Adipocyte-Specific Deficiency of NADPH Oxidase 4 Delays the Onset of Insulin Resistance and Attenuates Adipose Tissue Inflammation in Obesity

Hartigh, Laura J. den; Omer, Mohamed; Goodspeed, Leela; Wang, Shari; Wietecha, Tomasz; O’Brien, Kevin D.; Han, Chang Yeop

doi:10.1161/atvbaha.116.308749

Cited by 95 publications

(91 citation statements)

References 34 publications

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“…15,16 In line with this concept, using adipocyte-specific NADPH (nicotinamide adenine dinucleotide phosphate) oxidase 4-deficient mice, Den Hartigh et al 17 demonstrated that adipocyte NADPH oxidase 4-derived ROS contributed to the development of obesityrelated insulin resistance by triggering adipocyte inflammation. La Favor et al 18 developed a novel microdialysis technique that enables simultaneous measurement of ROS levels and microvascular endothelial functions in vivo.…”

Section: Reactive Oxygen Speciesmentioning

confidence: 96%

Endothelial Functions

Godo

Shimokawa

2017

ATVB

395

258

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e108T he endothelium plays important roles in modulating vascular tone by synthesizing and releasing an array of endothelium-derived relaxing factors, including vasodilator prostaglandins, NO, and endothelium-dependent hyperpolarization (EDH) factors, as well as endothelium-derived contracting factors.1,2 Such redundant mechanisms, like endogenous hyperglycemic hormones, are advantageous for ensuring proper maintenance of vascular tone under pathological conditions, where one of the vasoactive factor-mediated responses is compromised favoring a vasoconstrictor, prothrombotic, and proinflammatory state. Endothelial dysfunction is mainly caused by reduced production or action of endothelium-derived relaxing factors and could be an initial step toward cardiovascular disease.1 Indeed, evaluation of endothelial functions in humans has attracted much attention in the clinical settings because it serves as an excellent surrogate marker of cardiovascular events. For instance, endothelial dysfunction, as evaluated by impaired flow-mediated dilation of the brachial artery or digital reactive hyperemia index in peripheral arterial tonometry, is associated with future cardiovascular events in patients with coronary artery disease, 3-5 and 1-SD decrease in flow-mediated dilation or reactive hyperemia index is associated with doubling of cardiovascular event risk. 6 These observations suggest that endothelial function in peripheral vascular beds could predict future cardiovascular events.In this review, we will sum up the current advances and trends in the research on endothelial functions from bench to bedside with particular focus on recent publications in Arteriosclerosis, Thrombosis, and Vascular Biology. Earlier highlights of the journal on endothelial biology are extensively summarized in some review articles. 7-9 Emerging Modulators of Endothelial Functions Shear StressAs Lüscher and Corti 10 described in an editorial, flow is the signal of life. This physical force is sensed by the endothelium lining internal surface of the whole cardiovascular system to be translated into numerous downstream signaling pathways in a moment to moment manner in response to diverse physiological demands in the body. Indeed, shear stress is one of the important physiological cues that make endothelial cells synthesize and release endothelium-derived relaxing factors to cause relaxation of underlying vascular smooth muscle and vasodilatation. In this context, novel mechanisms of endothelial mechanotransduction in health and disease have been unveiled and summarized in a review series published recently in Arteriosclerosis, Thrombosis, and Vascular Biology. 11,12 Briefly, Zhou et al 12 emphasized the distinct roles of atheroprotective laminar or pulsatile shear stress versus atheroprone oscillatory shear stress or disturbed flow and discussed in detail the underlying molecular mechanisms that are dependent on these patterns of flow. Abe and Berk 11 further reviewed the current knowledge on the dual roles of shear stress with emphasis plac...

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Section: Reactive Oxygen Speciesmentioning

confidence: 96%

Endothelial Functions

Godo

Shimokawa

2017

ATVB

395

258

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“…NOX4-induced ROS will further stimulate the increase in the expression of chemotactic factors in cultured adipocytes that was reversed upon silencing of Nox4 [134]. Moreover, in diet-induced obese mice, specific deletion of Nox4 protects from nutrient-induced adipose inflammation and the early onset of insulin resistance [135]. It was shown that upon Nox4 deletion in adipocytes, there was a down-regulation in the expression of macrophage chemotactic factor genes Saa3 and Ccl2, mRNA expression of macrophage markers (Mac2, Cd11b, Cd11c, and Emr1), Mac2 protein, as well as expression of the pro-inflammatory cytokines IL-6 and TNF-α [135].…”

Section: The Cross-link Between Nadph Oxidases-induced Oxidative Strementioning

confidence: 99%

“…Moreover, in diet-induced obese mice, specific deletion of Nox4 protects from nutrient-induced adipose inflammation and the early onset of insulin resistance [135]. It was shown that upon Nox4 deletion in adipocytes, there was a down-regulation in the expression of macrophage chemotactic factor genes Saa3 and Ccl2, mRNA expression of macrophage markers (Mac2, Cd11b, Cd11c, and Emr1), Mac2 protein, as well as expression of the pro-inflammatory cytokines IL-6 and TNF-α [135]. In streptozotocin-induced ApoE − / − diabetic mice, deletion of Nox4, but not of Nox1, ameliorated kidney injury.…”

Section: The Cross-link Between Nadph Oxidases-induced Oxidative Strementioning

confidence: 99%

Role of the Nox4/AMPK/mTOR signaling axe in adipose inflammation-induced kidney injury

et al. 2020

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Diabetic kidney disease is one of the most serious complications of diabetes worldwide and is the leading cause of end-stage renal disease. While research has primarily focused on hyperglycemia as a key player in the pathophysiology of diabetic complications, recently, increasing evidence have underlined the role of adipose inflammation in modulating the development and/or progression of diabetic kidney disease. This review focuses on how adipose inflammation contribute to diabetic kidney disease. Furthermore, it discusses in detail the underlying mechanisms of adipose inflammation, including pro-inflammatory cytokines, oxidative stress, and AMPK/mTOR signaling pathway and critically describes their role in diabetic kidney disease. This in-depth understanding of adipose inflammation and its impact on diabetic kidney disease highlights the need for novel interventions in the treatment of diabetic complications.

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“…27,60,61 Although some studies have provided evidence for the protective effect of Nox4, 62,63 others have reported Nox4-mediated ROS as a molecular switch promoting the differentiation of preadipocytes, the onset of insulin resistance, and adipose tissue inflammation. 60,[64][65][66] Additionally, increased expression of Nox4 in white adipose tissue can result in the production of H 2 O 2, which can be converted to • OH radicals via the Fenton and Haber-Weiss reactions in the presence of Fe 2+ and Cu 2+ ions, eventually leading to oxidative DNA damage. 27 Weyemi et al 67 disease (NAFLD) and hepatocellular carcinoma (HCC).…”

Section: Obesity-induced Oxidative Stress Promotes Dna Damagementioning

confidence: 99%

Obesity and cancer: A mechanistic overview of metabolic changes in obesity that impact genetic instability

Kompella

Vásquez

2019

Molecular Carcinogenesis

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Obesity, defined as a state of positive energy balance with a body mass index exceeding 30 kg/m2 in adults and 95th percentile in children, is an increasing global concern. Approximately one‐third of the world's population is overweight or obese, and in the United States alone, obesity affects one in six children. Meta‐analysis studies suggest that obesity increases the likelihood of developing several types of cancer, and with poorer outcomes, especially in children. The contribution of obesity to cancer risk requires a better understanding of the association between obesity‐induced metabolic changes and its impact on genomic instability, which is a major driving force of tumorigenesis. In this review, we discuss how molecular changes during adipose tissue dysregulation can result in oxidative stress and subsequent DNA damage. This represents one of the many critical steps connecting obesity and cancer since oxidative DNA lesions can result in cancer‐associated genetic instability. In addition, the by‐products of the oxidative degradation of lipids (e.g., malondialdehyde, 4‐hydroxynonenal, and acrolein), and gut microbiota‐mediated secondary bile acid metabolites (e.g., deoxycholic acid and lithocholic acid), can function as genotoxic agents and tumor promoters. We also discuss how obesity can impact DNA repair efficiency, potentially contributing to cancer initiation and progression. Finally, we outline obesity‐related epigenetic changes and identify the gaps in knowledge to be addressed for the development of better therapeutic strategies for the prevention and treatment of obesity‐related cancers.

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Adipocyte-Specific Deficiency of NADPH Oxidase 4 Delays the Onset of Insulin Resistance and Attenuates Adipose Tissue Inflammation in Obesity

Cited by 95 publications

References 34 publications

Endothelial Functions

Endothelial Functions

Role of the Nox4/AMPK/mTOR signaling axe in adipose inflammation-induced kidney injury

Obesity and cancer: A mechanistic overview of metabolic changes in obesity that impact genetic instability

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