Glucose and lipid metabolism alterations in liver and adipose tissue pre-dispose p47 phox knockout mice to systemic insulin resistance

Free Radic Res. 2018 May;52(5):568-582. doi: 10.1080/10715762.2018.1453136. Epub 2018 Apr 3.

Abstract

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.

Keywords: Insulin resistance; metabolism; p47phox; reactive oxygen species.

MeSH terms

  • Adipose Tissue / metabolism*
  • Adipose Tissue / pathology
  • Animals
  • Cytokines / genetics
  • Cytokines / metabolism
  • Diet, Fat-Restricted
  • Diet, High-Fat
  • Dyslipidemias / etiology
  • Dyslipidemias / genetics
  • Dyslipidemias / metabolism*
  • Dyslipidemias / pathology
  • Gene Expression Regulation
  • Glucose / metabolism*
  • Glycogenolysis / genetics
  • Insulin Receptor Substrate Proteins / genetics
  • Insulin Receptor Substrate Proteins / metabolism
  • Insulin Resistance*
  • Lipid Metabolism / genetics
  • Liver / metabolism*
  • Liver / pathology
  • Male
  • Mice
  • Mice, Knockout
  • Muscle, Skeletal / metabolism
  • NADPH Oxidases / deficiency
  • NADPH Oxidases / genetics*
  • Obesity / etiology
  • Obesity / genetics
  • Obesity / metabolism*
  • Obesity / pathology
  • Oxidative Stress
  • Proto-Oncogene Proteins c-akt / genetics
  • Proto-Oncogene Proteins c-akt / metabolism
  • Reactive Oxygen Species / metabolism
  • Signal Transduction

Substances

  • Cytokines
  • Insulin Receptor Substrate Proteins
  • Irs1 protein, mouse
  • Reactive Oxygen Species
  • NADPH Oxidases
  • neutrophil cytosolic factor 1
  • Proto-Oncogene Proteins c-akt
  • Glucose