Adenosine and the Control of Adrenergic Regulation of Adipose Tissue Lipolysis During Lactation

Adenosine and the Control of Adrenergic Regulation of Adipose Tissue Lipolysis During Lactation

RICHARD G. VERNON, ERIC FINLEY, and PAUL W. WATT Department of Biochernisby and Molecular Biology

Hannah Research institute Ayr K46 5HL, Scotland, UK

ABSTRACT

Adenosine is a locally active factor that is produced intracellularly and extracellularly in adipose tissue. Adenosine binds to receptors in the plasma membrane of adipytes; this activates a gua- nine triphosphate binding protein that in- hibits adenylate cyclase activity and, hence, lipolysis. Lactation results in an enhanced responsiveness of adipocytes to pagonists, which stimulate lipolysis, and, paradoxically, to adenosine, which in- hibits lipolysis. These adaptations are partly due to increases in ligand binding and to changes in postreceptor compo- nents of the signal transduction systems. Somatotropin is implicated in the chronic adaptations of the p-adrenergic system, whereas insulin, somatotropin, glucocorticoids, and at least one unidentified factor have a role in the c h n i c control of the adenosine system of adipytes. (Key words: adenosine, adipose tissue, lipolysis)

Abbreviation key: DDA = 2’,5’dideoxyadenosine, GTP = guanosine triphosphate, K d = dissociation rate constant, NECA = 5‘-N-ethylcar- boxamide, PIA = fl-phenylisopropyladenosine.

INTRODUCTION

Adenosine is an enigmatic substance. It is apparently produced by all tissues and has a bewildering amy of effects. Of these, its cardiovascular effects (potent vasodilator) (6) and metabolic effects (modulator of adenylate cyclase activity) (14) are best documented. Claims have been made for the involvement of

Received September 7, 1989. Accepted January 29, 1990.

adenosine in central newous system function (including sleep, anxiety, and even self-mutila- tion behavior), renal function, pulmonary function, gastrointestinal function, and platelet ag- gregation among others (5, 38, 61). Many of these claims are based on findings that methylxanthines such as theophylline and caf- feine are adenosine antagonists. However, which of these putative roles will prove to have physiological relevance is another matter.

Effects of adenosine on adipose tissue were first demonstrated over 30 yr ago, by Dole (1 3), who showed that the substance was antilipolytic. Another key observation was the finding by Schwabe et al. (46) that adenosine accumulates in the suspending medium during incubation of isolated adipocytes in sufficient quantities to modify the actions of other hormones; for ex- ample, it maxkedly diminishes the lipolytic effect of catecholamines. The problem of controlling adenosine concentrations during the preparation and subsequent incubation of adipocytes was examined in great detail by H O M ~ et al. (24,25), who showed the benefits of including adenosine during isolation of adipocytes and then removing it during subsequent incubations by addition of adenosine deaminase. Effects of adenosine on adipocyte function and response to hormones are there- fore studied using analogues of adenosine, such as fl-phenylisopropyladenosine (PIA), which are not metabolized by adenosine deaminase. In addition to its metabolic effects on adipose tissue, adenosine appears to have an important role in modulating blood flow in the tissue (15, 48). This has metabolic implications, particu- larly for the control of lipolysis, because high rates of lipolysis can be limited by an inade- quate ability to remove released fatty acids from the tissue (52).

This essay focuses on the role of adenosine in the control of the adrenergic response of the adipoqte during lactation. First, a brief description is presented of the control of adenosine concentration and its mechanism of action.

1991 J Dairy Sci 74:695-705 695

696 VERNON ET AL.

SYNTHESIS AND METABOLISM

Within cells, adenosine is produced primarily from AMP by 5’-nucleotidase or by hydrol- ysis of S-adenosyl-homocysteine (16, 38). ‘Ihe relative importance of these two sources in adipocytes is not known, but in general 5’-nucleotidase is thought to be of greater importance (2, 16, 38). Synthesis from AMP pro- vides a mechanism for coupling adenosine production to the energy status of the cell. This and the vasodilatory activity of adenosine are the bases of a putative mechanism for modulating blood flow to meet the energy requirements of the cell (6). This idea has lead to the concept of adenosine being a “retaliatory” factor (37). Both AMP concentration and adenosine production are increased several fold during ische mia (2, 6, 16). Adenosine is also produced in the extracellular space by another 5’-nucleotidase, which is anchored to the outer surface of the plasma membrane (31); in most tissues, this is the major site of 5’-nucleotidase activity (the enzyme is widely used as a plasma membrane marker). This enzyme has a major role in the production of plasma adenosine (35). The source of AMP for the enzyme is uncertain. Stimulation of sympathetic nervous activity increases adenosine output from adipose tissue in dogs (15) and exercise increases adenosine output from muscle (3); this increase may be due to the release of adenine nucleotides from nerve endings in the tissue with subsequent hydroly- sis and adenosine production by the ectocellular 5‘-nucleotidase (38). Fredholm and Sollevi (16) questioned whether the release of nucleotides from nerve endings would be sufficient to account for the increased adenosine output and have suggested that adenine nucleotides may be released from endothelial and other cells.

Most adenosine produced extracellularly is probably taken up by cells within the tissue (the plasma membrane possesses a nucleoside trans- locase) (2, 16), and the endothelial cells are thought to provide a barrier to free passage of adenosine into the blood (36). Adenosine that escapes into the blood is rapidly metabolized (half-life about 1 s) (33, and plasma concentration is normally low, about 50 to 150 nM in recent studies on pigs (18), humans (33, and dogs (3).

Concentration of adenosine in adipose tissue is .5 to 1.0 nmol/g in humans (42), rats (39).

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TABLE 1. Activities of enzymes involved in adenosine metabolism in adipose tisrme.1

E v e Rat Sheep 5‘-Nrr~leotidase 1400 70 Adenosine deaminase 400 1500 Adenosine kinasc 18 15

minute per milligram of adipose tissue DNA (56, 58). ‘Enzyme activities are expressed as nanomoles per

and dogs (15). Concentration of adenosine in ruminant adipose tissue has not been reported, but in view of the lower 5‘-nucleotidase and higher adenosine deaminase in ruminants com- pared with that in rats (Table l), the concentration probably will be relatively low. Distribu- tion of adenosine in adipose tissue has not been defined, but some adenosine at least is thought to be bound; hence, the free intracellular concentration is not known (38). A recent study using microdialysis suggests that in humans extracellular adenosine concentration of adipose tissue is about 125 nM (30).

Within cells, adenosine is either phos- phorylated to AMP by adenosine kinase or deaminated by adenosine deaminase; the former enzyme has a lower dissociation rate constant (Kd, (about 1 ClM) than the deaminase (10 to 60 phf) (2, 23). In adipose tissue, the activity of the deaminase is much greater than that of the kinase (Table 1). Because the intracellular concentration of adenosine is probably very low (less than 1 JM), both enzymes make a significant contribution to adenosine metabolism.

Adipose tissue contains a mixed population of cells. In male and female rats, most adenosine kinase activity is associated with adipocytes (21, 56). In contrast, less than a third of the 5‘-nucleotidase and adenosine deaminase activities are associated with adipocytes; most of the activity of both enzymes is located in the stromovascular fraction of the tissue (21). Stromovasdar cells, although very much smaller than adipocytes, make up about 75% or more of the total cell population of adipose tissue in rats (7) and sheep (58). Thus, in adipose tissue most extracellular adenosine probably comes kom the stromovascular cells. For adipocytes, adenosine is primarily a para- crine factor, its concentration in the extracel-

SYMPOSIUM: NONMAMMARY METABOLISM IN SUPPORT OF LACTATION AND GROWTH 697

lular space is controlled mainly by enzymes of stromovascular cells. For adipocytes, the only significant option for control seems to be to vary their responsiveness to adenosine.

MECHANISM OF ACTION

Two types of adenosine receptor have been identified in the plasma membrane of cells (one termed A1 or Ri and the other A2 or R.& and an additional intracellular binding site, the “P” site, has also been identified (49, 61). The various receptors differ in their affinity for adenosine analogues; thus for Ri PIA > 5‘-N-ethylcahoxamide adenosine (NECA) >> 2’,5’dideoxyadenosine (DDA), for R, NECA > PJA >> DDA and for P-site DDA >> PIA. The Ri and Ra receptors are analogous to the p- and a2-adrenergic receptors in that the binding of agonist causes the dissociation and activation of guanosine triphosphate (GTP)-binding proteins (Gi and Ga. The a-subunit of these GTP- binding proteins interacts with adenylate cyclase with concomitant inhibition (a-Gi) or activation (a-G$ of the enzyme and hence change in the rate of cyclic AMP production (Figure 1) (29, 49). The resulting change in cyclic AMP concentration and hence change in phosphorylation status of key enzymes results in the altered metabolic fluxes (29).

The predominant plasma membrane receptor in adipocytes is the Ri receptor; hence, adenosine causes inhibition of adenylate cyclase in this cell type (14). In contrast, in the liver and kidney, the Ra receptor is the only or at least the dominant form, so that for these tissues adenosine causes activation of adenylate cyclase (11). A recent study (17) with adipocytes, in which the inhibitory pathway of adenosine action was blocked with pertussis toxin, suggests that R, receptors may also be in this cell type. Although the net effect of adenosine is inhibitory with respect to adenylate cyclase activity in adipocytes, adenosine, binding to ?he Ra receptor, may modulate the main signal via the Ri receptor. This is analogous to the dual effect of catecholamines acting via stimulatory (p-receptor) and inhibitory (m-receptor) path- ways.

Binding of adenosine to the P site results in inhibition of adenylate cyclase (14). This P site is present in adipocytes from rats (14, 17) and sheep (Plested et al., unpublished observation)

and may be a binding region on adenylate cyclase itself (14,49,61). However, the affinity of the P site for adenosine is low, so its physiological significance is uncertain (14, 61).

Although the effects of adenosine on lipolysis involve alteration of adenylate cyclase activity and cyclic AMP concentration, recent studies suggest that adenosine may alter glucose transport and sensitivity of adipocytes to insulin by another mechanism (29). The full mechanism has not yet been resolved but is thought to involve the protein Gi but not adenylate cyclase (29). In some cell types, adenosine may modulate calcium and potassium fluxes, again without any apparent involvement of cyclic AMP (61).

ADAPTATIONS TO PREGNANCY AND LACTATION

Beta-Adrenergic System

A period of negative energy balance often occurs in domestic ruminants during early lactation and in laboratory rats around peak lactation (4, 50, 51, 57). During such periods, a net mobilization of adipose tissue triacylglycerol occurs (4, 57).

The response of adipocytes from both cattle and sheep to the lipolytic effects of catecholamines can increase during early lactation (22, 28, 54). Some earlier studies that appear to show such an effect are compromised by ex- pressing data on a per gram tissue basis (50) (negative energy balance leads to a decrease in cell size and hence an increase in the number of cells per gram tissue). Most studies have also used either epinephrine or norepinephe, the natural agonists, but these have both bmedi- ated and a2-mediated effects (Figure 1). Gues- net et al. (22) used the &agonist isoproterenol, and their study with sheep shows that response to the agonist increases during pregnancy and remains high during early lactation. In addition, they found an increased affinity for the agonist (i.e., the concentration required to achieve half- maximum effect is decreased) (22). This latter effect was not observed using norepinephrine (54). possibly due to enhanced counteracting effects mediated via the a2-receptor.

The mechanisms and factors responsible for this increased responsiveness to p-agonists have not been fully elucidated. The number of


698 VERNON ET AL..

&adrenergic receptors of adipocytes from both cattle (28) and sheep (60) increases during lactation. However, other adaptations of the signal transduction system may also occur. In rats, the activity of cyclic AMP phosphodiesterase activity of adipocytes decreases during lactation (1).

Somatotropin is implicated as a key factor in eliciting changes in p-adrenergic responsive ness of adipocytes. Thus, treatment of cattle with somatotropin increases the subsequent lipolytic response to epinephrine in vivo (8,34, 41). Litter removal from lactating rats decreases the lipolytic response to noradrenaline, which is

prevented by concurrent administration of so- matotropm and is mimicked by treating lactat-

Further studies with rats have shown that these changes in response are paralleled by changes in &receptor number (Watt and Vernon, unpublished observation). Maintenance of sheep adipose tissue in culture for 48 h in the presence of somatotropin increases the number of $-adrenergic receptors of adipocytes (60) and the response and affinity of the tissue for isoproterenol (Vernon and Finley, unpublished observation).

ing rats with an alltiserum to somatotropin (55).

MECHANISM OF ADENOSINE ACl!I(TJ

Noradrenaline Adenosine Noradrenaline

I

I I I 1

Adenylate cyclase

Phosphodiesterase I AMP

I Figure 1. Mechanism of action of adenosine and its relationship to the mechanism of action of the catecholamine

norepinephrine. Plus and mirms signs refer to the stimulatory and inhibitory effects of the GB and Gi proteins, respectively, on adenylate cyclase activity. Dashed lints represent putative htemctm ’ m. GTP = Guanosine triphosphate.



Adenoslne Metabolism

The effect of pregnancy and lactation on the adenosine concentration of adipose tissue or plasma has not yet been reported for any spe- cies. For the rat, neither pregnancy (20) nor lactation (56) had any effect on activities of 5’-nuclmtidase, adenosine deaminase, or adenosine kinase, except for a small decrease in kinase activity of adipocytes during lactation. Thus, if changes OCCUT in adenosine concentration during lactation in the rat, they probably would be due to changes in substrate supply or adenosine removal rather than to a change in metabolic capacity. It appears that 5’-nucleotidase activity shows a seasonal variation in adipose tissue from nonlactating sheep with peak activity in May (58). This seasonal surge in 5’-nucleotidase activity in the spring was not found in lactating sheep, and the activity does not seem to change during pregnancy and lactation in sheep (58). Adenosine kinase activity was not altered by pregnancy or early lactation but was decreased around 45 d of lactation (58). In contrast to the other two enzymes, adenosine deaminase activity was markedly increased during late pregnancy and early lactation (58); hence, the ability of sheep adipose tissue to clear adenosine at these stages should be increased.

The factors controlling the maximum activities of these enzymes are poorly &lined. Streptozotocin diabetes increased adenosine deaminase activity in rat adipose tissue (20) and adipocytes (27). The hypoinsulinemia of late pregnancy and early lactation could account for the increase in adenosine deaminase activity in sheep, but then the enzyme did not increase in rats. Adrenalectomy deqreased adenosine kinase activity of rat adipose tissue (20), and hypothyroidism diminished 5’- nucleotidase and adenosine deaminase activity of rat adipocytes (27). Activities of the enzymes are under independent hormonal control, as may be inferred from the changes in activity during the lactation cycle.

Response to Adenosine

One might expect from the preceding sec- tions that the responsiveness of adipocytes to adenosine would decrease with lactation. On the contrary, the response increases. This was

first shown in studies with rats (56) and subse- quently with sheep (54). In contrast to rats, in which response to adenosine is low until parturition (1,56), maximum response to adenosine is achieved by late pregnancy in sheep (26). This is consistent with a switch from an ana- bolic to a catabolic state in sheep adipose tissue around 105 d of pregnancy (53). but not until just before parturition in rats.

This paradoxical increase in response appears to be confined to adenosine, because there is no increase in response of the %- adrenergic system of sheep adipose tissue during lactation (Figure 2). An initial finding of an increased response to az-agonist has not been confirmed in two subsequent experiments. The mediated antilipolytic effect (Figure 2) was assessed by comparing the response of adipose tissue to isoproterenol (an essentially pure p- agonist) with that of norepinephrine, which elicits p- effects and %effects. In essence, the greater the difference in response to these two agonists, the greater the qeffect. Lactation then results in both the adrenergic badrenergic and adenosine signal transduction systems of adipocytes becoming more responsive to agonists. In the rat, there is also an increased response to glucagon, which interacts with a distinct receptor but which is again linked to the Gs protein and adenylate cyclase (62). The physiological benefit of increasing the responsiveness of the antilipolytic system during lactation is not clear. Lactation is a period of greatly increased metabolic activity in the animal, so diurnal variations in energy balance will be accentuated. A heightened responsiveness of the systems controlling lipolysis may thus be an adaptation to meet the challenge of a period when diurnal changes in energy balance are much greater and may occur more rapidly than usual.

Mechanism and Factors Responsible for Enhanced Response to Adenosine

One mechanism that contributes to an increased response to adenosine during lactation in sheep is an increased numbex of receptors (Figure 2). The results of Figure 2 are expressed per milligram of membrane protein rather than per adipocyte, but because no significant change in adipocyte size occurred with lactation in this study, the results probably re-

loamal of Dairy Science Vol. 74, No. 2, 1991

700 VERNON ET AL.

flect changes in numbers of receptors per adipocyte.

Although both adenosine and p-adrenergic receptors increased with lactation, the factors responsible are not identical. Somatotropin pro- motes an increase in the number of p-receptors,

0

90

L - @

w E a 0

A

-

C

B NL

I

I

L NL L State

Figure 2. Effecls of lactation on responsiveness of sheep adipose tissue to A) &e adenosine analogue N6-

of norepinepbriac and the binding of ligand to C) adenosine receptors of sheep adipocytcs in nonlactating (NL) and lactating (L) sheep. Data for A arc ftom Vernon and Finley (54); other values arc means and standard mrs of at least fmc observations. The c~-adrenergic effect of norepinephrine is expressed as tbe difference in the rate of lipolysis (glycaol release.) in the presence of 10 isoproterenol and 10 @f noradrenalro . e divided by the rate in presence of 10 @f isoprotcrewl. Ligand Wing to adenosine receptors was asscssed using [3Huv6_ phenylisoprop yladenosinc.

~ W y l i s ~ ~ ~ ~ p y W i n e and B) tbe %-adrenngic effect

but this hormone had no effect on the number of either adenosine or a2-adrenergic receptors (Figure 3). The number of a2-receptors actually increased during tissue culture in the absence of any exogenous hormone. Insulin partly prevented this increase. Other studies using ac- tinomycin D (an inhibitor of gene transcription) suggest that the increase is due to production of new protein. Insulin had no effect on the number of adenosine receptors (Figure 3).

Although neither somatotropin nor insulin had any effect on the number of adenosine receptors (Figure 3), tissue culture of sheep adipose tissue with either hormone for 48 h decreased the response to both adenosine (PIA) and %-agonists (Figure 4). This suggests that the two hormones are having an effect on a step subsequent to receptor binding. This effect of insulin on response to adenosine could account for the increased response to adenosine during lactation, because animals usually become hypoinsulinemic in this state (51). In contrast, the effect of somatotropin is paradoxical, because the serum concentration of this hormone increases during lactation in ruminants (51). Some other factors apparently must suppress this effect of somatotropin during lactation. Evidence for this comes from studies with rats (Figure 5). Varying serum somatotropin in vivo with either an antiserum to the hormone or by injection of somatotropin altered the response of adipocytes to PIA (Figure 5). The effects of exogenous somatotropin were greater in rats that had their litters removed than in lactating rats (Figure 5), which is consistent with the above hypothesis. The nature of the factor that antagonizes the somatotropin effect during lactation is not known.

The response of adipocytes to adenosine is also modulated by glucocorticoids. Adrenalec- tomy in rats results in an enhanced response to the antilipolytic effect of PIA (12, 44), which may be due to a diminished adenylate cyclase activity of adipocytes (12). In contrast, culture of sheep adipose tissue with dexamethasone (a glucocorticoid analogue) prevented the decrease in response to PIA found when tissue was cultured in the absence of exogenous hormones (Figure 4). Dexamethasone also attenuates the effects of both insulin and somatotropin on the response to PIA (results not shown) and increases the response of adipose tissue to %- agonists (Figure 4). The mechanism has not



been fully elucidated, but preliminary experiments suggest that dexamethasone decreases adenylate cyclase activity (Watt and Vernon, unpublished observation). The reason for the

60

30

0

A b

6 0 [ B 30 b b

6o r c a

Do C I Treatment

j S

Figure 3. Effects of insulin and somatotropin on the

adrenergic receptors, and C) adenosine receptors of adipocyte membranes from nonktating sheep. Receptor binding was measured in adipocyte membranes prepared from fresh tissue (Do) or from tissue after maintenance in tissue culture for 48 h in the presence of no exogenous hormones (c), insulin 0, or somatotropin (S). Ligands used were [%ldihydr~a~ enalol (preceptor); [~raawol~cine (up rcccptor); [&-pheny&opropyladcnoyladcnosine (adcnosiue receptor). Jhta was analyzed by analysis of variance of log-transformed data: a si@cant effect of treatment was found for B and c+plrenergic receptors; columns within a set with diffemnt lower case letters denote v h e s that diffa (PC.05).

bin- of ligand to A) Badrcnergic -tors, B) %-

reciprocal response to glucocorticoids of the system in sheep and rats is not clear. However, in rats (19) and sheep (Vernon and Finley, unpublished observation) exposure of adipose tissue to glucocorticoids in vitro enhances the response to isoproterenol.

Although glucocorticoids seem to have an important role in modulating the response to

A

' B

d

ab

C n Do C I S

TREATMENT

a

D

Figure 4. chronic endocrine control of response to the adenosine d o p e N6-pJmylisopropyladenosiue (A) and the apadrenergic effect of norepinephxine (B) in adipose tissue from lactaw sheep. Results are for fresh tissue (Do), and tissue after maintenance in tissue culture for 48 h in the presence of no exogenous hormones (0, insulin (l), somatotropin (S), or the glucocorticoid analogue dex- amethmom @). Results am meam of five obscrvatio~ and were analyzed by analysis of ~ariancq treatment &wts were signifcant ( P d O 1 ) . SED for (A) and (B) were 6 2 and 6.1 respectively; columns with different lower case 1- represent mean values that differ (Pc.05).


702 VERNON ET AL.

ab ab I b

ai ad n 1

Br AS S LR LR+S

TREATMENT

Figure 5. Effect of varying somatotropin concentration in vivo and lactational state on inbibition of mmpinepbririe

adipocytes. Treatmmts: -, lactating controls injected with Carricr solutioos; Br, lactathg, injected with bnrmoaiptine twice daily for 2 d; As, lactating. injected with an antisa ram to sonmtobropin twice daily for 2 d; S htating, injected with somatotropin twice daily for 2 d; LR filter rcmoved 2 d Wore killing, injected with carricr solutions, LR + S litta nmoved, injected with somatotropin twice daily for 2 d startiag at time of litter removal. Rtsnlts are means of five to seven observations and were analyzed by analysis of variance, which revealed a si@cant treatment cffcct; SED ranges fium 7.7 to 8.3. Columns with different lower case letter8 denote resalts that differ (PcO5). For further details. see (55).

stimulated lipolysis by N 6 - p h a l ~ m p y M m o s i n e in rat

adenosine, their involvement in the altered response during lactatim is unclear. Serum glu- cmrticoid concentcation may increase during early lactation in cattle (lo), but we have found no evidence for change in total serum glucocorticoid concentrations in sheep (Vernon and Faulkner, unpublished observations). Thyroid hormones also modulate the response of a d i p cytes to adenosine; hypothyroidism results in an enhanced response (9. 32, 40, 43 , and hyperthyroidism results in a decreased response (43). The mechanisms are different: hyperthyroidism decreases the number of adenosine receptors (43), whereas the effects of hypothyroidism appear to be due to a change in the Gi protein (32). In contrast, prolactin does not appear to have any effect on the response of adipocytes to PIA or to norepinephrine in the lactating rat (55). Thus, a battery of hormones can modulate the response of adipocytes to adenosine. However, their contribution to the enhanced response seen during lactation remains unresolved and a subject for further research.

SUMMARY

A substantial body of data suggests that adenosine modulates adipose tissue metabolism

- ?

Figure 6. Postdated chronic endwint control of tbc adrenergic-adenosine signal transduction system in sheep adipose tissue. GI3 = somato(ropin, INS = insalin. dex = dexamethasone (a glucocorticoid aualogae); plus or minus in relation to dashed lines deawtea that the hormom elicit3 a chronic imease or decressc respectively in the activity of the componat. see FigIlrf# 1 for frmher information.

Joamal of Dairy Science Vol. 74, No. 2, 1991


directly by interacting with adipocytes them- selves and indirectly by modulating blood flow. Adenosine has the capacity to modulate adenylate cyclase activity acting through a well-defined signal transduction pathway. Neverthe less, its role in vivo is uncertain and has been challenged (33). Whereas adenosine at low (nM) Concentrations can alter lipolysis in isolated rat adipocytes, much higher concentrations are required to achieve effects with adipose tissue slices, which brings into question the physiological relevance of the findings der- ived from studies with isolated adipocytes (47). However, low concentrations (nM) of adenosine analogues such as PIA exert aritilipolytic effects on adipose tissue, suggesting that Shechter's findings (47) arise from a high capacity of tissue pieces to deaminate adenosine (most of the adenosine deaminase activity is located in stromovascular cells). The recent observation that concentrations of adenosine in the extracellular fluid of adipose tissue are around 125 nM, which is sufficient to exert an antilipolytic effect (30), adds considerable c re dence to the view that the antilipolytic effects of adenosine are physiologically relevant. Fur- ther indim3 evidence comes from the observations that the response to adenosine varies with physiological state. Would such adaptations occur if the substance had no physiological role? Even this argument is open to question, because effects of a number of antilipolytic factors (%-agonists, prostaglandins, and nicotinic acid) are mediated via the Gi protein and adenylate cyclase, and a change in activity of either of these proteins could give rise to a change in response to adenosine.

On balance, findings support a physiological role for adenosine as a modulator of lipolysis. During lactation, response to adenosine increases. Mechanisms and factors responsible have not been fully resolved, but an increase in nxeptor binding is at least partly responsible, and a number of hormones including somatotropin, insulin, glucocorticoid steroids,and per- haps thyroid hormones may be involved in the chronic control of the system during lactation (Figure 6). One final point: the ability of sorna- totropin to facilitate lipolysis m y involve at- tenuation of the antilipolytic system as well as enhancement of the adrenergic system, but during lactation the ability of somatotropin to curb antilipolytic activity is, paradoxically, im- P*

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Adenosine and the Control of Adrenergic Regulation of Adipose Tissue Lipolysis During Lactation

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