Blood circulation in adipose tissue.

PHYSIOLOGICAL REVIEWS Vol. 59, No. 4, October 1979 Printed in U.S.A.

Blood Circulation in Adipose Tissue SUNE Department

ROSELL

of Pharmacology,

AND

ERIK

Karolinska

BELFRAGE Institutet,

Stockholm,

Sweden

I. Introduction ......................................................... II. Vascular Anatomy and Innervation .................................... A. Vasculature ...................................................... B. Adrenergic innervation ............................................ C. Cholinergic innervation ............................................ III. Basic Hemodynamic Data ............................................. A. Resistance ....................................................... B. Exchange ........................................................ C. Plasma volume and interstitial space ................................ IV. Adrenergic Neural Control of Metabolism and Circulation in Adipose Tissue A. Metabolic effects .................................................. B. Vascularactions .................................................. C. Vascular neuroeffector mechanisms in adipose tissue ................. D. Regional differences in adrenergic innervation of adipose tissue. ....... V. Circulating Catecholamines ........................................... VI. Central Nervous Control .............................................. VII. Lipolysis and Blood Flow in Adipose Tissue ............................ VIII. Blood Flow in Adipose Tissue During Hypotension and Hemorrhagic Shock A. Metabolic consequences of restricted blood flow ...................... B. Rise in reesterification rate ........................................ C. Other metabolic effects ............................................ IX. Blood Flow During Reduced Temperature ..............................

I.

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INTRODUCTION

The first major review on the physiology of adipose tissue was that of Wertheimer and Shapiro in 1948 (165). They concluded that adipose tissue is supplied by a comparatively dense network of capillaries, a conclusion based mainly on quantitative data from Gersh and Still (72). Apart from data based on histological techniques, there was no information concerning blood flow in adipose tissue at that time. The next major review on adipose tissue appeared in 1965 as a section of the Handbook of Physiology (149, 152, 155). The rapid development of adipose tissue physiology during the intervening period was amply demonstrated by the over 4,000 references, compared with 90 in the earlier review. In the meantime, in 1956 Dole (46) and Gordon and Cherkes (74) recognized the great physiological importance of the free fatty acid (FFA) fraction in blood. Therefore it was possible to study the mobilization of fat from adipose tissue and to investigate how fat is transported in the blood to be oxidized in various organs. The mobilization of FFA is due to lipolysis, i.e., hydrolysis, of triglycerides stored 1078

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in the adipocytes. The nucleotide adenosine 3’,5’-monophosphate (cyclic AMP) is now generally believed to function as an intracellular mediator in the action of lipolytic agents via an adenylate cyclase system in the cell membrane (33). Lipolysis leads to an outflow of FFA and glycerol from adipose tissue. Glycerol is generally used as a measure of the rate of lipolysis because it is utilized in white adipose tissue to only a minor extent or not at all (155). The reason for this is that adipose tissue has a very limited capacity to phosphorylate glycerol (118, 137). Fatty acids, on the other hand, are generally reesterified to a certain extent, as indicated by the finding that often less than 3 mol FFA/mol glycerol are released in vitro (155) or appear in the venous outflow from adipose tissue in vivo (67). At the time of the 1965 review, the regulation of blood flow in adipose tissue and its functional relation to lipid mobilization and transport were just beginning to be investigated. Scow (152) presented data obtained from perfusion of the rat parametrial fat body with Tyrode solution containing albumin or blood. Around 1965 two other adipose tissue preparations were described that made physiological studies possible (91, 127). Since then the regulation of the blood circulation and its relation to the transport of fat in adipose tissue have been studied in animal experiments and in humans. This review is concerned mainly with the control of blood circulation in adipose tissue. However, as in other tissues, the blood flow is intimately related to the metabolism of the tissue and it has been proposed that the adipose tissue blood flow is controlled by the metabolic requirements of the tissue (78). Therefore, some metabolic events that may be related to the blood circulation in adipose tissue are also reviewed here in some detail. II.

VASCULAR

ANATOMY

AND

INNERVATION

A. Vasculature

Morphological descriptions of the blood supply to fat have been published by several authors since the nineteenth century. Gersh and Still (72) made the first quantitative study, which was followed by several other investigations (11, 24) and all conclude that in adipose tissue an extensive capillary network surrounds each adipocyte. The pattern of the microvessels is not very well recognizable, except in areas with only one or two layers of adipocytes such as the membranous part of the mesentery and the omentum of rats, rabbits, and cats (55, 95, 170). In those areas the part of the microvasculature close to the venous end forms a network that encloses each adipocyte. Several authors have reported a gradient of permeability in the microcirculation (101, 147) and Zweifach and Intaglietta (171) found a fourfold increase in the permeability of single capillaries of the rabbit omentum toward the venous end of the bed. Therefore, in relation to the microvessels, the adipocytes are located close to vessels with the highest


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permeability the lowest hydrostatic pressure, and the shortest I distance for transport of Inaterial from the adipocytes. This location may be i.mportant for transport of products of lipolysis in adipocytes, i.e., fatty acids and glycerol, to the general circulation. The rich vascular supply to each adipocyte gives morphological support for the opinion that the vascular bed in adipose tissue is well dimensioned for transcapillary exchange (126). In canine subcutaneous adipose tissue the average resting values for blood flow (6.5 ml.min+. 100 g-l) and for the capillary filtration coefficient (CFC: 0.027 ml l rein+ 100 g-l mmHg+) are approximately 1.5-2 times those found in resting skeletal muscle (126). In canine omental tissue the resting CFC (0.050 ml*mirP 100 g-l l mmHg+) is even higher (13). l

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B. Adrenergic

Innervation

The histochemical fluorescence method of Falck and Hillarp has been employed by several groups to determine the adrenergic nerve supply to adipose tissue. Wirsen (167, 168) suggested that in rats only the larger blood vessels in adipose tissue were supplied by adrenergic fibers. They could see them only around arteries and arterioles and occasionally around veins; there were pract ,ically no nerve terminals among the fat cells. Ballantyne and Raftery (8) confirmed this finding. Furthermore, according to Daniel and Derry (40), white adipose tissue of rats is poorly supplied with nerve fibers around the cells, in contrast to the brown fat that appears to have an abundance of nerves around the adipocytes. They proposed that this difference could be used as a criterion to distinguish white adipose tissue from brown. However, in contrast to the above reports, recent studies (11, 43) have provid .ed morphological support for the well-established fact that sympathetic nerve activity enhances lipolysis. Thus in mesenteric and epididymal fat of the rat, adrenergic nerve fibers are distributed extensively around both fat cells and capillaries (43). In the mesentery of the dog adrenergic nerves can be traced to d iscrete circumscribed areas, whereas adjacent areas seem to lack adrenergic innervation (11). This may be due to technical difficulties in identifying adrenergic fibers, especially in view of difficulties encountered by several workers in demonstrating adrenergic innervation of white adipose tissue. However, this pattern of innervation is a constant finding in the canine mesentery, omentum, and subcutaneous adipose tissues and may indicate that there are two pools of adipocytes in th e same tissue- one that is innervated by adrenergic fibers and another that is not. C. Cholinergic

Innervation

Salvador and Kuntzman (150) have identified cholinesterase in adipose tissue. On the basis of this finding, they proposed that adipose tissue may be


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innervated by cholinergic fibers of sympathetic or parasympathetic origin. It has been shown that a cholinesterase inhibitor, neostigmine, lowers the fasting concentration of plasma FFA in the conscious dog. This might be taken as an indication that stimulation of cholinergic receptors inhibits the release of FFA (37). Another possible explanation is that neostigmine inhibits the lipase activity (45). Using histochemical techniques, Weiss and Maickel(l64) observed that atropine can enhance the lipolytic response to nerve stimulation in isolated tissue. Ballantyne (7) demonstrated the presence of at least two cholinesterase enzymes in white adipose tissue from different species. The adipocytes appeared to contain both an acetyl- and a butyrylcholinesterase, whereas the nerve fibers to the vessels seemed to contain only butyrylcholinesterase. No direct nerve supply to the individual adipocytes was found. The fact that the nerves did not contain acetylcholinesterase led Ballantyne to conclude that there are no cholinergic fibers to adipose tissue. This conclusion is supported by the finding that the vascular responses to electrical stimulation of the nervous supply to canine subcutaneous adipose tissue are not influenced by atropine (124) and that acetylcholine has very weak vasomotor effects in that tissue. Thus acetylcholine is roughly 1,000 times less potent as a vasodilator than prostaglandin E,, and 100 times less potent than histamine (68). Naturally, these findings raise a number of questions about the existence of cholinergic fibers in white adipose tissue. III.

BASIC

HEMODYNAMIC

DATA

A. Resistance

Resting blood flow in adipose tissue is usually between 7 and 12 ml= min-l 100 g-l when recorded directly in experimental animals (105, 124). However, in man the values found by measuring the washout of inert gases are 2-3 ml min-l 100 g-l (107-109). This discrepancy is partly explained by uncertainties in the determination of the partition coefficients for the gases. The influence of the location of adipose tissue and the nutritional and neurohumoral states are also important factors (83). In addition, Di Girolamo et al. (44) have pointed out the importance of the number of adipocytes per unit tissue weight. Thus, the resting blood flow per unit weight is significantly lower in canine subcutaneous adipose tissue containing larger adipocytes than in adipose tissue with smaller ones (44). This agrees with histological data indicating that the capillary density increases as the fat cells become smaller (72). In humans, Larsen, Lassen, and Quaade (108) noted that the thicker the subcutaneous fat layer the smaller was the blood flow per unit weight. Maximal blood flow capacity, i.e., blood flow values found at maximal vasodilatation, amounts to only 25-30 m1.rnir-P 100 g-’ (126), compared with 50-70 ml. mirP 100 g-l in skeletal muscle. This indicates smaller dimensions of the resistance section in subcutaneous adipose tissue than in skeletal muscle. l

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B. Exchange

As mentioned previously, under resting conditions the average CFC in canine subcutaneous adipose tissue is 0.027 ml l in-l 100 g-’ (126). This value is approximately 1.5-2 times those found in resting skeletal muscle (36, 120), which shows that the hydrodynamic conductivity is comparatively high in adipose tissue. The high resting hydrodynamic conductivity does not seem to be due to a large exchange surface area, since the diffusion capacity for small molecules is somewhat lower than in skeletal muscle. Thus Linde and Gainer (114) found that the permeability-surface area (PS) product for 86Rb had a mean value of 2.5 ml min-l 100 g-l in canine subcutaneous adipose tissue. This should be compared with about 4.5 ml .min-l 100 g-l in the dog gracilis muscle or the cat gastrocnemius-plantaris muscle (135). Similarly, the capillary diffusion capacity for [ 51Cr]ethylenediaminetetraacetate ([ 51Cr]EDTA) in rabbit inguinal adipose tissue was about half that reported for skeletal muscle (130). The combination of a relatively high hydrodynamic conductivity and a rather low diffusion capacity for small molecules may indicate that the permeability in the vascular bed of adipose tissue is higher than in skeletal muscle. This suggestion is also supported by data on diffusion capacities of sucrose. Permeability-surface area of [14C]sucrose (mol wt 342) was determined during resting conditions and vasodilatation, respectively, with the single-injection technique (113). During resting conditions the transport of sucrose appears to be limited by flow. However, with vasodilator agents (papaverine and prostaglandin E,) it is possible to reach flow levels where the diffusion of sucrose is predominantly limited by the capillary barrier. For sucrose, PS during maximal vasodilatation was approximately 3 ml min-’ 100 g-l and during resting conditions probably about 1.5 ml min-l -100 g-l. These values are of the same order of magnitude as those found in the exercising human forearm, representing skeletal muscle at maximal vasodilatation (159). However, Gersh and Still (72) concluded that in rats the capillary surface area of adipose tissue is not more than one-third that of skeletal muscle. If this relationship is true also for other species, the permeability of adipose tissue capillaries is probably larger than that of skeletal muscle capillaries. This assumption is in accordance with the somewhat higher colloid osmotic pressure in the interstitial fluid from adipose tissue compared with that from skeletal muscle (6, 97). l

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C. Plasma

Volume

and Interstitial

Space

In canine subcutaneous adipose tissue the plasma volume calculated from the tissue and blood content of 51Cr-labeled erythrocytes was 6.6 t 0.8 ml. 100 g-’ (112). The interstitial space of adipose tissue is approximately 10% of the tissue weight (25, 42, 61, 112). This is about half of the body average. Since a large part of the body weight consists of adipose tissue, significant


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quantities of fluid are present in the interstitial space of adipose tissue and co uld be important in the regulation of blood volume, if mobilized into the blood IV.

ADRENERGIC IN

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A. Metabolic

CONTROL

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TISSUE

Effects

The metabolic events in adipose tissue are intimately related to the vascular reactions to adrenergic activity. The importance of the adrenergic control of lipolysis in white adipose tissue is well established (84). Stimulation of sympathetic nerves to canine subcutaneous and omental adipose tissue causes an increased outflow of FFA and glycerol, as well as vascular responses (13, 56, 124, 139). These effects are seen with stimulation frequencies that are supposed to be within the physiological range. Folkow (52) concluded that the impulse activity in postganglionic sympathetic nerves to skeletal muscle is in the order of l-2 Hz and rarely exceeds 6-8 Hz under physiological conditions. It is reasonable to assume that this is also the case in sympathetic nerves to adipose tissue. The maximum FFA release in canine subcutaneous adipose tissue is obtained with about 3 Hz (139). Release of FFA has also been found after supramaximal stimulation of nerves to isolated rat and rabbit adipose tissue in vitro (38). However, it is questionable whether lipolysis in rabbits is influenced by adrenergic sympathetic nerve activity under physiological conditions, because catecholamines have a weak adipokinetic action when added to adipose tissue from that species in vitro (149) and they are weak activators of rabbit adipocyte adenylate cyclase (28). 1. Phamacological

characterization

In most species catecholamine-induced lipolysis is mediated by P-adrenoceptors and norepinephrine is a more potent lipolytic stimulus than epinephrine (85). This agrees with the classification of Lands et al. (102) of lipolytic P-adrenoreceptors into the &-group. However, lipolytie &-adrenoreceptors also seem to be present together with the &receptors in humans (73) and dog (1, 15, 17). In blood-perfused in situ preparations P-adrenoceptor blockade inhibited lipolysis caused by sympathetic nerve activity in subcutaneous (61) as well as in omental adipose tissue (13). In the subcutaneous adipose tissue the lipolytic response to sympathetic nerve stimulation was much more readily blocked by &-antagonists than by &antagonists (15). This indicated that P,-adrenoceptors are of greater physiological importance than &receptors, because activation of the sympathetic nerves is the most important stimulus for short-term regulation of lipolysis (see above). Isolated fat cells from humans (32, 129) and hamsters (86) also seem to contain a-adrenoceptors that on stimulation reduced lipolysis. The physiological significance of these findings is unknown. In blood-perfused canine sub-


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cutaneous adipose tissue a-blockade did not potentiate the lipolytic response to intra-arterial norepinephrine (20). However, low concentrations of adrenergic a-receptor blocking agents potentiated the venous outflow of FFA and glycerol after stimulation of sympathetic nerves at physiological frequencies (69). One important factor for the potentiation seems to be the vascular reactions to sympathetic nerve activity in canine subcutaneous adipose tissue. The vasoconstriction after sympathetic nerve stimulation is converted into vasodilatation on stimulation after administration of a-receptor- blocking agents. Conceivably the increased blood flow promotes a more rapid and effective venous outflow of the products of lipolysis and thus may partly explain the shortened latency as well as the potentiation. Another important factor may be the existence of presynaptic a-adrenoceptors, which when stimulated reduce the release of norepinephrine from the sympathetic nerve endings (see below). A blockade of such receptors would increase transmitter release and thus increase lipolysis. B. Vascular

Actions

I. Resistance

Activation of the sympathetic nerves to canine subcutaneous and omental adipose tissues induces changes in all the consecutive vascular sections, i.e., the resistance, exchange, and capacitance sections. However, the mesenteric blood flow does not seem to be markedly influenced by sympathetic nerve activity (12). In the omentum and the subcutaneous adipose tissue the total blood flow decreased in proportion to the frequency of stimulation (13, 124). With continued stimulation for several minutes there was a gradual return of blood flow to prestimulatory levels. This is especially pronounced in the omentum, where the constriction may even be converted to a vasodilatation, despite continued stimulation. This reversal was especially pronounced at higher stimulation frequencies (6-9 Hz). The reversal of the total blood flow is very similar to the autoregulatory escape in the cat intestine (54) but the mechanisms for these vascular effects may not be the same, because the capillary and capacitance reactions are different. In the intestine the escape was confined to the resistance section (54, 161), whereas this was not the case in the omentum (13). The vasoconstriction is characterized as an a-receptor effect. After a-blockade, sympathetic nerve stimulation induced a pronounced vasodilatation, which in turn was blocked by P-receptor-blocking agents (13, 124). 2. Capillary

surface area

To study the response of the capillary surface area to sympathetic nerve stimulation, elimination rates of locally deposited 133Xe and 1251- were studied


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during constant-flow perfusion (114). The blood flow was kept constant to eliminate the influence of changes in total blood flow on the capillary transport. Nerve stimulation (l- 15 Hz) caused a frequency-related, a-receptor -mediated decrease in the elimination rates of these compounds, a response found even at 1 Hz. No difference between the responses of 133Xe and 1251- was found, although the surface area available for diffusion of 133Xe is much larger than that for 1251- (133). When nerve stimulation was continued beyond 10 min, a decrease in the elimination rate of f33Xe during constant blood flow occurred in parallel with the escape of the resistance vessels from the constrictor-fiber influence. These experiments indicate that the capillary surface area is decreased during sympathetic activity. This hypothesis is further supported by two other types of experiment. In one series of experiments the fractional extraction of continuously infused 86Rb was determined under constant-flow conditions and the PS products were calculated (114). The PS products for 86Rb decreased during nerve stimulation in a frequency-related manner at frequencies above 2 Hz. In another series the effects of sympathetic nerve stimulation (4-20 Hz) on oxygen uptake were compared with the effects of mechanical reductions in blood flow of the same magnitude under free-flow conditions (66). Nerve stimulation caused a significantly greater decrease in oxygen uptake than did mechanical flow reduction causing a similar (50% or more) decrease in blood flow. Thus, sympathetic nerve stimulation to subcutaneous adipose tissue results in decreased transport of hydrophilic ( 1251- and 86Rb) and lipophilic ( 133Xe and 0,) compounds from blood to tissue as well as in the reverse direction. The common factor influencing the transport of the different indicators is presumably the diffusion distances in the interstitial space. Distances between perfused capillaries seem to be enlarged to such an extent that the exchange of even oxygen and xenon is limited. Increases in diffusion distances most probably result from a decrease in the number of perfused capillaries. This reduces the capillary surface area and results in uneven perfusion in open vessels, especially during constant-flow perfusion. The concept of a decrease in the number of perfused capillaries is directly supported by a study of microvascular flow velocity in omental adipose tissue, where sympathetic stimulation completely stopped the flow of erythrocytes in a number of vessels (144). Since the resistance vessels constrict during nerve stimulation, the precapillary sphincters probably also constrict. This is supported by the results of Eriksson and Lisander (49), who, using intravital microscopy of skeletal muscle, could not distinguish morphologically between the vascular sections responsible for resistance and for capillary flow distribution. Also in other organs, e.g., skeletal muscle and intestine, sympathetic vasoconstriction resulted in diminished exchange of hydrophilic and lipophilic compounds under both free-flow and constant-flow conditions (26, 47, 132, 135, 153). In these tissues this response has also been interpreted as being due to a decrease in the number of open capillaries.


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3. Permeability

Sympathetic nerve stimulation induces an increase in CFC both in subcutaneous and omental adipose tissue, despite a concomitant decrease in total blood flow (68). This is surprising, because in other vascular beds, including skeletal muscle, skin, and intestine, there is a decrease in CFC under similar conditions (120). This has been taken as support for the hypothesis that sympathetic nerve activity increased the tone of the precapillary sphincter vessels, thus diminishing the number of capillaries open to flow and consequently the surface area over which filtration occurs. By the same token, an elevated CFC in adipose tissue would indicate a relaxation of the precapillary sphincter tone and thus an increased capillary surface area. However, as already indicated, there is considerable experimental support for the hypothesis that sympathetic activation causes a decrease in capillary surface area. Thus there is an apparent discrepancy between the results from the filtration and diffusion measurements. To explain this difference the hypothesis was advanced that sympathetic nerve activity not only affects the precapillary sphincter tone but also the permeability of the exchange vessels (64, 140). The hydrodynamic conductivity, as measured by the CFC, depends not only on the total capillary surface area available for exchange processes but also on the permeability (the number of dimensions of the pores), and alterations in the CFC do not provide information about which of these two factors has changed (see 136). Therefore the pronounced increase in CFC may be due to an increase in pore size that is, however, to some extent offset by an increased precapillary sphincter tone. Indirect support for the idea that sympathetic nerve activity may actually increase the pore size is provided by the fact that the high CFC values found in subcutaneous adipose tissue after sympathetic nerve stimulation could cmly be induced by infusion of vasodilator substances that are known to increase permeability in other tissues, e.g., histamine and bradykinin (68). On the other hand, infusion of prostaglandin El, acetylcholine, or isoprenaline in concentrations high enough to produce maximal vasodilatation and consequently a maximal capillary surface area caused only a moderate increase in CFC. To induce pronounced increments in the CFC, like those found on sympathetic nerve stimulation, another factor or factors have to be operating and increased permeability may be such a factor. This hypothesis is also supported by the finding that when nerve stimulation was superimposed during infusion of prostaglandin E 1, acetylcholine, or isoprenaline, a further increase in CFC was obtained. This did not occur when sympathetic nerve activity was induced during infusion of histamine or bradykinin (68). Rosell, Intaglietta, and Chisolm (143) found that the average isovolumetric pressure (Pci) decreased from 9.4 mmHg to 5.6 mmHg on sympathetic nerve stimulation with frequencies between 1 and 10 Hz. The decrease in P,i may be explained in several ways, including reduction in blood flow due to the vasoconstriction or absorption of fluid from the extravascular space due to a decrease in the capillary pressure during sympathetic nerve activity. The latter


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would tend to reduce the colloid osmotic pressure difference between blood and tissue and thus reduce the hydrostatic pressure necessary to keep the tissue isovolumetric. Another possibility is that sympathetic nerve activity may produce osmoti call y active substances that accumulat ,e in the extravascular space and thus reduce the blood- tissue osmotic gradient. After having shown experimentally that such mechanisms were less likely to account for the effect, the authors suggested that the decrease in P,i was a result of an increased capillary permeability that allowed osmotically active substances to cross the capillary membrane to a greater extent. Consequently the blood-tissue difference in osmotic pressure would diminish and the hydrostatic pressure, which counterbalances all pressures tending to cause fluid absorption in an isovolumetric state, may decrease. The observation that histamine, but not prostaglandin E,, also decreased the P,i supports this hypothesis, since histamine, but not prostaglandin ES, is known to increase permeability in other vascular beds (119, 154). To further examine possible changes in permeability of the vascular wall in canine subcutaneous adipose tissue during sympathetic nerve stimulation, the diffusion capacity for molecules that pass from the vessels into the tissue has been determined (113). The single-injection, indicator-diffusion method described by Chinard et al. (35) and Crone (39) was used to determine the PS products for two molecules of different sizes, [14C]sucrose (mol wt 342) and [3H]polyethylene glycol ([3H]PEG: mol wt 800-l,OOO), during and after nerve stimulation at 0.5-6 Hz. Determinations were performed both during vasoconstriction and in the escape phase after the vasoconstriction had subsided (see sect. IV@) or at low stimulation frequencies producing no vasoconstriction. During sympathetic nerve stimulation PS for sucrose increased by 15% in spite of a vasoconstriction. When superimposed on a maximal vasodilatation, sympathetic nerve stimulation induced an increase in PS for sucrose of approximately 40% and for PEG of about 20%. The increases in the PS products probably are not due to changes in blood flow, because the transvascular diffusion was predominantly barrier limited. The increases in the PS products are also unlikely to be due to an increase in capillary surface area, because significant increases in PS were found also during vasoconstriction, i.e., when the capillary surface area was decreased. Increases in PS were even greater than those produced by a maximal vasodilatation. Is it also possible that during nerve stimulation blood flow was distributed to parts of the adipose tissue having higher permeability? Although this cannot be excluded entirely, it appears unlikely, because the shapes of the concentration-time curves were similar under control conditions and during nerve stimulation, indicating a similar distribution of transit times under these conditions. Thus, these results also indicate that in subcutaneous adipose tissue sympathetic nerve stimulation causes an increase in the vascular permeability for solutes. The increases in the PS products for sucrose and PEG during nerve stimulation may appear to be in contradiction to the


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decrease in PS for continuously infused 86Rb during nerve stimulation (114). This apparent discrepancy probably 1s due mainly to the fact that the PS for continuously infused 86Rb depends to only a small extent on the capillary barrier in adipose tissue and to a large extent reflects extracapillary factors, especially during nerve stimulation. a) Possible effector mechanisms. One possible site for a permeability increase could be the vessels at the far venous end of the exchange system where smooth muscle cells are present. Contraction of such vessels might occur without a measurable change in the total vascular resistance, which depends on the postcapillary vessels to only a minor extent. However, due to the small surface area of these vessels in relation to the entire exchange surface area (l66), it seems unlikely that a permeability increase in these vessels alone would be measurable as an increase in PS for small molecules. In contrast, an increase in filtration capacity should be found even if a permeability change took place over only a small part of the surface area, provided that there was a change in pore size. This influences filtration to a much larger extent than diffusion, since filtration depends on the fourth and diffusion on the second power of the pore radius. Increased hydrostatic pressure has been advanced as a possible mediator of increased permeability produced by the histamine-type mediators, a mechanism known as the “stretched-pore phenomenon” (148,162). However, it was later shown that this permeability increase also occurred without changes in hydrostatic capillary pressure (30, 115). Furthermore, the mean capillary pressure does not seem to change during sympathetic nerve activation in adipose tissue (111). The permeability increase caused by histamine occurs predominantly in venules, particularly in those that lack smooth muscle cells (116). In fact, it has been suggested that the increased permeability induced by histamine occurs by contraction of endothelial cells (117). By use of fluorescein-labeled antibodies Becker and Murphy (14) found indications of the presence of a contractile protein, actomyosin, in endothelial cells. Using the rabbit ear chamber in vivo, Sanders et al. (151) described sympathetic nerve-induced changes in capillary endothelial cells of the type later found with histamine and bradykinin by Majno et al. (117), which suggests endothelial cell contraction. Moreover, Svensjo (156) reported that histamine, bradykinin, and several prostaglandins applied topically on the everted hamster cheek pouch increased the leakage of fluorescein dextran (mol wt 145,000) into the microcirculation at postcapillary venules on ly. Electron microscopy of leaking postcapillary venu les indicated that the leakage was due to endothelial cell contraction. Interestingly enough, the leakage was reduced in the presence of the adrenergic &agonist terbutaline (157). Actions of adrenergic cw-receptor-blocking agents were not studied. One hypothesis therefore is that increased vascular permeability in adipose tissue during sympathetic nerve stimulation occurs by endothelial cell contraction, possibly toward the venous end of the exchange section, where the intercellular junctions seem looser (117). An entirely different mechanism by which an increase in vascular perme-


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ability during nerve stimulation could occur is by stimulation of an active transport system, e.g., vesicular transport (131). This possibility cannot be ruled out at present. The increase in vascular permeability most probably is mediated by a-adrenoceptors, possibly on endothelial cells. The increase in the filtration coefficient and the decrease in the isovolumetric capillary pressure during nerve stimulation were blocked by a-adrenergic blocking agents (126,143). Bevan and Duckles (21) have found evidence for a-adrenergic receptors on endothelial cells from rabbit aorta. Although a direct adrenergic effect on endothelial cells is likely, other mediators of the effect of sympathetic nerve stimulation on permeability should be considered. As has been pointed out, histamine is commonly considered to increase vascular permeability and adipose tissue 1s richly supplied with mast cells (43) that contain 1.arge amounts of histamine (60) Histamine also causes increases in . the PS products for sucrose and PE;; above the PS values produced by prostaglandin E, and papaverine, in doses giving vasodilatation of the same magnitude (113). The increase in the PS for sucrose due to histamine was dependent on dose. However, the increase in vascular permeability after sympathetic nerve activity does not appear to be mediated by histamin e, since the H, blocker mepyramine did not change the characteristic CFC increase after sympathetic nerve stimulation (68). Further, when the histamine H2 blocker cimetidine was given in combination with mepyramine in amounts that completely abolished the vascular and metabolic effects of histamine, the CFC increase induced by sympathetic nerve stimulation still remained (Belfrage, unpublished observations). Thus, there is experimental support for the hypothesis that sympathetic nerve stimulation in subcutaneous adipose tissue causes an increase in the vascular permeability and that this occurs by activation of adrenergic a-receptors. The effector mechanism could be located in the endothelial cells. These may increase vascular permeability by contraction, thus enlarging intercellular gaps, perhaps in venules. Another possibility is that these cells increase their capacity for vesicular transport. b) FunctionaL aspects. A possible function of an increase in vascular permeability during nerve stimulation may be to promote the transvascular transport of large molecules, such as albumin, which are barrier limited under physiological cond itions. Although direct measurements of protein transport have not yet been made, indirect m .easurements, by means of determining the Pci, support this idea (143). Greater availability of albumin in the extracellular water compartment may increase the possibility for fatty acids to diffuse from the fat cells to blood. Fatty acids are water insoluble and in blood are transported by albumin, and albumin may act as an acceptor of fatty acids also in the extravascular compartment. Moreover, Rodbell (138) has shown that fatty acids act as regulators of lipolysis. The addition of albumin, acting as an acceptor of fatty acids, markedly enhanced the lipolytic rate. The effect of fatty acids presumably is due to inhibition of adenylate cyclase, leading to a decreased accumulation of cyclic AMP (50, 51). The effect is appreciable when the fatty


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acid/albumin molar ratio exceeds 3 (50). The interstitial space of adipose tissue, where the fatty acids may accumulate during increased lipolysis and where the albumin concentration is lower than in blood, is the most likely place where a high concentration ratio may be found. The fatty acid concentration in canine subcutaneous adipose tissue in vivo is elevated by sympathetic nerve stimulation (56). Therefore an increased outward diffusion of albumin due to increased permeability during sympathetic nerve activity may counteract a rise in the fatty acid/albumin molar ratio in the interstitial space. Consequently, the lipolytic rate may not be reduced as would otherwise be the case and the outward diffusion of fatty acids may also be facilitated. Thus, the permeability change may constitute a link between lipid mobilization from the adipocytes and the diffusion of fatty acids to the blood circulation. Quantitative data on fatty acid and albumin concentrations in the interstitial space of adipose tissue during different degrees of lipolysis are lacking. Such data would be important to test the validity of the proposed function of permeability changes. 4. Net transvascular

movement

of fluid

The interstitial sucrose space of adipose tissue measures approximately 10% of the tissue wet weight (112). This is somewhat smaller than the interstitial space of skeletal muscle (48), the most important tissue in the mobilization of extravascular fluid during hypovolemic states. However, in view of the total amount of adipose tissue in the body (16-20% of body wt), considerable quantities of fluid are also present interstitially in adipose tissue. For example, in a 70-kg person l-l.5 liters may be present in this compartment. To see if this fluid can be mobilized from adipose tissue Linde (111) investigated the effects of sympathetic nerve stimulation (l- 15 Hz, 10 min) on the net transvascular movement of fluid by combining plethysmographic recording of the tissue volume with external monitoring of the blood volume. The decrease in total volume could be accounted for by the decrease of the blood volume, except during the first minutes at 15 Hz, when a small net absorption was noted. After cessation of the nerve stimulation no significant net filtration was found. Thus, mobilization of fluid from the interstitial space in adipose tissue into the blood does not seem to occur by sympathetic nerve activity. The most likely explanation for the absence of net transvascular fluid movement during nerve stimulation in adipose tissue is that the mean hydrostatic capillary pressure is essentially unaltered and therefore the precapillaryto-postcapillary resistance ratio does not change. Thus, although adipose tissue contains considerable quantities of fluid in the interstitial space and although the capacity for fluid exchange is high, fluid is not mobilized by nerve activity as in skeletal muscle and skin (120). The vascular effects in adipose tissue of circulating catecholamines (epinephrine and norepinephrine) differ considerably from those of norepinephrine released from the adrenergic nerve terminal system (see below). Circulating epinephrine seems to play a prominent role in the development of vascular reactions in adipose tissue during hypo-


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tension (see below). For these reasons it would be of interest to know whether circulating catecholamines, in contrast to adrenergic nerve activity, can mobilize fluid from adipose tissue. Studies that would elucidate this question have not been reported. The absence of fluid mobilization during nerve stimulation may constitute a protective mechanism to maintain local fluid homeostasis, as suggested for the splanchnic organs (53). Mechanical reduction in blood flow did not cause net transvascular fluid movement either, implying “autoregulation” of the mean capillary pressure under these circumstances. Henriksen (82) found that elevation of the transmural pressure in human subcutaneous adipose tissue caused an active constrictor response in the resistance vessels, counteracting a rise in mean capillary pressure. Thus, the mean capillary pressure in adipose tissue appears to be carefully balanced under several conditions that might disturb the local balance. The inability of baroreceptor mechanisms to activate the sympathetic nerves to adipose tissue (77, 124) may perhaps be considered an additional protective mechanism. C. Vascular 1.

Neuroeffector

Release and metabolism

Mechanisms

in Adipose

of the adrenergic

Tissue

transmitter

As in other tissues, there was an immediate increase in the venous outflow of [3H]norepinephrine on electrical stimulation of the sympathetic nerves in canine subcutaneous adipose tissue prelabeled with [3H]norepinephrine (70). Experiments with cocaine suggested that reuptake into the adrenergic neurons is an important mechanism for inactivation of the released transmitter (20; see also sect. IV, CZ). Enzymatic degradation by monoamine oxidase (MAO) and catechol 0-methyltransferase (COMT) also occurred, as indicated by the presence of deaminated and 0-methylated norepinephrine metabolites in the venous effluent (70). However, the importance of COMT for the inactivation of the transmitter at the vascular adrenoceptors is minimal (18), as indicated by the fact that the vasoconstrictor and vasodilator responses to sympathetic nerve stimulation were unaltered by blockade of COMT. On the other hand, several findings suggest that COMT may be important for the regulation of transmitter concentration at the adipocytes. There is considerable COMT activity in isolated fat cells (93, 158). In addition, both the products of lipolysis and the 0-methylated norepinephrine metabolites occurred in parallel in the venous effluent after cessation of sympathetic nerve stimulation, whereas the increased norepinephrine outflow occurred during the stimulation in parallel with the vascular response (70). Furthermore, inhibition of COMT increased the lipolytic response to norepinephrine in canine adipose tissue in vitro, as well as to sympathetic nerve stimulation and to intra-arterial norepinephrine in canine adipose tissue in vivo (18). Based on studies of different tissues in vitro several substances acting on the norepinephrine neurons have been proposed as physiological regulators of


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epinephrine rel .ease (for references see 103). In canine subcutaneous adipose tissue blockade of cy-adrenoceptors grea ,tly increased the lipolytic response to (69) but not to intra-arterial norepinephrine sYm pathetic ne Nrve stimulation outflow during (20) and such a blockade also greatly increased norepinephrine sympathetic nerve stimulation (70). These data suggest that presynaptic a-adrenoceptors may be important for feedback regulation of norepinephrine release. A positive feedback of norepinephrine release through presynaptic P-adrenoceptors seems less likely, because P-adrenoceptor blockade did not alter the vasoconstrictor response to brief sympathetic nerve stimulation (15). It has been suggested that endogenous prostaglandins negatively modulate the release of norepinephrine from the sympathetic nerve terminal system in a number of organs (79). Most studies supporting this hypothesis have been performed on isolated organs in vitro or organs perfused with salt solutions. However, in blood-perfused canine subcutaneous adipose tissue prostaglandin E, had no effect on transmitter overflow (62). Similarly, indomethacin had no effect on transmitter overflow, which further indicates that, in this tissue at least, prostaglandins are of minor importance in the physiological regulation of the adrenergic transmitter (63; cf. 59). Adenosine was formed during sympathetic nerve stimulation in dog adipose tissue in situ (60) and intra-arterial administration of adenosine lowered the venous outflow of norepinephrine during sympathetic nerve stimulation (80). Therefore it has been suggested that adenosine may be involved in the regulation of transmitter release in adipose tissue. However, it is not yet known if the endogenously obtained concentrations of adenosine are enough to counteract the release of the adrenergic transmitter. 2. Distribution

of adrenergic

receptors

Neuronally released norepinephrine invariably causes an a-adrenoceptormediated vasoconstriction in adipose tissue (92; 124). This vasoconstrictor response was unaltered by inhibition of P-adrenoceptors (15) or by inhibition of COMT (18). However, blockade of the neuronal uptake, by pretreatment with cocaine or chronic denervation, potentiated the vasoconstrictor response to both sympathetic nerve stimulation and to intra-arterial norepinephrine (20, 142). Because COMT is mainly confined to extraneuronal sites (cf. 75) and because bl ockade of neuronal uptake influences the norepinephrine concentrat .ion main 1Y when the neuromuscular gap is narrow (23; cf. 22), these data suggest that the vascular cy-adrenoceptors in adipose tissue are located predominantly on those effector cells in close contact with the adrenergic nerve terminals at the adventitial-medial border. This localization of the cx-adrenoceptors may be a prerequisite for the rapid and precise sympathetic control of peripheral resistance. Although brief sympathetic nerve stimulation did not seem to activate vascular P-adrenoceptors (15), circulating norepinephrine did. Thus intravenous infusion of norepinephrine may cause vasodilatation in adipose tissue in humans (125), monkeys (92), and dogs (9, 88, 121). Inhibition of COMT


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TISSUE

(18), but not of neuronal uptake (20, 142), potentiated the vasodilator effects of intravascular norepinephrine. These data have been taken to support the hypothesis that vascular P-adrenoceptors, in contrast to the cy-adrenoceptors, are located far from the nerve terminals. From the functional point of view, the ar-adrenoceptors may be termed innervated receptors, whereas the P-adrenoceptors may be termed noninnervated (or humoral) receptors. As discussed below, these arrangements make it possible that norepinephrine released from nerve terminals and circulating norepinephrine have different functions in the regulation of the adipose tissue blood flow. D. Regional

Differences

in Adrenergic

Innervation

of Adipose

Tissue

Most studies of adrenergic innervation have been performed on canine subcutaneous adipose tissue. However, regional differences in the responses to stimulation of the sympathetic nerves have been found. Thus activation of the appropriate sympathetic nerves to the canine mesentery has very little effect on the outflow of glycerol or FFA or on circulation (12). Furthermore, to induce lipolysis, norepinephrine had to be injected in approximately 10 times the dose required to produce similar effects in subcutaneous adipose tissue. Therefore, catecholamine receptors seem less abundant in the mesenteric adipose tissue than in the subcutis or in the omentum of the same species (13). Aronovsky et al. (5) suggested that in some regions the adipose tissue may have a supportive function rather than serving as an energy depot. They found that catecholamines did not exert any “adipokinetic” effects when added to adipose tissue from the orbital socket and the paw of the cat. The results of studies with microcirculatory techniques suggest that there are important differences in the adrenergic innervation within the same tissue. Rose11 et al. (144) measured the microvascular erythrocyte velocity in cat omental adipose tissue and found three different types of response on stimulation of the sympathetic nerves: 1) a decrease in flow velocity (75% of the vessel), 2) no response (7%), and 3) an increase in flow (18%). Both increases and decreases in flow velocities were related to the stimulus frequency. It is not known whether the different reactions of the microvessels in the omentum are correlated with the distribution of the adrenergic nerves. Morphological (11) and hemodynamic evidence indicates the presence of two compartments in adipose tissue: one that is predominantly innervated by adrenergic fibers and thus responds to sympathetic discharge with increased lipolysis and vascular reactions and another compartment that is not. V.

CIRCULATING

CATECHOLAMINES

It has been reported (see sect. IV, C2) in several studies in man and animals that intravenous infusion of norepinephrine may cause P-adrenoceptor-mediated vasodilatation in subcutaneous adipose tissue (9, 88, 121, 122, 125). Furthermore, Hoffbrand and Forsyth (92) showed that subcutaneous adipose tissue was


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the only tissue that responded with vasodilatation during intravenous infusion of norepinephrine. Moreover vasoconstriction induced by intra-arterial injection of norepinephrine was potentiated by P-adrenoceptor blockade to a much greater extent in adipose tissue than in skeletal muscle (89). On the other hand, in dogs intra-arterial infusion of epinephrine caused vasoconstriction in subcutaneous adipose tissue (10, 16, 31), whereas in a concomitantly perfused gracilis muscle the vascular response was vasodilatation (16). Thus epinephrine and norepinephrine may induce qualitatively different vascular responses in skeletal muscle and subcutaneous adipose tissue. One possible explanation for the difference may be that the a-adrenoceptors differ in the two tissues. This does not seem to be the case because epinephrine was a more potent vasoconstrictor than norepinephrine in both tissues after P-adrenoceptor blockade (16). Another possibility is that there is a P-adrenergic vasodilator mechanism in adipose tissue that is unusually sensitive to norepinephrine and that the type of p-adrenoceptor mediating vasodilatation varies between the two tissues, because epinephrine predominantly activates &-adrenoceptors and norepinephrine may be considered to be &selective (102). This possibility has been tested experimentally by means of a pharmacological analysis. Compared with isoprenaline, the &selective agonist salbutamol was 4-6 times more potent as a vasodilator in the gracilis muscle than in the subcutaneous adipose tissue, whereas the fil-selective agonists H 80/62 (Hassle) and Tazolo (Syntex) caused vasodilatation in adipose tissue but not in the muscle (16). Furthermore, the &selective antagonist practolol blocked the vasodilatating effects of norepinephrine in adipose tissue (15). These results suggest that the P-adrenoceptors mediating vasodilatation in adipose tissue are mainly the &-type, in contrast to those in skeletal muscle, which are mainly the &type. The observation that intravenous epinephrine causes vasoconstriction in adipose tissue concomitant with vasodilatation in skeletal muscle (16) suggests that vascular P,-adrenoceptors are of minor importance in adipose tissue. In contrast to the action in skeletal muscle, the major vascular actions of epinephrine in subcutaneous adipose tissue thus may be vasoconstrictory. These different actions of epinephrine in adipose tissue and in skeletal muscle may partly explain why blood flow decreased much more in subcutaneous adipose tissue than in skeletal muscle during hemorrhagic shock (146; see below). During bleeding the concentration of epinephrine is increased (163) and epinephrine tends to vasodilate the vascular bed of skeletal muscle, whereas in subcutaneous adipose tissue epinephrine vasoconstricts. Resting norepinephrine plasma concentrations of less than 0.5 ng . ml+ have been reported in dogs (169) and humans (94, 134) and in humans tilting may increase norepinephrine concentrations to 2-3 ng*mP (94). In isolated canine fat cells the norepinephrine concentration needed to induce lipolysis was as low as 3 lo-* M (-6 ng *ml-l) (17). Because the sensitivity to catecholamines is probably lower in vitro than in vivo, possibly concentrations lower than 6 ng .rnl+ may be effective in vivo. Support for this view was obtained by intravenous infusion of norepinephrine in dogs. The plasma levels of norepinephl


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rine were determined and the vascular and metabolic effects were monitored (Hjemdahl and Belfrage, manuscript in preparation). Increased plasma glycerol levels occurred at norepinephrine concentrations in plasma of 2-3 ng*ml? Thus, although the sympathetic nerves seem to be far more important for short-term regulation of lipolysis (cf. 56, 141), it cannot be excluded that high levels of circulating norepinephrine may be important in some situations. ’ Epinephrine, on the other hand, is 2-5 times less potent than norepinephrine as a lipolytic agent (85, 102). This finding, in combination with the pronounced vasoconstrictor properties of epinephrine, makes it unlikely that circulating epinephrine plays an important part in the physiological regulation of lipolysis. VI.

CENTRAL

NERVOUS

CONTROL

Most information about the influence of sympathetic nervous activity on lipid mobilization and circulatory adjustments stems from studies in which these nerves have been activated peripherally. Such studies do not provide information concerning the central nervous control of lipid metabolism (i.e., the location of the integrative areas), the afferent nervous influence, or the efferent pattern of activity. Therefore, only limited information is available about the central nervous control of adipose tissue circulation. The “defense reaction” is a visceromotor adjustment that can be evoked from the corticohypothalamic integration areas. It includes increased cardiac output, augmented muscle blood flow due to activation of cholinergic sympathetic vasodilator nerves, and concomitant vasoconstriction in most other vascular regions, including the kidney, skin, and gastrointestinal tract. In addition, there is an increased release of catecholamines from the adrenals (160). The defense reaction is thought to be elicited in situations involving emotional distress, such as anticipatory adjustments to flight or fight (2, 27, 160). Concomitant metabolic adjustments have been studied to only a limited extent. However, electrical stimulation of the defense area in the hypothalamus in anesthetized dogs did not elevate the plasma concentration of FFA or glycerol (128). Similarly, the blood flow in canine subcutaneous adipose tissue did not change significantly during stimulation of the hypothalamic defense area (124). These findings indicate that activation of the sympathetic nerves to the adipose tissue does not constitute an essential link in the defense reaction. This may be surprising in view of the opinion that the visceromotor adjustments are believed to occur in anticipation of strenuous exercise, including flight or fight. However, such situations certainly require work of maximal intensity, and therefore carbohydrates, rather than fat, may be the most important fuel. This and other aspects of the metabolic link of the visceromotor adjustments in connection with the defense reaction deserves further study. Ore et al. (128) found an elevated concentration of plasma FFA after electrical stimulation in diencephalic areas closely related to H, and H, fields of Fore1 from which cardiovascular responses similar to those seen during


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exercise on a treadmill can be elicited. The elevation of plasma FFA concentrations was abolished after treatment with ganglionic blocking agents, but not indicating that the effect was due to activation of by adrenalectomy, sympathetic nerves to the adipose tissues. These experiments indicate that there are discrete diencephalic areas from which the mobilization of lipids in adipose tissue is regulated via the sy ,mpathe tic nervous outflow. It is not known how afferent nervous activity may modify thi .s outflow 9 and experiments designed to reflexly change the sympathetic nervous activity to adipose tissue have not been successful so far. .For example, activation of the barore scepter reflex by occlusion of the common carotids did not cause any marked changes in plasma FFA concentration or in the release of FFA from subcutaneous adipose tissue in the dog (128). Moreover, the vascular resistance in subcutaneous adipose tiss #ue was little affected by occlusion of the carotids (124). These negative results may indicate that adipose tissue, or at leas t subcutaneous tissue, does not participate in the reflex adjustments of the peripheral vascular resistance elicited via the carotid baroreceptors. This reflex is intimately connected to the blood pressure homeostasis, and there is the interesting possibility that the vascular bed of adipose tissue may instead be linked to “metabolic” reflexes of some as yet unknown sort. VII.

LIPOLYSIS

AND

BLOOD

FLOW

IN

ADIPOSE

TISSUE

Mobilization of fat by means of lipolysis is the principal metabolic event in adipose tissue. Therefore the relation between the Iipolytic rate and blood flow in adipose tissue is of special interest. By means of 133Xe-clearance techniques it has been found that infusion of norepinephrine or glucagon into human subjects in doses that evoked increased lipolysis was accompanied by an increase in adipose tissue blood flow and it was suggested that the vasodilatation was a secondary effect produced by the products of lipolysis (105, 106, 125). However, blockade of the lipolysis in dogs with nicotinic acid did not impair the vasodilatation caused by norepinephrine (121). Furthermore, in spite of the fact that there was a fourfold increase in lipolysis under basal conditions in starved dogs (66), the blood flow in subcutaneous adipose tissue in fed and starved dogs did not differ significantly when expressed per fat-pad. The blood flow per unit weight in subcutaneous adipose tissue was about 50% higher in starved than in fed dogs. However, a substantial part of the higher blood flow per unit weight in the fasted dogs was due to the decreased adipose tissue mass, which should mainly affect the cell size, and thus not due to a functional hyperemia secondary to the increased lipolysis. These data indicate that there is no simple relation between lipolytic rate and blood flow in adipose tissue. Stimulation of the adrenergic nerves to subcutaneous adipose tissue during prolonged periods of time (15 min or more) caused a gradual decrease in the vasoconstrictor tonicity (139). This escape was hardly seen at a frequency of 1.5 Hz but was very pronounced at 4 Hz (15). There are several possible explanations of this phenomenon. The slow onset of the escape might suggest


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that it is secondary to increased metabolism in the tissue. However, there is no simple relationship between the escape and lipolysis, since the lipolysis at 1.5 Hz was almost as large as at 4 Hz (15). The combination of increased metabolism and a high degree of vasoconstriction may be important, since it may lead to accumulation of vasodilatating products. Thus, drugs that inhibited the inactivation of adenosine in the tissue potentiated the vasoconstrictor escape (71). Moreover the escape at high frequencies may be due to activation of P-adrenoceptors in the vasculature, since P-adrenoceptor blockade diminished the escape to a great extent (15). At higher frequencies there might be a gradual overflow of norepinephrine from the nerve terminals at the adventitialmedial border to the noninnervated P-adrenoceptors in the media of the blood vessels. At a lower frequency, such as 1.5 Hz, the amount of norepinephrine reaching the vascular /Sadrenoceptors may be too small to cause any significant activation of these receptors. At higher frequencies the formation of vasodilatating products may also help to facilitate the diffusion of norepinephrine released from the adrenergic nerve terminal system. This norepinephrine may then get access to the noninnervated vascular P-receptors. Mechanisms of this sort may explain the autoregulatory escape during prolonged nerve stimulation and also the findings of an increased blood flow in human adipose tissue during increased lipolysis caused by intravenous infusion of norepinephrine (125) or prolonged exercise (34). VIII.

BLOOD AND

FLOW

IN

HEMORRHAGIC

ADIPOSE

TISSUE

DURING

HYPOTENSION

SHOCK

The function of adipose tissue seems more severely impaired by hemorrhagic shock than that of most other tissues (61,100,146). This was shown by the use of a standardized shock procedure. Chloralose-anesthetized dogs were bled to 55 mmHg for 90 min and for a further 90-min period to 35 mmHg. The shed blood was then reinfused. On the average, during bleeding to 55 mmHg for 90 min the blood flow in the subcutaneous adipose tissue was reduced to about 10% of the resting blood flow. This decrease was much more pronounced than the decrease that occurred in most other organs under similar conditions. In skeletal muscle, liver, myocardium, and hypothalamus the blood flow fell to about 60% of the resting flow and the renal cortical blood flow to about 40%. After 180 min of hypotension reinfusion of the blood failed to restore a normal blood flow in the subcutaneous adipose tissue, indicating vascular damage. This suggests that subcutaneous adipose tissue may be one of the organs where irreversible shock is manifested at an early stage. Acute denervation before the bleeding period did not prevent the severe reduction in blood flow. In contrast, dogs pretreated with phenoxybenzamine, an cu-receptor-blocking drug, did not develop signs of vascular damage during the bleeding periods. This indicates that circulating catecholamines (epinephrine), rather than activity in the sympathetic nerves, were of greatest importance for the development of damage. The blood flow remained at about 70% of the resting blood flow


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during bleeding and reinfusion restored blood flow to normal. Conceivably the protective effect of phenoxybenzamine was largely because of its ability to maintain a comparatively high blood flow during the hypotensive period. Presumably, phenoxybenzamine treatment resulted in maintained tissue blood flow for two reasons. It gave protection from vasoconstriction by a-receptor blockade and unmasked the vasodilatation due to P-receptor stimulation. Mechanical reduction of blood flow does not cause irreversible damage in adipose tissue. Thus, restriction of blood flow to 15% of control for 60-90 min by mechanical clamping of the arterial inflow (19, 99) or by intra-arterial injection of methoxamine (19) did not damage the tissue. Under these circumstances adipose tissue oxygen tension was reduced only slightly (66) and glycerol and FFA outflow, as well as glucose uptake as a result of adrenergic nerve stimulation, was almost identical during observation periods before and after blood-flow restriction (19). On the other hand, intra-arterial norepinephrine, in doses causing both vasoconstriction and metabolic activation, lowered adipose tissue oxygen tension substantially (66). Differences in metabolic reactions may explain why experimental hemorrhage resulting in an overall intense sympathoadrenal activation, in contrast to mechanical reduction of blood flow, rapidly caused irreversible damage to adipose tissue. A. Metabolic

Consequences

of Restricted

Blood Flow

The impairment of blood flow in subcutaneous adipose tissue has metabolic consequences. Despite a presumably high sympathoadrenal activity during bleeding, the release rate of FFA did not rise (1.00). Instead fatty acids accumulated in the tissue (3). There was also a marked reduction in oxygen uptake in subcutaneous adipose tissue during blood-flow restriction (66). These local changes in metabolism of adipose tissue evidently have consequences for lipid metabolism in the whole animal. This is indicated by the tendency for the plasma FFA concentration to fall during hemorrhage, which restricts the supply of FFA to, for example, skeletal muscle, because the uptake of fatty acids in peripheral organs is related to the inflow of FFA (plasma flow x arterial FFA I concentration) (76). B. Rise in Reestem@ation

Rate

The reduced blood flow in adipose tissue presumably is not the only reason why FFA release is severely restricted during bleeding. Another factor that may play a role in this connection is the elevated lactate concentration, which is known to inhibit the release of fatty acids (96, 123). Fredholm (56, 57) has demonstrated that Na L(+)-lactate at blood concentrations above 5 mM inhibits the release of FFA caused by electric stimulation of the sympathetic nerves to the subcutaneous adipose tissue. Interestingly enough, glycerol release was not significantly affected by lactate infusion. The decreased release


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of FFA concomitantly with an unchanged glycerol release suggested an enhanced reesterification of fatty acids in the adipose tissue (57). These findings thus indicate that not only the rate of hydrolysis of triglycerides but also the rate of reesterification is important in regulating the outflow of FFA from adipose tissue. Since the modulation of the reesterification has been shown to operate at normal plasma levels of lactate, lactate probably functions as a physiological brake on the lipid inflow to the plasma pool in situations where carbohydrates may be the predominant source of fuel. Thus, lactate may prevent the peripheral organs from being flooded with unneeded fatty acids (56). This situation may arise during heavy exercise with work loads demanding 60% or more of maximal oxygen uptake (145) as well as after trauma. C. Other Metabolic

Effects

Acidosis usually occurs in hemorrhagic shock, and acidosis is a potent antilipolytic factor that probably also contributes to the decreased release of fatty acids from the adipose tissue during shock (see 87). Concentrations of highenergy phosphate (ATP, CP) decreased more drastically and irreversibly in adipose tissue than in skeletal muscle during hemorrhage in cats (61). This decrease may be an effect partly produced by accumulated fatty acids (4, 81). IX.

BLOOD

FLOW

DURING

REDUCED

TEMPERATURE

Apart from its energy-storage function, white adipose tissue may also be important for the heat insulation of the body. The temperature of subcutaneous adipose tissue is decreased when the ambient temperature is lowered (29). During local cooling of canine subcutaneous adipose tissue resting blood flow was markedly reduced (90) in agreement with vascular responses in other tissues, including canine kidney (110) and spleen (41). The vasoconstrictor effect of norepinephrine, as well as that of adrenergic nerve stimulation, was enhanced by cooling, whereas vasodilatator components were virtually abolished. Hjemdahl and Sollevi (90) concluded that cooling increases the sensitivity to vasoconstrictor stimuli partly because of inhibition of metabolic vasodilator mechanisms. The enhanced vasoconstrictor action of sympathetic nerve activity caused by cooling may reduce the heat dissipation and thus increase the insulator function. REFERENCES 1. ABLAD, B., I. BORJESSON, E. CARLSSON, AND G. JOHANSSON. Effects of metoprolol and propranolol on some metabolic responses to catecholamines in the anesthetized dog. Acta Phuwuzcol. Tozicol. 36, Suppl. V: 85-95, 1975. 2. ABRAHAMS, V. C., S. M. HILTON, AND A. W. ZBROZYNA. The role of active muscle vasodilatation in

the alerting stage of the defence reaction. J. Physiol. London 171: 189-202, 1964. 3. ANGEL, A., K. DESAI, AND M. L. HALPERIN. Free fatty acid and ATP levels in adipocytes during lipolysis. Metabolism 20: 8’7-99, 1971. 4. ANGEL, A., K. S. DESAI, AND M. L. HALPERIN. Reduction in adipocyte ATP by lipolytic agents: relation to


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intracellular free fatty acid accumulation. J. Lipid Res. 12: 203-213, 1971. 5. ARONOVSKY, E., R. LEVARI, W. KORNBLUETH, AND E. WERTHEIMER. Comparison of metabolic activities of orbital fat with those of other adipose tissues. Invest. Ophthalmol. 2: 259-264, 1963. 6. AUKLAND, K., AND H. M. JOHNSEN. Protein concentration and colloid osmotic pressure of rat skeletal muscle interstitial fluid. Acta Physiol. Stand. 91: 354-364, 1974. 7. BALLANTYNE, B. Histochemical and biochemical aspects of cholinesterase activity of adipose tissue. Arch. Int. Pharmucodyn. Ther. 173: 343-350, 1968. 8. BALLANTYNE, B., AND A. T. RAFTERY. The neurochemistry of adipose tissue. J. Physiol. London 205: 31P-33P, 1969. 9. BALLARD, K. Blood flow in canine adipose tissue during intravenous infusion of norepinephrine. Am. J. Physiol. 225: 1026-1031, 1973. 10. BALLARD, K., C. A. COBB, AND S. ROSELL. Vascular and lipolytic responses in canine subcutaneous adipose tissue following infusion of catecholamines. Acta Physiol. Stand. 81: 246-253, 1971. 11. BALLARD, K., T. MALMFORS, AND S. ROSELL. Adrenergic innervation and vascular patterns in canine adipose tissue. Microvasc. Res. 8: 164-171, 1974. 12. BALLARD, K., AND S. ROSELL. The unresponsiveness of lipid metabolism in canine mesenteric adipose tissue to biogenic amines and to sympathetic nerve stimulation. Acta Physiol. Stand. 77: 442-448, 1969. 13. BALLARD, K., AND S. ROSELL. Adrenergic neurohumoral influences on circulation and lipolysis in canine omental adipose tissue. Circ. Res. 28: 389-396, 1971. 14. BECKER, C. G., AND G. E. MURPHY. Demonstration of contractile protein in endothelium and cells of the heart valves, endocardium intima, arteriosclerotic plaques, and Aschoff bodies of rheumatic heart disease. Am. J. Pathol. 55: l-29, 1969. 15- BELFRAGE, E. Vasodilatation and modulation of vaseconstriction in canine subcutaneous adipose tissue caused by activation of @adrenoceptors. Acta Physiol. Stand. 102: 459-468, 1978. 16. BELFRAGE, E. Comparison of /3-adrenoceptors mediating vasodilatation in canine subcutaneous adipose tissue and skeletal muscle. Acta Physiol. Stand. 102: 469-476, 1978. 17. BELFRAGE, E. Studies on the Control ofBlood Flow and Lipolysis by a- and @-Adrenoceptors in Canine Subcutaneous Adipose Tissue (Thesis). Stockholm: Karolinska Institutet, 1978. 18. BELFRAGE, E., B. B. FREDHOLM, AND S. ROSELL. Effect of catechol-0-methyl-trferase (COMT) inhibition on the vascular and metabolic responses to noradrenaline, isoprenaline and sympathetic nerve stimulation in canine subcutaneous adipose tissue. Naunyn-Schmiedebergs Arch. Phurmacol. 300: ll- 17, 1977. 19. BELFRAGE, E., P. HJEMDAHL, AND B. B. FREDHOLM. Metabolic effects of blood flow restriction in adipose tissue. Acta Physiol. Stand. 105: 222-227, 1979. 20. BELFRAGE, E., AND S. ROSELL. The role of neuronal uptake at a- and fl-adrenoceptor sites in subcutaneous adipose tissue. Naunyn-Schmiedebergs Arch. Phwmacol. 294: 9-15, 1976. 21. BEVAN, J. A., AND S. P. DUCKLES. Evidence for a-adrenergic receptors on intimal endothelium. Blood Vessels 12: 307-310, 1975. 22. BEVAN, J. A., AND C. SU. Sympathetic mechanisms in blood vessels: nerve and muscle relationships. Ann. Rev. Pharmacol. 13: 269-285, 1973.

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Mechanics of in the rabbit.


Blood pressure and adipose tissue linoleic acid.

Metabolic effects of blood flow restriction in adipose tissue.

Measurement and manipulation of human adipose tissue blood flow using xenon washout technique and adipose tissue microinfusion.

Enhanced localization of liposomes with prolonged blood circulation time in infected lung tissue.

Capillary permeability in adipose tissue.

Brown adipose tissue in humans.

Steroid biosynthesis in adipose tissue.

Glycerokinase in human adipose tissue.

Convertible adipose tissue in mice.

Differential Adipose Tissue Proteomics.

Brown adipose tissue mitochondria.

Adipose tissue biology in 2014: Advances in our understanding of adipose tissue homeostasis.

Adipose tissue fibrosis.

Adipose Tissue Stem Cells.

Defining dermal adipose tissue.

Adipose tissue angiogenesis assay.

Imaging of adipose tissue.

Glucagon and adipose tissue.

Insulin action in muscle and adipose tissue in type 2 diabetes: The significance of blood flow.

Diet-induced changes in subcutaneous adipose tissue blood flow in man: effect of beta-adrenoceptor inhibition.

Chronic adrenergic stimulation induces brown adipose tissue differentiation in visceral adipose tissue.

Circulating Blood Monocyte Subclasses and Lipid-Laden Adipose Tissue Macrophages in Human Obesity.

Do adipose tissue macrophages promote insulin resistance or adipose tissue remodelling in humans?

Xenotransplantation of human fetal adipose tissue: a model of in vivo adipose tissue expansion and adipogenesis.