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Major shifts in human lifestyle and dietary habits toward sedentary behavior and refined food intake triggered steep increase in the incidence of metabolic disorders including obesity and Type 2 diabetes. Patients with metabolic disease are at a high risk of cardiovascular complications ranging from microvascular dysfunction to cardiometabolic syndromes including heart failure. Despite significant advances in the standards of care for obese and diabetic patients, current therapeutic approaches are not always successful in averting the accompanying cardiovascular deterioration. There is a strong relationship between adipose inflammation seen in metabolic disorders and detrimental changes in cardiovascular structure and function. The particular importance of epicardial and perivascular adipose pools emerged as main modulators of the physiology or pathology of heart and blood vessels. Here, we review the peculiarities of these two fat depots in terms of their origin, function, and pathological changes during metabolic deterioration. We highlight the rationale for pharmacological targeting of the perivascular and epicardial adipose tissue or associated signaling pathways as potential disease modifying approaches in cardiometabolic syndromes.

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Background The complexity of the interaction between metabolic dysfunction and cardiovascular complications has long been recognized to extend beyond simple perturbations of blood glucose levels. Yet, structured interventions targeting the root pathologies are not forthcoming. Growing evidence implicates the inflammatory changes occurring in perivascular adipose tissue (PVAT) as early instigators of cardiovascular deterioration. Methods and Results We used a nonobese prediabetic rat model with localized PVAT inflammation induced by hypercaloric diet feeding, which dilutes inorganic phosphorus (Pi) to energy ratio by 50%, to investigate whether Pi supplementation ameliorates the early metabolic impairment. A 12‐week Pi supplementation at concentrations equivalent to and twice as much as that in the control diet was performed. The localized PVAT inflammation was reversed in a dose‐dependent manner. The increased expression of UCP1 (uncoupling protein1), HIF‐1α (hypoxia inducible factor‐1α), and IL‐1β (interleukin‐1β), representing the hallmark of PVAT inflammation in this rat model, were reversed, with normalization of PVAT macrophage polarization. Pi supplementation restored the metabolic efficiency consistent with its putative role as an UCP1 inhibitor. Alongside, parasympathetic autonomic and cerebrovascular dysfunction function observed in the prediabetic model was reversed, together with the mitigation of multiple molecular and histological cardiovascular damage markers. Significantly, a Pi‐deficient control diet neither induced PVAT inflammation nor cardiovascular dysfunction, whereas Pi reinstatement in the diet after a 10‐week exposure to a hypercaloric low‐Pi diet ameliorated the dysfunction. Conclusions Our present results propose Pi supplementation as a simple intervention to reverse PVAT inflammation and its early cardiovascular consequences, possibly through the interference with hypercaloric‐induced increase in UCP1 expression/activity.

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