Review Article
Regulation of adipose tissue energy availability through blood flow control in the metabolic syndrome

https://doi.org/10.1016/j.freeradbiomed.2012.03.003Get rights and content

Abstract

Maintenance of blood flow rate is a critical factor for tissue oxygen and substrate supply. The potentially large mass of adipose tissue deeply influences the body distribution of blood flow. This is due to increased peripheral resistance in obesity and the role of this tissue as the ultimate destination of unused excess of dietary energy. However, adipose tissue cannot grow indefinitely, and the tissue must defend itself against the avalanche of nutrients provoking inordinate growth and inflammation. In the obese, large adipose tissue masses show lower blood flow, limiting the access of excess circulating substrates. Blood flow restriction is achieved by vasoconstriction, despite increased production of nitric oxide, the vasodilatation effects of which are overridden by catecholamines (and probably also by angiotensin II and endothelin). Decreased blood flow reduces the availability of oxygen, provoking massive glycolysis (hyperglycemic conditions), which results in the production of lactate, exported to the liver for processing. However, this produces local acidosis, which elicits the rapid dissociation of oxyhemoglobin, freeing bursts of oxygen in localized zones of the tissue. The excess of oxygen (and of nitric oxide) induces the production of reactive oxygen species, which deeply affect the endothelial, blood, and adipose cells, inducing oxidative and nitrosative damage and eliciting an increased immune response, which translates into inflammation. The result of the defense mechanism for adipose tissue, localized vasoconstriction, may thus help develop a more generalized pathologic response within the metabolic syndrome parameters, extending its effects to the whole body.

Graphical abstract

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Factors affecting adipose tissue blood flow control in the metabolic syndrome.

Highlights

► Decreased blood flow protects adipose tissue from excess energy. ► Obese adipose tissue shows vasoconstriction despite high NOradical dot production. ► NOradical dot and oxidative radicals alter the lipids of cell membranes, increasing rigidity. ► Decreased blood flow in adipose tissue induces hypoxia and oxidative free radicals. ► Hypoxic adipose tissue increases lactate production from glucose.

Introduction

Blood flow rate is a critical factor for any tissue to obtain an adequate and constant supply of oxygen and substrates, to eliminate excretion products, to maintain thermal homeostasis, and, in general, for direct interrelationship and chemical communication with the rest of the body. The potentially large size of adipose tissue deeply influences the distribution of blood in the body, because an enlarged body mass requires an increased heart output [1]. In uncomplicated obesity, the amount of blood derived to the white adipose tissue (WAT) may be up to half the heart output [2], with no significant effects on blood pressure [3]. However, in most cases of obesity, part of the inflammation-related metabolic syndrome, blood circulation to adipose tissue is more limited, despite its size, and is related to insulin resistance [4]. In addition, the large tissue mass may help increase peripheral resistance and force the heart to pump at a higher pressure and rate, contributing to hypertension, another component of the metabolic syndrome [5].

WAT is a disperse organ, with a number of different sites with a shared function, energy storage [6], but which play other roles related to energy partition and handling [7]. There are differences in cell size, enzyme distribution, physiological role, immune system cell penetration, and even the turnover rate of their lipid [8]. WAT, in a number of locations, plays a fundamental role in the control of the function of adjoining tissues or structures by means of its paracrine secretions: pericardial WAT [9], perivascular WAT [10], [11], etc. There is also a significant amount of adipocytes or small masses of WAT interspersed between other organs, such as muscle, with storage (and control) functions [12]. The regulation of WAT function could not be simplified, but as a whole, the challenge of nutrient overloading, such as the excess glucose in plasma under insulin resistance, requires a generalized response.

A sustained excess of energy intake promotes the development of the metabolic syndrome [13], [14], with practically unchecked growth of WAT, in part because WAT is the last energy sink [15] for unused substrates (mainly glucose and blood lipids) not being taken up elsewhere. The maintenance of high blood levels of substrates, and an unchanged blood flow, may overload the WAT and force its hypertrophic and hyperplasic growth by accumulation of triacylglycerols. The strain posed on the metabolic control systems of WAT and the impossibility of fulfilling its energy storage role in a sustained way (i.e., within physiological limits) produce functional and regulatory damages in the tissue [16], [17]. The immune system tries to stem the aggression, but to no avail, because its defense mechanisms are ineffective against a type of tissue aggression for which no defense system has ever been developed throughout evolution [18]. The effects of the presence of macrophages and other immune cells on WAT only contribute to magnifying the problem and to export its effects to the whole body [19], [20] through the secretion of cytokines [21] and deep alterations of WAT functions, affecting energy partition and handling [22], [23].

An effective system to prevent the overloading of WAT with unwanted substrates such as glucose or lipids (i.e., those in excess that could not be metabolized) is the limitation of blood flow across the tissue. This decreases the availability of substrates to tissue cells. This limitation could not be imposed without consequences, but in the end is effective enough to limit WAT overgrowth. Consequently, the control of blood flow has evolved as a key defense system for WAT, a tissue designed to act as an energy buffer to provide energy under scarcity, to prevent the negative consequences of continued excess energy availability. In this review, the possible consequences of WAT blood flow regulation are explored, including hints at its possible regulation.

Section snippets

How is WAT blood flow controlled?

The intuitive belief that obesity, part of the metabolic syndrome (MS), is essentially a WAT disease may in the end be largely true. But this is—essentially—because WAT is at the bottom of the pecking order for substrate homeostasis: excess lipid and excess glucose (and in part excess amino nitrogen (N)) are finally WAT's problem because there is nowhere else to take these energy sources out of the blood. Faced with large loads of substrates, WAT can either grow indefinitely or defend itself by

Nitric oxide and the control of blood flow in the obese

The higher overall production of NOradical dot in inflammatory states [36] is not directly translated in vasodilatation, because the action of NOradical dot is impaired in obesity [37], [38]. Despite the high availability of NOradical dot, a potent hypotensive agent, relative WAT blood flow in the obese is lower than in normal-weight individuals [24]. This may be due, in part, to a lower NOradical dot bioavailability [29], [39]. It has been postulated that WAT may become hypoxic because of cellular engorging [40], unless higher blood

Limited WAT blood flow in the metabolic syndrome

Low adipose blood flow in the obese [24], [61] may help limit obligatory tissue engorging with the blood-carried substrates that no other organ wants: lower flow results necessarily in a lower uptake of lipids and glucose. Probably, this is not a consequence of diminished angiogenesis, because the expression of the angiogenic factors is not deeply altered by obesity [62], and NOradical dot itself enhances angiogenesis [63].

However, decreased blood flow induces relative anoxia and a number of

Altered red blood cell function in the metabolic syndrome

Red blood cells' main role is to carry oxygen. In mammals, they are not true cells, lacking nuclei, most organelles, and metabolic pathways; they are, essentially, hemoglobin carriers. These cells can be repaired to only a very limited extent because of their bare simplicity. As a consequence, they accumulate the damages acquired during their 100- to 120-day median life [84], which represent (in humans, at least) about half a million complete tours of circulation, including their passage

WAT vasoconstriction

The relative discontinuity in the supply of oxygen to endothelial cell mitochondria may facilitate the production of higher proportions of superoxide anions, because the two-electron transfer to oxygen requires excess oxygen [110]. This abundance of reactive oxygen species further promotes the oxidation of NOradical dot to highly reactive peroxynitrite and finally to nitrite [111]; both series of oxidative and nitrative radicals may damage the red blood cell membranes and the endothelial lining of vessels

Adipose tissue hypoxia and acidosis

Most of the substrates taken up by WAT are used to build up its lipid droplet [134], because its energy needs for normal function are low. Decreased blood irrigation to WAT has the advantage of limiting access to blood-carried substrates, but also decreases the supply of oxygen to most of the WAT mass.

Exercise- or anoxia-induced adrenergic release stimulates both lipolysis and glycolysis (the latter mainly from glycogen stores) [135], [136], releasing lactate and protons to the bloodstream [49]

Catecholamine vasoconstriction in the metabolic syndrome

Altered hemodynamic changes in peripheral organs by increased NOradical dot synthesis, and hypoxia or NOradical dot-triggered catecholamine bursts, may result in overall altered tone in the muscle sheath of blood vessels, also contributing to hypertension. Combination of hypertension, hyperlipidemia, and the inflammatory atherosclerotic response synergistically increases cardiovascular risk. The irregular rhythm and frequency of catecholamine bursts may be in part the cause for the increasing incidence of atrial

Whole-body consequences of reduced blood flow in adipose tissue

The combination of low blood flow (consequence of vasoconstriction, small number of capillaries, and hypertension), glycation (consequence of hyperglycemia and acidosis), acidosis (consequence and cause of hypoxia and of hyperglycemia), oxidation (consequence of oxygen burst release elicited by acidosis), and nitrosation/isomerization (consequence of raised NOradical dot synthesis because of excess amino N and vasoconstriction) may be lethal in the long term for adipose tissue. This deleterious

Conclusions

WAT's role as the main energy storage depot is linked to its ability to maintain the optimal size of fat reserves; its overloading with excess available energy severely limits this capacity, causing it to go over the upper functional limit of fat storage and developing obesity. WAT cannot grow indefinitely, but neither can it stop the incorporation of energy substrates carried by the blood and rejected elsewhere, because they continue to arrive at the tissue. WAT's only effective defense is to

Acknowledgments

This work was supported by Grant SAF2009-11739 from the Plan Nacional de Investigación en Biomedicina of the Government of Spain.

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