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 InformationFunded by AUB‐FM MPP grant #320148