Hypoxia in Obesity and Diabetes: Potential Therapeutic Effects of Hyperoxia and Nitrate.

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metabolic syndrome 1 endocrinologydiseases
obesity 46 endocrinologydiseases
Insulin 6 endocrinologydiseasesdrugs
glucose intolerance 2 endocrinologydiseases
hyperglycemia 2 endocrinologydiseases

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Insulin 4661 Table 1 shows some characteristics of different adipocytes.3. Inflammation of Obese Adipose Tissue and Insulin Resistance3.1. Obese Adipose Tissue3.1.1. Adipocyte Death and TurnoverIn humans, the turnover of adipocytes
Insulin 9095 adipose tissues [[16]]. Some secreted hormones or molecules of adipose tissues are listed in Table 2.3.2. Insulin Resistance in ObesityThe insulin signaling pathways have been previously reported in detail by several
Insulin 23320 [114]]. In summary, hypoxia decreases NO bioavailability and causes endothelial dysfunction.4.2.5. NO and Insulin ResistanceExogenously delivered NO (sodium nitroprusside as a NO donor) stimulates uptake and transendothelial
Insulin 23655 dephosphorylates the IRS-1 and IRS-2 tyrosines, as well as inhibiting insulin signaling and TET [[115]]. Insulin resistance increases mitogen-activated protein kinase (MAPK) activity via blocking phosphatidylinositol
Insulin 31578 [157]], viz. on hyperbaric versus normobaric hyperoxia, simultaneously with nitrate intervention.Figure 1 Insulin resistance in obesity. Obesity is associated with hypoxia, inflammation, and lipolysis. These conditions
Insulin 32171 all the above signaling occurs in every cell. GLUT: Glucose transporter; IKKB: IκB kinase β; IR: Insulin receptor; mTORC: Mammalian target of rapamycin complex; PDK1: 3-Phosphoinositide-dependent protein kinase
Select Disease Character Offset Disease Term Instance
glucose intolerance 1035 are associated with oxidative stress, inflammation, endothelial dysfunction, insulin resistance, and glucose intolerance . Obesity, a chronic hypoxic state that is associated with decreased nitric oxide (NO) bioavailability,
glucose intolerance 8238 resistance, low insulin production, and/or hyperphagia can worsen the situation and lead to hyperglycemia, glucose intolerance , and eventually diabetes.3.1.3. Adipose Tissue Macrophages and InflammationIt has been estimated that
hyperglycemia 8223 insulin resistance, low insulin production, and/or hyperphagia can worsen the situation and lead to hyperglycemia , glucose intolerance, and eventually diabetes.3.1.3. Adipose Tissue Macrophages and InflammationIt has
hyperglycemia 13063 been reported that hypoxia-induced vascular endothelial growth factor (VEGF) expression is impaired in hyperglycemia /diabetes [[73]]. A 44% decrease in capillary density and 58% in VEGF mRNA in obese compared to lean
metabolic syndrome 29200 some researchers indicate that high altitudes and hypoxia can lead to weight loss and lower risk of metabolic syndrome [[143], [144]], these might also have some adverse effects [[145]] such as decrease in muscle mass instead
obesity 867 Madrid, SpainPublication date (ppub): /2017Publication date (epub): 5/2017AbstractThe prevalence of obesity and diabetes is increasing worldwide. Obesity and diabetes are associated with oxidative stress, inflammation,
obesity 1562 and NO-dependent vascular and cellular dysfunctions are responsible for other consequences linked to obesity -related disorders. Although hyperoxia could reverse hypoxic-related disorders, it increases the production
obesity 1880 and has antioxidant properties, and recent data support the beneficial effects of nitrate therapy in obesity and diabetes. Although it seems reasonable to combine hyperoxia and nitrate treatments for managing
obesity 1988 and diabetes. Although it seems reasonable to combine hyperoxia and nitrate treatments for managing obesity /diabetes, the combined effects have not been investigated yet. This review discusses some aspects of
obesity 2184 some aspects of tissue oxygenation and the potential effects of hyperoxia and nitrate interventions on obesity /diabetes management. It can be proposed that concomitant use of hyperoxia and nitrate is justified for
obesity 2304 management. It can be proposed that concomitant use of hyperoxia and nitrate is justified for managing obesity and diabetes.1. IntroductionObesity and diabetes, two major health problems worldwide, have shown an
obesity 2748 hypoxia and low blood flow [[4]]. In this sense, hyperoxia exposure has been evaluated as a treatment for obesity and its related disorders [[5], [6]]. Although hyperoxia has shown beneficial effects for obesity management,
obesity 2846 for obesity and its related disorders [[5], [6]]. Although hyperoxia has shown beneficial effects for obesity management, it may result in nitric oxide (NO) depletion and induction of oxidative stress [[7]–[9]].
obesity 3195 [[11]]. This study reviews the effects of hyperoxia and nitrate interventions on the management of obesity and type 2 diabetes.2. Adipose TissueThere are three types of adipocytes or adipose tissues [[12]].
obesity 4860 turnover of adipocytes is low, that is, ~10% per year, a rate that does not change in the early stages of obesity [[22]]. During the generation of WAT adipocytes, the expression of antiapoptotic factors such as B-cell
obesity 5701 CASP8, and CASP9) is increased, while the expression of Bcl2 (an antiapoptotic factor) is decreased in obesity [[25]]. Inflammatory factors such as TNF-α, IL-6, IL-1β, monocyte chemoattractant protein-1 (MCP1),
obesity 5860 IL-1β, monocyte chemoattractant protein-1 (MCP1), and macrophage recruitment are also increased in obesity ; these factors negatively affect adipocyte metabolism and its lipid storage capacity [[2], [25], [27]].
obesity 6208 macrophage migration inflammatory factor (MIF), which is a proinflammatory and atherogenic factor [[28]]. In obesity , BAT cell apoptosis is increased due to the decrease in Bcl2 [[29]] and increase in TNF-α [[30]]; however,
obesity 7075 functions of these tissues; for instance, the high levels of blood fatty acids and TNF-α occurring in obesity can induce insulin resistance [[32]–[34]]. Furthermore, long-term effects of medium- and long-chain
obesity 8749 M1, classically activated and M2, alternatively activated. A shift from M2 to M1 has been reported in obesity and inflammation [[40]]. Increased TNF-α upregulates MCP1 expression and leads to adipose tissue macrophage
obesity 8882 Increased TNF-α upregulates MCP1 expression and leads to adipose tissue macrophage infiltration in obesity [[16]]. In addition to MCP1, other chemoattractants are also involved in macrophage recruitment to adipose
obesity 10664 [[57]].Circulating levels of inflammatory factors including free fatty acids and TNF-α are higher in obesity [[55], [57], [60]]; these factors activate JNK-1, resulting in insulin resistance, as aforementioned
obesity 11301 lead to insulin resistance [[62]–[64]].3.3. Cellular Stress in Obesity3.3.1. Mitochondrial StressIn obesity , the overproduction of ROS leads to adipocyte dysfunction. Increased substrates of the electron transport
obesity 11616 increased ROS, in particular the superoxide anion [[65]]. In addition, high glucose level in some cases of obesity can lead to increased ROS signaling [[66]]. The superoxide anion is converted to H2O2 by the enzyme
obesity 13236 58% in VEGF mRNA in obese compared to lean individuals indicate that low PO2 levels in overweight and obesity do not result in neovascularization [[74]]. In obesity, free fatty acids are increased [[75]], which
obesity 13291 indicate that low PO2 levels in overweight and obesity do not result in neovascularization [[74]]. In obesity , free fatty acids are increased [[75]], which can induce the uncoupling of oxidation from phosphorylation
obesity 13674 leading to cell hypoxia [[76]]. There is one report that despite the low blood flow of adipose tissues in obesity , it was suggested that there is an increase in oxygen tension due to low oxygen consumption in mitochondria
obesity 14004 controversial results. To sum up, several studies have emphasized the hypoxic state of adipose tissues in obesity [[4]].4.2. Cellular Responses to HypoxiaHypoxia can increase cell necrosis and apoptosis in humans and
obesity 14456 increase in adipocyte size and macrophage recruitment [[78]]. Hypoxia has a key role in initiating obesity disorders through affecting multiple gene expressions (over 1000 genes) in adipocytes [[79]], in particular
obesity 14655 [[79]], in particular HIF-1α [[76]]. Inhibition of ANT2 and/or HIF-1α can reverse the complications of obesity , for example, insulin resistance [[76]]. Furthermore, insulin can induce HIF-1α in 3T3-L1 adipocytes
obesity 20583 a high-fat diet, fat mass was decreased, adiponectin induced, and these mice did not develop either obesity or insulin resistance [[97]].(2) The Effect of HIF-1α on BAT and WAT. HIF-1α may have a dual role
obesity 20713 [[97]].(2) The Effect of HIF-1α on BAT and WAT. HIF-1α may have a dual role in the development of obesity -related disorders, because of its different functions in WAT and BAT cells; Zhang et al. reported that
obesity 21143 However, it has been reported that the vascular network is diminished in both BAT and WAT in diet-induced obesity ; decreased capillary density is higher in BAT than in WAT, leading to BAT whitening; that is, BAT shows
obesity 21624 consumption. The use of hyperoxia or natural nitrate-containing vegetables may be a strategy to reverse obesity disorders; in support of the nitrate intervention, NO has a positive effect on vascular and capillary
obesity 22904 hypoxia [[111]], TNF-α, and superoxide anion (derived from uncoupled eNOS) [[112]], all occurring in obesity and can act together increasing the susceptibility to diabetes in obese individuals. In vitro hypoxia
obesity 24861 GLUT4 translocation to the cell membrane via nitrosylation of GLUT4 [[51]].Elevated free fatty acids in obesity and hypoxia [[55]] induce inhibitor of kappa B (IκB) kinase β (IKKβ), which phosphorylates serine
obesity 25317 activating Toll-like receptors (TLRs), in particular TLR4, as shown in Figure 1 [[123], [124]].To summarize, obesity and hypoxia cause oxidative stress and NO depletion, leading to endothelial dysfunction, and consequent
obesity 25429 hypoxia cause oxidative stress and NO depletion, leading to endothelial dysfunction, and consequent obesity disorders. Inorganic nitrate/nitrite apart from replenishing decreased NO bioavailability has antioxidant
obesity 28972 disorders including cardiovascular disease and diabetes. In recent years, to prevent the adverse effects of obesity , some interventions have been suggested, such as drugs, exercise, and healthier diet patterns [[140]–[142]].
obesity 29714 healing [[146], [148], [149]]. Hyperoxia could be considered as a new strategy for the management of obesity and type 2 diabetes. Exposure to higher doses of oxygen, however, could produce adverse effects [[150]–[152]]
obesity 30993 hyperoxia.Recent data support the beneficial effects of a nutritional-based nitrate/nitrite therapy in obesity and diabetes [[108], [155]]. Nitrate has also antioxidant properties [[11]], and it can restore NO depletion
obesity 31165 properties [[11]], and it can restore NO depletion induced by hyperoxia. Therefore, for the management of obesity , it seems reasonable to combine hyperoxia and nitrate. To the best of our knowledge, there is no study
obesity 31336 best of our knowledge, there is no study to address the effect of this combination therapy to manage obesity /diabetes, warranting the need for evaluating the effects of hyperoxia with different durations and oxygen
obesity 31600 versus normobaric hyperoxia, simultaneously with nitrate intervention.Figure 1Insulin resistance in obesity . Obesity is associated with hypoxia, inflammation, and lipolysis. These conditions can lead to insulin
obesity 34264 mitochondriaLowHighHigh[[12], [13]]Main functionLipid storageHeat producerHeat producer[[12], [13]]Effect on obesity ObesogenicAntiobesityAntiobesity[[13]]Histological phenotypeLarge cells with one huge lipid vacuoleSmall
obesity 34285 [13]]Main functionLipid storageHeat producerHeat producer[[12], [13]]Effect on obesityObesogenicAnti obesity Antiobesity[[13]]Histological phenotypeLarge cells with one huge lipid vacuoleSmall cells with several
obesity 34296 functionLipid storageHeat producerHeat producer[[12], [13]]Effect on obesityObesogenicAntiobesityAnti obesity [[13]]Histological phenotypeLarge cells with one huge lipid vacuoleSmall cells with several lipid vacuolesSmall
obesity 35079 sensitivity via AMPK, increases glucose uptake, and glucose tolerance. Decreased adiponectin is related to obesity , TNF-α upregulation, and eNOS downregulation.[[41], [42]]Sfrp5Is increased by calorie restriction diet
obesity 35410 glucose metabolism, and decreases insulin resistance and inflammation.[[44]]ApelinInhibits diet-induced obesity , due to its improvement of vascular integrity. It is positively correlated with BMI, and it is upregulated
obesity 35539 improvement of vascular integrity. It is positively correlated with BMI, and it is upregulated by insulin in obesity .[[45]–[47]]PPARγInduces storage of lipids and adipogenesis and reduces lipotoxicity; it also regulates
obesity 35864 expenditure. It impairs NO-mediated component.[[49]]ResistinIs increased in genetic- and diet-induced obesity models. It is specific for WAT and causes insulin resistance.[[50]]AMPK: adenosine monophosphate-activated

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