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Review
. 2014 Aug;73:383-99.
doi: 10.1016/j.freeradbiomed.2014.05.016. Epub 2014 May 28.

Regulation of Obesity and Insulin Resistance by Nitric Oxide

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Free PMC article
Review

Regulation of Obesity and Insulin Resistance by Nitric Oxide

Brian E Sansbury et al. Free Radic Biol Med. .
Free PMC article

Abstract

Obesity is a risk factor for developing type 2 diabetes and cardiovascular disease and has quickly become a worldwide pandemic with few tangible and safe treatment options. Although it is generally accepted that the primary cause of obesity is energy imbalance, i.e., the calories consumed are greater than are utilized, understanding how caloric balance is regulated has proven a challenge. Many "distal" causes of obesity, such as the structural environment, occupation, and social influences, are exceedingly difficult to change or manipulate. Hence, molecular processes and pathways more proximal to the origins of obesity-those that directly regulate energy metabolism or caloric intake-seem to be more feasible targets for therapy. In particular, nitric oxide (NO) is emerging as a central regulator of energy metabolism and body composition. NO bioavailability is decreased in animal models of diet-induced obesity and in obese and insulin-resistant patients, and increasing NO output has remarkable effects on obesity and insulin resistance. This review discusses the role of NO in regulating adiposity and insulin sensitivity and places its modes of action into context with the known causes and consequences of metabolic disease.

Keywords: Diabetes; Free radicals; Insulin resistance; Mitochondria; Nitric oxide; Obesity; eNOS.

Figures

Figure 1
Figure 1. Distal and proximal causes of obesity
Graphical illustration of the common causes of, or factors that contribute to, obesity: Influencing factors distal to the disease, such as policy as well as structural and chemical “obesogens” of the built and social (cultural) environment, may contribute to the prevalence of obesity. Funding for obesity research, dietary guidelines, physical education policies, and sidewalk standards are examples of potential influences related to Policy, which is most distal to the actual disease. The Built environment, which comprises places created or modified by people—i.e., where individuals work, their transportation systems, and life outside their homes—is another cause distal to obesity. The Social or cultural environment includes those family or cultural influences that affect behavioral activity, occupation (which may involve shift work), and social and media norms, all of which could affect eating habits and physical activity. Lastly, direct mechanisms that control hunger, satiety, energy expenditure, and nutrient absorption are Proximal causes of obesity. Commonly, these proximal causes are more tangible targets for anti-obesity/diabetes therapies compared with distal causes and are commonly regulated by nitric oxide.
Figure 2
Figure 2. Mechanisms for decreased endothelial-derived NO in obesity and diabetes
Schematic of changes in NOS3 or NO: (A) Decreased NOS3 expression commonly occurs in obese and diabetic states. The mechanisms proposed for diminished expression include TNF-α-mediated destabilization of NOS3 mRNA, which may involve eEF1A1. High levels of NO may regulate NOS3 abundance through cGMP-mediated or via NF-κB-SNO feedback regulatory pathways. A small 27-nt RNA regulates NOS3 expression also, although it is not known whether this mechanism is invoked in obesity or diabetes. (B) Decreased NOS3 activity in obesity and diabetes is largely attributed to insulin resistance, which may be mediated by free fatty acid (FFA)-induced activation of TLR2, TLR4, and NF-κB. In addition, activation of PKCβII may diminish Akt signaling, which normally promotes phosphorylation of NOS3 on Ser1177. Phosphorylation at this site increases NO output by the enzyme. Hyperglycemia may also lead to increased O-GlcNAcylation of NOS3, which decreases Ser1177 phosphorylation and inhibits its activity. In addition, conditions leading to obesity promote upregulation of Cav-1, which is a negative regulator of NOS3, and ceramide accumulation disrupts the NOS3-Akt-HSP90 complex, diminishing activity of the enzyme. (C) NOS3 may also be uncoupled or NO quenched in obese and diabetic states. Diminished levels of substrates and cofactors, such as L-arginine or tetrahydrobiopterin (BH4), lead to uncoupling of the enzyme, which is commonly associated with the presence of NOS3 monomers rather than dimers and can produce superoxide instead of NO. Endogenous inhibitors of NOS3 such as ADMA are also increased in obese conditions and can promote NOS uncoupling. Elevated production of reactive oxygen species such as superoxide can quench NO and result in its oxidation to highly reactive peroxynitrite, which damages biomolecules and can oxidize BH4 to BH2.
Figure 3
Figure 3. Working model of the systemic effects of NO on obesity and metabolism
Illustration of major organs and processes affected by NO and nitrogen oxides derived from NOS3, NOS1, and NOS2: The NOS3 isoform shows anti-obesogenic and insulin-sensitizing effects, which appears to be based in the ability of the enzyme to decrease lipid synthesis and promote fat oxidation in the liver and skeletal muscle. Additionally, NOS3 may be implicated in the secretion of hepatic insulin sensitizing substance (HISS), which might support insulin sensitivity in peripheral tissues such as skeletal muscle. NOS3 is important also for maximizing delivery of insulin and substrates to skeletal muscle, and this is likely critical in regulating insulin sensitivity and glucose tolerance. Through its actions in liver and pancreas, NOS3 may also suppress gluconeogenesis and prevent hyperinsulinemia, respectively. Additionally, NO increases the abundance of mitochondria and stimulates substrate oxidation capacity in adipose tissue, effectively promoting “browning” of white adipocytes. Conversely, other isoforms of NOS appear to have a more malevolent role in metabolism. NO derived from NOS1 promotes hyperphagia, and NOS2-derived nitrogen oxides can promote insulin resistance and inflammation in key peripheral tissues such as liver, skeletal muscle, and adipose tissue. In addition, NOS2 may affect glucose homeostasis by increasing glucose output from the liver and by impairing the endocrine activities of the pancreas.

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