Inhibition of lipolysis in visceral adipose tissue from obese mice and humans prevents impairment of endothelial Kir2.1 channels.

Accumulation of abdominal visceral adipose tissue (VAT) is a major risk factor for cardiovascular disease. Obesity-induced endothelial dysfunction is a precursor to severe disease, and we and others have shown that arteries embedded in VAT, but not subcutaneous adipose tissue, exhibit robust endothelial dysfunction. Using a mouse model of diet-induced obesity, we recently linked VAT from obese mice to the impairment of endothelial Kir2.1, a critical regulator of endothelial function. However, the mechanism by which VAT impairs Kir2.1 is unclear. As Kir2.1 impairment is dependent on endothelial CD36, we hypothesized that lipolytic VAT induces Kir2.1 impairment through fatty acids (FA). To test this, we first treated endothelial cells with palmitic acid (PA) to determine whether the addition of exogenous FAs recapitulated our original finding of Kir2.1 dysfunction when challenged with VAT. PA inhibited Kir2.1 assessed via whole-cell patch-clamp electrophysiology, an effect that was dependent on endothelial CD36. To determine whether inhibiting VAT lipolysis prevents Kir2.1 dysfunction in the presence of VAT in obese mice and humans, VAT was pretreated with small molecule inhibitors of adipose triglyceride lipase prior to incubating endothelial cells with adipose tissue. This approach also prevented VAT-induced impairment of endothelial Kir2.1 suggesting that VAT-derived FAs may play a role. Furthermore, inhibition of lipolysis in the VAT of obese mice and humans significantly reduced endothelial FA uptake, similar to that observed when CD36 was downregulated. These findings advance our understanding of the relationship between VAT and endothelial Kir2.1 impairment and place VAT-derived FAs as potential paracrine mediators.