Abstract
Our group has previously reported that lack of adipose tissue (lipodystrophy) leads to glucose intolerance and impaired endothelial-dependent vasorelaxation (EDR) via reduced signaling of the adipokine, leptin in the endothelium. However, the identity of the adipose depot responsible for endothelial leptin signaling activation and the underlying mechanism remains ill-defined. Our new data indicate that the perivascular adipose tissue (PVAT) is an important source of leptin. Thus, we hypothesized that leptin specifically derived from PVAT restores EDR and glucose tolerance in a mouse model with global deficiency in adipose tissue (lipodystrophic, BSCL2 -/- ). Restoration of PVAT in BSCL2 -/- mice corrected systemic glycemic status (GTT AUC, BSCL2 -/- + PVAT 635.3 ± 31.28 vs sham 741.6 ± 45.87, p<0.05). Moreover, PVAT transplantation restored EDR locally (abdominal aorta EDR AUC, BSCL2 -/- + PVAT 224.9 ± 23.97 vs 109 ± 19, P<0.05) but not systemically (thoracic aorta EDR AUC, BSCL2 -/- + PVAT 143.8 ± 22.29 vs sham 131.3 ± 11.54, P<0.05), indicating a distinctive paracrine role for PVAT-derived leptin in the vasculature. Concomitantly, we reported that inhibition of endothelial glycolysis, the main bioenergetic pathway of endothelial cells, via inhibition of 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 3 (PFKFB3), a major regulator of the glycolytic pathway, significantly improved endothelial function in both lipodystrophic mice and endothelial leptin receptor (LepR) deficient mice, as leptin does. Also, endothelial cells extracted from aortas of BSCL2 -/- mice showed a trend towards an increase in PFKFB3 mRNA expression compared to WT mice. Moreover, we found that overexpression of PFKFB3 in aortic rings and endothelial cells impaired EDR and increased the ROS generating enzyme, Nox1 expression, respectively. Collectively, our results showed the critical role of PVAT-driven leptin and endothelial leptin receptor signaling in regulating systemic glucose disposal as well as endothelial function via a mechanism that potentially regulates endothelial glycolysis and oxidative stress-mediated via PFKFB3/NOX1.
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