose inflammation. TF reverses signs of cardiovascular impairment. Future studies will be conducted to assess the effect of TF on PVAT inflammation. Support or Funding Information Funded by AUB‐FM MPP grant #320148

Modulatory Effect of Intermittent Fasting on Adipose Tissue Inflammation: Amelioration of Cardiovascular Dysfunction in Early Metabolic Impairment

“…Interestingly, the change in fat pad size was found to be triggered by IF alone, regardless of the daily caloric intake, and independent of the change in body weight as animal studies showed a decrease in size and weight of adipose depots, with mild or no change in total body weight (Varady et al, 2007;Varady et al, 2009;Varady et al, 2010;Liu et al, 2019b). Certainly in our work, a calorie restricted regimen of a HFD failed to exert any corrective effect on CAN and PVAT inflammation involvement in rats (Al-Assi et al, 2018) as opposed to isocaloric IF (12-h feeding/12-h fasting) (Dwaib et al, 2020). In studies involving obese human subjects, IF appeared to reduce total fat mass with varying fasting protocols such as intermittent continuous energy restriction for 2 days a week and alternate day fasting (Harvie et al, 2011;Bhutani et al, 2013;Tinsley and La Bounty, 2015), and circulating markers of inflammation (Harvie et al, 2011;Wang et al, 2020), the latter effect being more marked in obese than in normal weight subjects (Wang et al, 2020).…”

“…Another study on a rat model found that both 40% calorie restriction and alternate day fasting reduced the low frequency component in the diastolic blood pressure variability, a marker of reduced sympathetic activity, and increased high frequency component in heart rate variability, which is reflective of the parasympathetic tone, both being indicative of positive modulation of cardiovascular state (Mager et al, 2006). Specifically, in the context of early metabolic dysfunction, preliminary data indicate that not only did IF (12-h feeding/12-h fasting) improve parasympathetic cardiac autonomic neuropathy, this was also associated with amelioration of PVAT inflammation in an HFD-fed rat model of metabolic dysfunction (Dwaib et al, 2020).…”

Predictive Capacity of Beat-to-Beat Blood Pressure Variability for Cardioautonomic and Vascular Dysfunction in Early Metabolic Challenge

“…Calorie intake was determined for each rat based on the amount of food consumed daily. Anesthetized rats were sacrificed by decapitation after 12 (age = 17 weeks) or 24 weeks (age = 29 weeks) of feeding (Dwaib et al, 2020).…”

Cardiac Autonomic Neuropathy: A Progressive Consequence of Chronic Low-Grade Inflammation in Type 2 Diabetes and Related Metabolic Disorders

“…While the search for such tools is ongoing, simple interventions leading to this outcome might include modification of caloric intake. Indeed, previous research showed that approaches involving caloric restriction and intermittent fasting were associated with an ameliorative effect on both perivascular adipose inflammation and CAN [99,136].…”