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Investigation of NADPH Oxidase as a Link Between Vascular and Metabolic Dysfunction.

紀錄類型:	書目-電子資源 : Monograph/item
正題名/作者:	Investigation of NADPH Oxidase as a Link Between Vascular and Metabolic Dysfunction./
作者:	Meza, Cesar Arturo.
出版者:	Ann Arbor : ProQuest Dissertations & Theses, : 2023,
面頁冊數:	88 p.
附註:	Source: Dissertations Abstracts International, Volume: 85-04, Section: B.
Contained By:	Dissertations Abstracts International85-04B.
標題:	Physiology. -
電子資源:	https://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=30530487
ISBN:	9798380413343

Investigation of NADPH Oxidase as a Link Between Vascular and Metabolic Dysfunction.
Meza, Cesar Arturo.

Investigation of NADPH Oxidase as a Link Between Vascular and Metabolic Dysfunction. - Ann Arbor : ProQuest Dissertations & Theses, 2023 - 88 p.

Source: Dissertations Abstracts International, Volume: 85-04, Section: B.

Thesis (Ph.D.)--The Florida State University, 2023.

INTRODUCTION: Obesity is associated with increased cardiometabolic disease risk, although the vascular and metabolic features of obesity are often studied independently. Resistance to both insulin-mediated suppression of lipolysis and increases in microvascular blood flow are important risk factors for cardiometabolic diseases. Emerging evidence points to heightened NADPH oxidase (Nox) activity as a critical feature of reduced vascular and metabolic function. Overproduction of Nox-derived reactive oxygen species (ROS) is a major source of microvascular dysfunction in obesity and increased adipose tissue Nox activity is a main determinant of insulin resistance. In addition, Nox-derived ROS is an important component of increased lipolysis; however, the mechanisms by which Nox regulates lipolysis are unknown. In addition, the mechanistic basis for Nox in the intricate relationship between insulin control of vascular and metabolic responses is not well described. PURPOSE: The{acute}{80}{89}overall objective{acute}{80}{89}of this study was to investigate whether increased Nox-derived ROS production impairs blood glucose profiles by reducing insulin-mediated suppression of lipolysis. METHODS: Sixteen sedentary, non-obese, otherwise healthy males and females (males = 1, females = 15; age: 21.7 {phono}{lstrok} 5 years; body mass index: 22.7 {phono}{lstrok} 4 kg/m2 ) participated in this study. Participants completed three study visits, each after a ten-hour overnight fast. During the first study visit, anthropometric assessments were completed, as well as measurement of fasting blood glucose and blood pressure. During the second study visit, assessments of body composition (via dual-energy x-ray absorptiometry, DXA) and maximal aerobic capacity (VO2peak) were completed. The final study visit was the main experimental visit, where participants underwent microdialysis and hyperinsulinemic-euglycemic procedures to monitor local adipose tissue (total and Nox-dependent) ROS production and lipolysis (measured as dialysate glycerol) under basal as well as hyperinsulinemic conditions. Total dialysate H2O2 concentrations, including dismutated superoxide, were detected via perfusion of Amplex UltraRed reagent, horseradish peroxidase and superoxide dismutase through microdialysis probes. Further, microdialysis probes were perfused with either isoproterenol ({CE}{ostrok}-adrenergic agonist) or atrial natriuretic peptide (ANP) to stimulate lipolysis through independent signaling pathways, then additionally perfused with apocynin (Nox inhibitor) to determine the contributions of Nox to lipolysis. RESULTS: Upon perfusion of apocynin, the dialysate concentrations of H2O2 decreased in the control (without apocynin:{A0}1.17 {phono}{lstrok} 0.5 {phono}{aelig}M, with apocynin: 0.66 {phono}{lstrok} 0.2 {phono}{aelig}M; p = 0.003) and isoproterenol probes (without apocynin: 1.09 {phono}{lstrok} 0.6 {phono}{aelig}M, with apocynin: 0.68 {phono}{lstrok} 0.3 {phono}{aelig}M; p = 0.03). Isoproterenol and ANP perfusion significantly increased dialysate glycerol concentrations compared to the control probe (control: 56.0 {phono}{lstrok} 21.9, isoproterenol: 125.6 {phono}{lstrok} 59.8, ANP: 130.9 {phono}{lstrok} 47.7 {phono}{aelig}mol/L; p < 0.0001). However, apocynin perfusion had no effect on dialysate glycerol concentrations in the control (p = 0.99), isoproterenol (p = 0.99) or ANP (p = 0.59) probes in the basal state. During the clamp, apocynin perfusion decreased dialysate H2O2 concentrations in control (without apocynin: 1.3 {phono}{lstrok} 0.6 {phono}{aelig}M, with apocynin: 0.79 {phono}{lstrok} 0.3 {phono}{aelig}M; p = 0.046), isoproterenol (without apocynin: 1.58 {phono}{lstrok} 0.8 {phono}{aelig}M, with apocynin: 0.83 {phono}{lstrok} 0.3 {phono}{aelig}M; p = 0.02) and ANP (without apocynin: 1.60 {phono}{lstrok} 0.60 {phono}{aelig}M, with apocynin: 0.95 {phono}{lstrok} 0.3 {phono}{aelig}M; p = 0.04) probes. Hyperinsulinemia decreased dialysate glycerol concentrations compared to the basal state (basal: 56.0 {phono}{lstrok} 21.9 {phono}{aelig}mol/L, clamp: 32.8 {phono}{lstrok} 20.2 {phono}{aelig}mol/L; p = 0.02). In addition, dialysate glycerol concentrations decreased in the isoproterenol probe following apocynin perfusion during the clamp procedure (without apocynin: 126.1 {phono}{lstrok} 38 {phono}{aelig}mol/L, with apocynin: 91.9 {phono}{lstrok} 25.7 {phono}{aelig}mol/L; p = 0.002). Further, there was a correlation between basal adipose tissue lipolytic rates and Nox contributions to basal adipose tissue lipolysis (r = - 0.66, p = 0.005), and individuals with lower insulin sensitivity (glucose disposal rate) tended to have high basal Nox-mediated ROS production (r = 0.56, p = 0.04). CONCLUSIONS: The novel findings of this study are that Nox is a stimulus of adipose tissue ROS production in healthy individuals, and this effect contributes to increases in adipose tissue lipolysis during hyperinsulinemic conditions. The mechanism by which Nox increases lipolysis involves {CE}{ostrok}-adrenergic signaling and is independent of the ANP pathway. These data have important implications for individuals with insulin resistance and excess adiposity, as basal adipose tissue Nox activity was highest in individuals with lower insulin sensitivity and higher basal lipolytic rates, which may impair blood glucose regulation and vascular function. Overall, these study findings provide in vivo evidence of a novel regulator of adipose tissue lipolysis.{A0}

ISBN: 9798380413343Subjects--Topical Terms:

518431
Physiology.
Subjects--Index Terms:

Adipose tissue

Investigation of NADPH Oxidase as a Link Between Vascular and Metabolic Dysfunction.
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245 1 0 $a Investigation of NADPH Oxidase as a Link Between Vascular and Metabolic Dysfunction.
260 1 $a Ann Arbor : $b ProQuest Dissertations & Theses, $c 2023
300 $a 88 p.
500 $a Source: Dissertations Abstracts International, Volume: 85-04, Section: B.
500 $a Advisor: Hickner, Robert C.
502 $a Thesis (Ph.D.)--The Florida State University, 2023.
520 $a INTRODUCTION: Obesity is associated with increased cardiometabolic disease risk, although the vascular and metabolic features of obesity are often studied independently. Resistance to both insulin-mediated suppression of lipolysis and increases in microvascular blood flow are important risk factors for cardiometabolic diseases. Emerging evidence points to heightened NADPH oxidase (Nox) activity as a critical feature of reduced vascular and metabolic function. Overproduction of Nox-derived reactive oxygen species (ROS) is a major source of microvascular dysfunction in obesity and increased adipose tissue Nox activity is a main determinant of insulin resistance. In addition, Nox-derived ROS is an important component of increased lipolysis; however, the mechanisms by which Nox regulates lipolysis are unknown. In addition, the mechanistic basis for Nox in the intricate relationship between insulin control of vascular and metabolic responses is not well described. PURPOSE: The{acute}{80}{89}overall objective{acute}{80}{89}of this study was to investigate whether increased Nox-derived ROS production impairs blood glucose profiles by reducing insulin-mediated suppression of lipolysis. METHODS: Sixteen sedentary, non-obese, otherwise healthy males and females (males = 1, females = 15; age: 21.7 {phono}{lstrok} 5 years; body mass index: 22.7 {phono}{lstrok} 4 kg/m2 ) participated in this study. Participants completed three study visits, each after a ten-hour overnight fast. During the first study visit, anthropometric assessments were completed, as well as measurement of fasting blood glucose and blood pressure. During the second study visit, assessments of body composition (via dual-energy x-ray absorptiometry, DXA) and maximal aerobic capacity (VO2peak) were completed. The final study visit was the main experimental visit, where participants underwent microdialysis and hyperinsulinemic-euglycemic procedures to monitor local adipose tissue (total and Nox-dependent) ROS production and lipolysis (measured as dialysate glycerol) under basal as well as hyperinsulinemic conditions. Total dialysate H2O2 concentrations, including dismutated superoxide, were detected via perfusion of Amplex UltraRed reagent, horseradish peroxidase and superoxide dismutase through microdialysis probes. Further, microdialysis probes were perfused with either isoproterenol ({CE}{ostrok}-adrenergic agonist) or atrial natriuretic peptide (ANP) to stimulate lipolysis through independent signaling pathways, then additionally perfused with apocynin (Nox inhibitor) to determine the contributions of Nox to lipolysis. RESULTS: Upon perfusion of apocynin, the dialysate concentrations of H2O2 decreased in the control (without apocynin:{A0}1.17 {phono}{lstrok} 0.5 {phono}{aelig}M, with apocynin: 0.66 {phono}{lstrok} 0.2 {phono}{aelig}M; p = 0.003) and isoproterenol probes (without apocynin: 1.09 {phono}{lstrok} 0.6 {phono}{aelig}M, with apocynin: 0.68 {phono}{lstrok} 0.3 {phono}{aelig}M; p = 0.03). Isoproterenol and ANP perfusion significantly increased dialysate glycerol concentrations compared to the control probe (control: 56.0 {phono}{lstrok} 21.9, isoproterenol: 125.6 {phono}{lstrok} 59.8, ANP: 130.9 {phono}{lstrok} 47.7 {phono}{aelig}mol/L; p < 0.0001). However, apocynin perfusion had no effect on dialysate glycerol concentrations in the control (p = 0.99), isoproterenol (p = 0.99) or ANP (p = 0.59) probes in the basal state. During the clamp, apocynin perfusion decreased dialysate H2O2 concentrations in control (without apocynin: 1.3 {phono}{lstrok} 0.6 {phono}{aelig}M, with apocynin: 0.79 {phono}{lstrok} 0.3 {phono}{aelig}M; p = 0.046), isoproterenol (without apocynin: 1.58 {phono}{lstrok} 0.8 {phono}{aelig}M, with apocynin: 0.83 {phono}{lstrok} 0.3 {phono}{aelig}M; p = 0.02) and ANP (without apocynin: 1.60 {phono}{lstrok} 0.60 {phono}{aelig}M, with apocynin: 0.95 {phono}{lstrok} 0.3 {phono}{aelig}M; p = 0.04) probes. Hyperinsulinemia decreased dialysate glycerol concentrations compared to the basal state (basal: 56.0 {phono}{lstrok} 21.9 {phono}{aelig}mol/L, clamp: 32.8 {phono}{lstrok} 20.2 {phono}{aelig}mol/L; p = 0.02). In addition, dialysate glycerol concentrations decreased in the isoproterenol probe following apocynin perfusion during the clamp procedure (without apocynin: 126.1 {phono}{lstrok} 38 {phono}{aelig}mol/L, with apocynin: 91.9 {phono}{lstrok} 25.7 {phono}{aelig}mol/L; p = 0.002). Further, there was a correlation between basal adipose tissue lipolytic rates and Nox contributions to basal adipose tissue lipolysis (r = - 0.66, p = 0.005), and individuals with lower insulin sensitivity (glucose disposal rate) tended to have high basal Nox-mediated ROS production (r = 0.56, p = 0.04). CONCLUSIONS: The novel findings of this study are that Nox is a stimulus of adipose tissue ROS production in healthy individuals, and this effect contributes to increases in adipose tissue lipolysis during hyperinsulinemic conditions. The mechanism by which Nox increases lipolysis involves {CE}{ostrok}-adrenergic signaling and is independent of the ANP pathway. These data have important implications for individuals with insulin resistance and excess adiposity, as basal adipose tissue Nox activity was highest in individuals with lower insulin sensitivity and higher basal lipolytic rates, which may impair blood glucose regulation and vascular function. Overall, these study findings provide in vivo evidence of a novel regulator of adipose tissue lipolysis.{A0}
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