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Involvement of NOX-dependent oxidative stress in the pathophysiology of metabolic disorders as well as in the maintenance of metabolic homeostasis has been demonstrated previously. In the present study, the metabolic profile in p47phox–/– and WT mice fed on a chow diet was evaluated to assess the role of metabolites in glucose intolerance and dyslipidemia under altered oxidative stress conditions. p47phox–/– mice displayed glucose intolerance, dyslipidemia, hyperglycemia, insulin resistance (IR), hyperinsulinemia, and altered energy homeostasis without any significant change in gluconeogenesis. The expression of genes involved in lipid synthesis and uptake was enhanced in the liver, adipose tissue, and intestine tissues. Similarly, the expression of genes associated with lipid efflux in the liver and intestine was also enhanced. Enhanced gut permeability, inflammation, and shortening of the gut was evident in p47phox–/– mice. Circulating levels of pyrimidines, phosphatidylglycerol lipids, and 3-methyl-2-oxindole were augmented, while level of purine was reduced in the serum. Moreover, the cecal metabolome was also altered, as was evident with the increase in indole-3-acetamide, N-acetyl galactosamine, glycocholate, and a decrease in hippurate, indoxyl sulfate, and indigestible sugars (raffinose and melezitose). Treatment of p47phox–/– mice with pioglitazone, marginally improved glucose intolerance, and dyslipidemia, with an increase in PUFAs (linoleate, docosahexaenoic acid, and arachidonic acid). Overall, the results obtained in p47phox–/– mice indicate an association of IR and dyslipidemia with altered serum and cecal metabolites (both host and bacterial-derived), implying a critical role of NOX-derived ROS in metabolic homeostasis. [ABSTRACT FROM AUTHOR]

Oxidative stress due to enhanced production or reduced scavenging of reactive oxygen species (ROS) has been associated with diet (dyslipidemia) induced obesity and insulin resistance (IR). The present study was undertaken to assess the role of p47phox in IR using wild type (WT) and p47phox−/− mice, fed with different diets (HFD, LFD or Chow). Augmented body weight, glucose intolerance and reduced insulin sensitivity were observed in p47phox−/− mice fed with 45% HFD and 10% LFD. Further, body fat and circulating lipids were increased significantly with 5 weeks LFD feeding in p47phox−/− mice, while parameters of energy homeostasis were reduced as compared with WT mice. LFD fed knockout (KO) mice showed an enhanced hepatic glycogenolysis, and reduced insulin signalling in liver and adipose tissue, while skeletal muscle tissue remained unaffected. A significant increase in hepatic lipids, adiposity, as well as expression of genes regulating lipid synthesis, breakdown and efflux were observed in LFD fed p47phox−/− mice after 5 weeks. On the other hand, mice lacking p47phox demonstrated altered glucose tolerance and tissue insulin sensitivity after 5 weeks chow feeding, while changes in body weight, respiratory exchange ratio (RER) and heat production are non-significant. Our data demonstrate that lack of p47phox is sufficient to induce IR through altered glucose and lipid utilization by the liver and adipose tissue. [ABSTRACT FROM AUTHOR]

Involvement of NOX-dependent oxidative stress in the pathophysiology of metabolic disorders as well as in the maintenance of metabolic homeostasis has been demonstrated previously. In the present study, the metabolic profile in p47 phox-/- and WT mice fed on a chow diet was evaluated to assess the role of metabolites in glucose intolerance and dyslipidemia under altered oxidative stress conditions. p47 phox-/- mice displayed glucose intolerance, dyslipidemia, hyperglycemia, insulin resistance (IR), hyperinsulinemia, and altered energy homeostasis without any significant change in gluconeogenesis. The expression of genes involved in lipid synthesis and uptake was enhanced in the liver, adipose tissue, and intestine tissues. Similarly, the expression of genes associated with lipid efflux in the liver and intestine was also enhanced. Enhanced gut permeability, inflammation, and shortening of the gut was evident in p47 phox-/- mice. Circulating levels of pyrimidines, phosphatidylglycerol lipids, and 3-methyl-2-oxindole were augmented, while level of purine was reduced in the serum. Moreover, the cecal metabolome was also altered, as was evident with the increase in indole-3-acetamide, N-acetyl galactosamine, glycocholate, and a decrease in hippurate, indoxyl sulfate, and indigestible sugars (raffinose and melezitose). Treatment of p47 phox-/- mice with pioglitazone, marginally improved glucose intolerance, and dyslipidemia, with an increase in PUFAs (linoleate, docosahexaenoic acid, and arachidonic acid). Overall, the results obtained in p47 phox-/- mice indicate an association of IR and dyslipidemia with altered serum and cecal metabolites (both host and bacterial-derived), implying a critical role of NOX-derived ROS in metabolic homeostasis.

Oxidative stress due to enhanced production or reduced scavenging of reactive oxygen species (ROS) has been associated with diet (dyslipidemia) induced obesity and insulin resistance (IR). The present study was undertaken to assess the role of p47 phox in IR using wild type (WT) and p47 phox-/- mice, fed with different diets (HFD, LFD or Chow). Augmented body weight, glucose intolerance and reduced insulin sensitivity were observed in p47 phox-/- mice fed with 45% HFD and 10% LFD. Further, body fat and circulating lipids were increased significantly with 5 weeks LFD feeding in p47 phox-/- mice, while parameters of energy homeostasis were reduced as compared with WT mice. LFD fed knockout (KO) mice showed an enhanced hepatic glycogenolysis, and reduced insulin signalling in liver and adipose tissue, while skeletal muscle tissue remained unaffected. A significant increase in hepatic lipids, adiposity, as well as expression of genes regulating lipid synthesis, breakdown and efflux were observed in LFD fed p47 phox-/- mice after 5 weeks. On the other hand, mice lacking p47 phox demonstrated altered glucose tolerance and tissue insulin sensitivity after 5 weeks chow feeding, while changes in body weight, respiratory exchange ratio (RER) and heat production are non-significant. Our data demonstrate that lack of p47 phox is sufficient to induce IR through altered glucose and lipid utilization by the liver and adipose tissue.