NADPH Oxidase Stimulates Adipose Tissue Lipolysis In Humans

NADPH oxidase (Nox) activation leads to increased adipocyte lipolysis; however, the mechanisms regulating this process are unknown. PURPOSE: To determine if Nox-derived reactive oxygen species (ROS) production increases lipolysis through the canonical β-adrenergic pathway or a non-canonical atrial natriuretic peptide (ANP) pathway. METHODS: Young (22.3 ± 6.2 years) healthy individuals (n = 8; BMI: 24.8 ± 9.5 kg/m2) were studied. Local ROS and glycerol (lipolysis) were measured via microdialysis in the subcutaneous abdominal adipose tissue before and during a hyperinsulinemic-euglycemic clamp (clamp). Total H2O2 concentrations, including dismutated O2·, were detected via perfusion of Amplex UltraRed, horseradish peroxidase and superoxide dismutase through microdialysis probes. Further, microdialysis probes were perfused with either isoproterenol (Iso; β-adrenergic agonist) or ANP, then additionally perfused with apocynin (Nox inhibitor). RESULTS: The clamp elicited higher ROS compared to the basal state (clamp vs. basal, H2O2 mean ± SD, control 1.63 ± 1.06 vs.1.04 ± 0.46; Iso 1.09 ± 0.69 vs. 0.84 ± 0.36; ANP 1.77 ± 0.87 vs.1.08 ± 0.58 μM). The extent to which local Nox inhibition reduced ROS was greater during the clamp than the basal state (clamp vs. basal, control -39.1 vs. -33.8%; Iso -34.0 vs. -22.9%; ANP -41.5 vs. 27.7%). Iso and ANP perfusion resulted in higher dialysate glycerol compared to the control probe during basal (control 43.4 ± 21.5; Iso 146.7 ± 56.7; ANP 110.5 ± 29.5 μmol/L) and clamp (control 22.6 ± 9.4; Iso 137.8 ± 42.7; ANP 71.3 ± 20.1 μmol/L) states. Local Nox inhibition did not alter dialysate glycerol in the fasted state or in the control and ANP probes during the clamp; however, there was a marked decrease in dialysate glycerol upon local Nox inhibition in the Iso probe during the clamp (137.8 ± 42.7 vs. 80.5 ± 23.8 μmol/L). CONCLUSIONS: The novel findings of this study are that Nox is a stimulus of adipose tissue ROS production in humans, and that this response is augmented during hyperinsulinemia. In addition, the increased Nox activity during the clamp contributes to increased lipolysis through the β-adrenergic pathway. These data have important implications for people with obesity, as obesity is associated with elevated adipose Nox, as well as high basal and postprandial lipolysis.