Diabetes Metab J.  2016 Aug;40(4):272-279. 10.4093/dmj.2016.40.4.272.

Roles of Reactive Oxygen Species on Insulin Resistance in Adipose Tissue

• Han CY

• KMID: 2368513
• DOI: http://doi.org/10.4093/dmj.2016.40.4.272

Abstract

Obesity resulting from the delivery of an excess amount of energy to adipose tissue from glucose or free fatty acids is associated with insulin resistance and adipose tissue inflammation. Reactive oxygen species (ROS) have been implicated as contributors to both the onset and the progression of insulin resistance. ROS can be generated by overloading the mitochondrial oxidative phosphorylation system, and also by nicotinamide adenine dinucleotide phosphate oxidases (NOX) produced by either adipocytes, which only produce NOX4, or by macrophages, which produce mainly NOX2. The source of the ROS might differ in the early, intermediate and late stages of obesity, switching from NOX4-dependence in the early phases to NOX2-dependence, in the intermediate phase, and transiting to mitochondria-dependence later in the time course of obesity. Thus, depending on the stage of obesity, ROS can be generated by three distinct mechanisms: i.e., NOX4, NOX2, and mitochondria. In this review, we will discuss whether NOX4-, NOX2-, and/or mitochondria-derived ROS is/are causal in the onset of adipocyte insulin resistance as obesity progresses. Moreover, we will review the pathophysiological roles of NOX4, NOX2, and mitochondria-derived ROS on adipose tissue inflammation.

Keyword

Adipocytes; Insulin resistance; Mitochondria; NADPH oxidase; Obesity; Reactive oxygen species

MeSH Terms

Adipocytes
Adipose Tissue*
Fatty Acids, Nonesterified
Glucose
Inflammation
Insulin Resistance*
Insulin*
Macrophages
Mitochondria
NADP
NADPH Oxidase
Obesity
Oxidative Phosphorylation
Oxidoreductases
Reactive Oxygen Species*
Fatty Acids, Nonesterified
Glucose
Insulin
NADP
NADPH Oxidase
Oxidoreductases
Reactive Oxygen Species

Figure

• 

  Fig. 1 Hypothesis for a mechanism by which excess glucose and saturated free fatty acids (SFAs) affect reactive oxygen species (ROS) generation in adipocytes in early stages of obesity. Excess glucose generates ROS via the pentose phosphate pathway, rather than by overloading mitochondrial oxidative phosphorylation, while SFA generate ROS following activating, Toll-like receptor 4 (TLR4) or lipid rafts. Nicotinamide adenine dinucleotide phosphate (NADPH) oxidase 4 (NOX4) might be the common mediator of ROS generation by both excess glucose and SFAs. ROS generated by both glucose and SFA activate nuclear factor κB (NF-κB). LR, lipid raft; SAA3, serum amyloid A3; MCP-1, monocyte chemoattractant protein-1.

• 

  Fig. 2 Hypothesis for a mechanism by which mitochondrial β-oxidation of free fatty acid (FFA) from triglyceride stores affects reactive oxygen species (ROS) generation in adipocytes in the late stage of obesity. Uptake of excess glucose and FAA are inhibited, resulting in a decrease of pentose phosphate pathway and nicotinamide adenine dinucleotide phosphate (NADPH) oxidase 4 (NOX4) activity. FFA from fat stores overload mitochondrial oxidative phosphorylation and generate ROS. Mitochondria-derived ROS activate nuclear factor κB. IR, insulin receptor; IRS, insulin receptor substrate; GLUT4, glucose transporter 4; LPL, lipoprotein lipase; FATP, fatty acid transport protein; HSL, hormone-sensitive lipase.

• 

  Fig. 3 Scheme of all mechanisms by which these three distinct sources of reactive oxygen species (ROS) might affect adipocyte insulin resistance and adipose tissue inflammation. NOX, nicotinamide adenine dinucleotide phosphate (NADPH) oxidase.

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