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Review
. 2017 Jun;174(12):1570-1590.
doi: 10.1111/bph.13498. Epub 2016 May 15.

Targeting the NO/superoxide ratio in adipose tissue: relevance to obesity and diabetes management

Aleksandra Jankovic  1 , Aleksandra Korac  2 , Biljana Buzadzic  1 , Ana Stancic  1 , Vesna Otasevic  1 , Péter Ferdinandy  3   4 , Andreas Daiber  5 , Bato Korac  1
Affiliations
Review

Targeting the NO/superoxide ratio in adipose tissue: relevance to obesity and diabetes management

Aleksandra Jankovic et al. Br J Pharmacol. 2017 Jun.

Abstract

Insulin sensitivity and metabolic homeostasis depend on the capacity of adipose tissue to take up and utilize excess glucose and fatty acids. The key aspects that determine the fuel-buffering capacity of adipose tissue depend on the physiological levels of the small redox molecule, nitric oxide (NO). In addition to impairment of NO synthesis, excessive formation of the superoxide anion (О2•- ) in adipose tissue may be an important interfering factor diverting the signalling of NO and other reactive oxygen and nitrogen species in obesity, resulting in metabolic dysfunction of adipose tissue over time. Besides its role in relief from superoxide burst, enhanced NO signalling may be responsible for the therapeutic benefits of different superoxide dismutase mimetics, in obesity and experimental diabetes models. This review summarizes the role of NO in adipose tissue and highlights the effects of NO/О2•- ratio 'teetering' as a promising pharmacological target in the metabolic syndrome.

Linked articles: This article is part of a themed section on Redox Biology and Oxidative Stress in Health and Disease. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v174.12/issuetoc.

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Figures

Figure 1
Figure 1
Adipocytes export fatty acids during times of energy deficit (involved pathways are marked with green arrows). The rise in cAMP, a sign of increased glucagon or adrenergic stimulation, and low insulin stimulate hydrolysis of triglycerides into glycerol and fatty acids. The increased cAMP pool activates PKA that, in turn, phosphorylates hormone‐sensitive lipase (HSL) and perilipins to increase lipolysis. Glycerol and fatty acids are mostly exported into the circulation for systemic utilization. A proportion of fatty acids is re‐esterified within the adipocytes, while another part may, after activation to form acetyl‐CoA, enter the mitochondria for β‐oxidation through carnitine palmitoyl transferase‐1 (CPT‐1). This rate‐limiting enzyme is inhibited by malonyl‐CoA, an intermediate of de novo lipogenesis regulated by acetyl carboxylase (ACC). ACC prevents the oxidation of fatty acids when adipocytes are in a lipogenic state. Inhibition of ACC by AMPK relieves this inhibition for β‐oxidation. Under positive energy balance, insulin regulates glucose and fatty acid uptake in adipose tissue, and expression and activity of enzymes involved in their metabolism and deposition into TAG, that is, lipogenesis (marked by red arrows). In short, insulin through binding to its cell surface receptor stimulates tyrosine kinase activity, which phosphorylates key residues on several ‘docking proteins’, IRS proteins. Assembly of a stable complex leads to the regulation (in most cases, activation) of downstream signalling pathways. Recruited proteins include the p85 regulatory subunit of PI3‐kinase, which stimulates signalling pathways ultimately leading to PI3‐kinase‐dependent serine/threonine PKAkt/PKB activation. Phosphorylation of Akt1 at two regulatory residues, Ser473 and Thr308, is critical for complete Akt/PKB activation in adipose tissue. Akt stimulates the translocation of the glucose transporter, GLUT4, to the plasma membrane, thereby promoting uptake of glucose into the cell. A high level of circulating insulin also stimulates PDE3B, promoting cAMP hydrolysis, lowering PKA activity and PKA‐dependent HSL phosphorylation, activation and lipolysis. Chronic insulin signalling enhances cAMP production through β‐adrenoceptor activation in adipocytes but also disrupts the signalling pathway between β‐adrenoceptors and PKA. Imported as well as de novo synthesized fatty acids from excess glucose combine with CoA, and after successive esterification, form TAG. The (re)‐esterification process requires production of glycerol‐3‐phosphate as a substrate for fatty acid re‐esterification into TAG. Glycerol‐3‐phosphate is mostly derived from glucose in the fed state (glycolytic intermediates). Because the glucose supply to the tissue is limited in the fasting state (lipolytic stimulation) and adipocytes have no significant glycerol kinase activity, glycerol‐3‐phosphate is acquired from lactate or pyruvate.
Figure 2
Figure 2
Adipose tissue is loose connective tissue composed of adipocytes and stromal‐vascular cells, anatomically organized in distinct adipose tissue depots. In terms of energy balance, adipose tissue depots may appear as predominantly white – energy saving, brown – energy dissipating, or beige (brite or convertible), depending on the relative amount of white, beige or brown adipocytes. All adipose tissue depots in the body are functionally integrated in a highly dynamic multidepot adipose organ. The main brown (deep neck), beige (paravertebral) and white (gluteo‐femoral) adipose tissue depots of the adult human adipose organ are presented.
Figure 3
Figure 3
Appearance of UCP1 in the mitochondria of unilocular, white adipocyte in retroperitoneal white adipose tissue of rats maintained at room temperature after 3 days of l‐arginine treatment. Light (A), electron (B) microscopy and immunogold (C) revealed the presence of UCP1 (arrows) in white adipocytes mitochondria. Bars: (A) 20, (B) 2 and (C) 1 μm.
Figure 4
Figure 4
Interaction of NO and superoxide in the physiology and pathophysiology of adipose tissue. FA, fatty acid.
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