The Impact of Dietary Interventions on Cardiovascular Dysfunction and Adipose Tissue Inflammation in Non-Obese Prediabetic Rats

Abstract

Cardiovascular diseases are the most common and serious complications of type 2 diabetes mellites (T2DM). Recent evidence suggested that CVDs start at the earliest point of metabolic derangement in the prognosis of diabetes, the prediabetes stage. However, this early onset of CVDs at this subclinical phase makes it harder to diagnose and treat, as according to the international diabetes federation half of prediabetic patients are undiagnosed. In our Sprague-dawley male rats, hypercaloric (HC) feeding for 12-24 weeks exerted signs of metabolic impairment mimicking prediabetes in humans: hyperinsulinemia and insulin resistance with normoglycemia. In addition to increased adiposity with normal body weight. They also presented signs of early cardiovascular insults, endothelial dysfunction, and cardiac autonomic imbalance (the subclinical phase of cardiac autonomic neuropathy). Interestingly, these early cardiovascular events were associated with negative adipose remodeling in a very confined and small pool, the thoracic perivascular pad was observed. Perivascular adipose dysfunction was consistently characterized by hypertrophied adipocytes accompanied with elevated expression of uncoupling protein 1 (UCP1) and the inevitable hypoxia and proinflammatory markers. Our previous work showed that hyperinsulinemia alongside this hypoxia machinery in PVAT were responsible for fueling its inflammation and further exaggerating the observed early cardiovascular impairments. Hence, in this work we try to target different components of this hypoxia machinery using safe and translational dietary interventions, inorganic phosphate supplementation and therapeutic fasting (TF). Moreover, our previous data was based on male rats, so we will try to establish sex differences in the etiology and prognosis of early cardiovascular insults related to early metabolic derangements and adipose inflammation. Indeed, as expected estrogen in ovulating and estrogen treated ovariectomized female rats seemed to protect from HC-induced early metabolic and cardiovascular insults, by improving insulin sensitivity and interrupting the hypoxia machinery in PVAT. Certainly, the loss of endogenous estrogen seemed to exacerbate the outcomes of HC feeding leading to obese prediabetic phenotype, with cardiovascular dysfunction. However, 12 weeks of TF was able to reverse this non- obese prediabetic phenotype in males, and the obese prediabetic one in ovariectomized females, resetting the hypoxia machinery in PVAT and preventing the subsequent cardiovascular dysfunction. Lastly, using inorganic phosphate supplementation was able to interfere with UCP1 activity and expression, disrupting the hypoxia machinery in PVAT, correcting hyperinsulinemia, and eventually preventing early cardiovascular insults.