NADPH oxidase-derived reactive oxygen species regulates adipose tissue lipolysis in humans
Authors: Meza Cesar , Ali Mostafa , Baker Paul , Hasenhuttl Eva , Clarke Holly , Nieves Ely , Paz Karelia 
Published: May 2024

There is mounting evidence suggesting that reactive oxygen species (ROS) generated by NADPH oxidase (NOX) regulate physiological processes, as NOX has been shown to promote increases in lipolysis in cultured adipocytes. PURPOSE: To determine the mechanisms by which NOX stimulates adipose tissue lipolysis. METHODS: Young healthy females (n = 17; mean ± SD; age: 21.7 ± 5 years; body mass index: 22.2 ± 3.8 kg/m2) participated in this study. Participants underwent microdialysis and hyperinsulinemic-euglycemic clamp (clamp) procedures. Three microdialysis probes were inserted into subcutaneous abdominal adipose tissue to monitor local adipose tissue ROS (H2O2) production and lipolysis (as indicated by dialysate glycerol). To determine whether NOX stimulates lipolysis via distinct signaling pathways, microdialysis probes were perfused with either isoproterenol (Iso; β-adrenergic agonist to stimulate canonical lipolysis signaling) or atrial natriuretic peptide (ANP to stimulate non-canonical lipolysis signaling), then perfused with a local NOX inhibitor (apocynin). A control probe was perfused with apocynin but without any agonists of lipolysis. The microdialysis procedures were then repeated under hyperinsulinemic conditions during the same study visit. RESULTS: In the fasted state, dialysate H2O2 concentrations were lower in the control and Iso probes upon apocynin perfusion (control probe without apocynin: 1.06 ± 0.5 μM, with apocynin: 0.62 ± 0.2 μM; p = 0.005; Iso probe without apocynin: 1.01 ± 0.4 μM, with apocynin: 0.66 ± 0.2 μM; p = 0.003). Apocynin perfusion did not alter dialysate H2O2 concentrations in the ANP probe under the fasted state (p = 0.11). Dialysate glycerol concentrations did not change upon apocynin perfusion under any of the microdialysis probe conditions in the fasted state (p > 0.05). During the clamp, apocynin perfusion resulted in lower dialysate H2O2 concentrations in the three conditions (control probe without apocynin: 1.22 ± 0.6 μM, with apocynin: 0.75 ± 0.3 μM; p = 0.03; Iso probe without apocynin: 1.55 ± 0.8 μM, with apocynin: 0.79 ± 0.3 μM; p = 0.01; ANP probe without apocynin: 1.55 ± 0.6 μM, with apocynin: 0.92 ± 0.3 μM; p = 0.03). Dialysate glycerol concentrations were lower in the Iso probe upon apocynin perfusion during the clamp (Iso probe without apocynin: 124.7 ± 38 μM, with apocynin: 90.9 ± 25 μM; p = 0.003). CONCLUSIONS: This study presents adipose tissue NOX as a source of in vivo ROS production in human participants. In addition, we reveal a novel mechanism of NOX in adipose tissue function whereby NOX exerts increases in β-adrenergic-mediated lipolysis during hyperinsulinemia. Our findings highlight the roles of ROS as signaling mediators and suggest that an imbalance between NOX activity and insulin action on adipose tissue could negatively affect systemic fatty acid metabolism. Porter Pre-doctoral Fellowship from the American Physiological Society and an NIH National Research Service Award (F31HL154642). This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.