Perivascular Adipose Tissue Controls Insulin-Stimulated Perfusion and Glucose Uptake in Muscle through Adipomuscular Microvascular Anastomoses

Abstract

Insulin-mediated microvascular recruitment (IMVR) regulates delivery of insulin and glucose to insulin-sensitive tissues. We have previously proposed that perivascular adipose tissue (PVAT) controls glucose metabolism and vascular function through outside-to-inside communication and through vessel-to-vessel, or “vasocrine” signaling. Here, we studied this hypothesis in mice by examining effects of removal of local intramuscular PVAT on muscle blood flow and glucose metabolism. Using the hyperinsulinemic, euglycemic clamp (HEC) in combination with positron emission tomography, we found that local PVAT removal transiently reduces muscle glucose uptake by ±50 percent. Contrast-enhanced ultrasonography and intravital microscopy of the gracilis artery (GA) during the HEC showed that PVAT removal abolishes insulin-induced increases in GA diameter and abrogated insulin-stimulated muscle blood volume (microvascular recruitment or IMVR). The effect of PVAT on IMVR was mediated by distinct microvessels or anastomoses, which we showed using lightsheet microscopy of mice expressing mCherry in endothelial cells. Proteomics analysis revealed that PVAT removal significantly alters expression of 109 of 1719 detected proteins in muscle. Observed changes in protein expression included reduction of a mitochondrial protein cluster and of vesicle-associated membrane protein 5 (Vamp5), involved in Glut4 trafficking. In conclusion, we have found that PVAT within muscle regulates muscle perfusion, glucose uptake and muscle protein expression, communicating with the distal microcirculation via microvascular anastomoses. These data highlight the importance of PVAT in vascular and metabolic physiology, and are relevant for type 2 diabetes and associated muscle dysfunction. Disclosure A.H. Turaihi: None. E.H. Serne: None. C. Molthoff: None. M.T. Goumans: None. C.J. Jimenez: None. J.S. Yudkin: None. Y.M. Smulders: None. V.W. van Hinsbergh: None. E.C. Eringa: None.