Role of the liver in the metabolic control of eating: What we know—and what we do not know

Neuroscience and Biobehavioral Reviews, Vol. 20, No. 1, pp. 145-153, 1996 Copyright © 1995 Elsevier Science Ltd Printed in Great Britain. All rights reserved 0149-7634/96 $9.50 + .00

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Role of the Liver in the Metabolic Control of Eating: 'What we K n o w - - a n d What we do Not Know WOLFGANG

LANGHANS

1

Institute for A n i m a l Sciences, Swiss Federal Institute o f Technology, 8092 Zurich, Switzerland

LANGHANS, W. Role of the liver in the metabolic control of eating: What we know--and what we do not know. NEUROSCI BIOBEHAV REV 20(1), 145-153, 1996. --Profound meal-related changes in the supply of metabolites to the liver and in hepatic metabolism occur, and there is ample evidence that neural signals from hepatic metabolic sensors can affect eating. Hepatic afferent nerves presumably represent glucosensors which contribute to the control of eating by monitoring their own glucose utilization. Yet, the nature of the putative sensors that respond to the oxidation of other metabolites than glucose has not been identified. ATP and sodium pump activity may link hepatic oxidative metabolism and membrane potential, because hepatic phosphate-trapping by 2,5-anhydro-mannitol, and inhibition of sodium pump activity by ouabain is associated with a stimulation of eating. Hepatocyte membrane potential is also subject to changes in transmembranal potassium flow through volumetrically controlled membranal potassium channels. Yet it is unknown if and how hepatocytes are l~inkedto afferent nerves. It is also unclear how the effects of glucagon and insulin fit into the hepatic metabolic control of eating. Glucagon appears to induce satiety through its actions in the liver, but the involved mechanism is still unclear. Recent studies suggest that insulin, which has mainly been explored as a centrally acting long-term satiety signal, has an immediate effect on meal size, but it is presently unknown whether an hepatic action of insulin is involved. Metabolism

Liver

Hepatic sensors

Glucagon Insulin

b e e n reported (23,35,48,54,66). Information derived f r o m hepatic metabolism, like other peripheral signals, does not seem to be necessary for an adequate control of eating under most conditions, but a role of the liver in the metabolic control of eating is widely accepted. Yet, several questions concerning the nature and functioning of the hepatic sensors that register and transmit the metabolic message to the brain remain to be answered.

INTRODUCTION

C O N T E M P O R A R Y H Y P O T H E S E S of the metabolic control of eating assume that eating is inversely related to the rate of fuel utilization (14,36,51,68). This requires that fuel utilization is monitored b y sensors which are connected to the CNS circuitry Controlling eating behavior. The liver is generally believed to be a prominent location for those sensors. Evidence for a role of the liver in the metabolic control of eating is mainly derived from: (1) the profound changes in the supply of metabolites to the liver and in hepatic metabolism that can be detected in relation to eating; (2) the fact that experimental manipulations of these changes have often been shown to affect eating; and (3) reports that m a n y of these effects on eating depend on intact afferent nerve connections between liver and brain. Although partial or total liver denervation per se generally failed to substantially affect eating (6,8,9,35,62), some m o d e r a t e effects of hepatic branch vagotomy on eating under certain conditions have

HEPATIC METABOLIC SENSORS IN EATING CONTROL Sensors for Glucose

Russek (89) was the first to suggest that hepatic glucosensors are involved in the control of eating. H e r e p o r t e d that intraportal but not intrajugular infusion of glucose suppressed food intake in 22 h fasted dogs (90). Although attempts to replicate these original findings and to extend them to other species yielded conflicting results (a decrease in food intake, e.g.

1To whom correspondence and reprint requests should be addressed at: Institut fiir Nutztierwissenschaften, ETH-Zentrum, 8092 Ziirich, Switzerland 145

146 74,75,122; no effect on food intake, e.g., 7,103; an increase in food intake, 45), more recent systematic tests of portal glucose infusions by Tordoff and Friedman convincingly demonstrated that glucose infusions that produced metabolic changes within the physiological range and did not affect systemic blood glucose levels, reduced food intake (109,110,114). Interestingly, food intake was reduced by the same amount irrespective of the concentration of the glucose solution and the amount of glucose infused intraportally (114). Therefore, the critical metabolic event in the liver that influences food intake seems to be only indirectly coupled to portal glucose levels (114). Other aspects of the glucose supply like the portal-arterial glucose gradient (114) or the rate of glucose delivery into the portal vein (73) may be crucial. Thus, while food intake seems to be reduced when glucose is delivered at rates that match the physiological norm (114), meal size, meal duration and cumulative food intake seem to be increased when glucose or other hexoses are delivered at a higher rate (73). Some evidence for an hepatic glucosensitive mechanism in the control of eating is also derived from studies with the glucose antimetabolite 2-deoxy-glucose (2DG). Infusion of 2-DG into the hepatic portal vein in rabbits caused a more rapid and greater increase in food intake than infusion into the jugular vein, and the effect was reduced by complete subdiaphragmatic vagotomy (76). In rats, both intrajugular and intraportal infusions of 2-DG produced a similar increase in food intake (93), and hepatic branch vagotomy did not reduce the stimulatory effect of 2-DG on eating in rats during the day (111). Delprete and Scharrer (22,24) recently confirmed this finding, but additionally observed that the eating response to 2-DG was reduced by hepatic branch vagotomy under some conditions, for instance when 2-DG was injected in the early dark phase of the lighting cycle and especially after consumption of a test meal. The finding that the disruption of postprandial satiety by 2-DG is partially dependent on an intact hepatic branch of the vagus supports the hypothesis that glucose utilization by hepatic glucosensors contributes to the maintenance of postprandial satiety. It is also interesting in this context that complete subdiaphragmatic as well as hepatic branch vagotomy disrupted the otherwise reliable coupling between the pre-meal decline in blood glucose levels and meal initiation in the rat: whereas the transient pre-meal declines in blood glucose in both vagotomized groups were quantitatively similar to those observed in intact rats, they predicted meal initiation in only 55% of all trials compared to the 100% coupling of these events in intact rats (17). These findings are consistent with the idea that hepatic glucosensors play a role in the detection of the transient pre-meal decline in blood glucose and the reliable translation of this decline into meal initiation (17). Sensors for Other Fuels There is ample evidence that hepatic sensors can also monitor the utilization of other metabolites than glucose, and that such metabolic cues affect eating. For

LANGHANS instance, the reduction of spontaneous food intake brought about by continuous total parenteral nutrition in the rat was markedly attenuated by anterior subdiaphragmatic vagotomy (121). The often reported hypophagic effects of lactate, pyruvate and some other metabolites also seem to be mediated mainly by hepatic sensors which are linked to the brain through the vagus, as subcutaneous injection of these metabolites failed to suppress eating in rats with hepatic branch vagotomy (53). Lactate and pyruvate may well be involved in the physiological control of food intake. An increase in portal vein plasma lactate concentration in response to intragastric glucose loads has been observed in unrestrained, chronically catheterized rats (47,69) and dogs (99). Eating after mild food deprivation in rats is also accompanied by an increase in portal vein and hepatic lactate concentration (50), and in man, peripheral lactate concentration increases in response to carbohydrate meals (106). Fatty acids are major fuels for the liver, and fatty acid oxidation presumably also affects eating in part through hepatic sensors. Inhibition of fatty acid oxidation by various substances is associated with enhanced eating (lipoprivic eating), especially when a fat-rich diet is consumed (34,96). We found that the hyperphagia of rats fed an 18% fat diet in response to mercaptoacetate, which inhibits the acyl-CoAdehydrogenases located in the mitochondrial matrix (5), was markedly attenuated by hepatic branch vagotomy (55). More recently, Beverly et al. (13) confirmed these findings; in addition they showed that hepatic branch vagotomy eliminated the stimulating effect of mercaptoacetate on eating in rats receiving total parenteral nutrition (13). There is one report in which hepatic branch vagotomy failed to attenuate the hyperphagic effect of mercaptoacetate significantly (86). This discrepancy cannot readily be explained, but the residual eating response to mercaptoacetate in rats with hepatic branch vagotomy suggests that extrahepatic sensors may in part be involved in mercaptoacetate's effect on food intake, or that hepatic afferents that are spared in hepatic branch vagotomy contribute. It should be noted in this context that hepatic metabolic sensors may also be linked to the brain through splanchnic afferents (72,97). Since mercaptoacetate retained its potency to stimulate eating after peripheral blockade of cholinergic transmission by atropine methyl nitrate (55), fatty acid oxidation seems to affect eating at least in part through vagal afferents and not efferents. Moreover, capsaicin pretreatment, subdiaphragmatic vagotomy, and lesions of the vagal sensory terminal fields in the area-postrema/nucleus of the solitari tract abolished lipoprivic eating (84,85), and eating could not be elicited by injection of mercaptoacetate into the lateral or fourth ventricle of rats (84). All these findings are consistent with the assumption that the metabolic sensors involved in lipoprivic eating reside primarily in the liver, and maybe other viscera. Indirect evidence for a role of hepatic fatty acid oxidation in control of eating is derived from studies showing that food intake of rats decreases as early as 1 h after feeding or intragastric administration of

HEPATIC METABOLIC CONTROL OF EATING medium-chain triglycerides (39,94). The observed hypophagia was only slightly attenuated by the CCKA-receptor antagonist Devazepide, indicating that it is only in part related to the release of endogenous CCK by medium-chain fatty acids (39). Upon digestion and absorption of a meal containing fats, the liver is presented with at least some medium-chain fatty acids which feed into the mitochondrial fatty acid oxidation pathway. The oxidation of medium-chain fatty acids is more efficient than that of long-chain fatty acids (4) because of: (1) the faster and more complete hydrolysis of medium-chain triglycerides; (2) their rapid portal route of delivery to the circulation; (3) the fact that they do not require fatty acid binding protein to be carried through the cytosol; and (4) their ability to bypass carnitine acyltransferase llransport across the mitochondrial membrane. A rapid and tremendous increase in blood ketone body lew~ls, reflecting an increase in hepatic fatty acid oxidation, has actually been observed after ingestion of pure medium chain triglycerides in man (79). A transient prandial increase in the peripheral blood 13-hydroxybutyrate (BHB) level can also be observed after ingestion of a fat-rich meal in man: in 43 healthy male volunteers, mean plasma BHB transiently rose in response to consumption of an American style high-fat breakfast (33% carbohydrate, 52% fat, 15% protein) from 37+2 (x_ SEM) to 47+3 and 45+2 lamolh at 30 and 50 min after meal onset (p<0.05). Thereafter, plasma BHB continuously decreased and leveled off at about 10 lamol/l at 150 rnin. In rats, the liver continued to release BHB after ingestion of an 18% fat meal, and at meal end and at 30 min after the meal the hepatic release of BHB was sigaificantly higher compared to meal onset (105), showing that rat liver oxidizes considerable amounts of fatty acids in response to an 18% fat meal. Given the observed short-term inhibition of eating by medium-chain fatty acids (39,94) and the fact that lipoprivic eating depends on sensory~presumably hepatic, afferents (13,55,84,85), these findings are consistent with a role of hepatic fatty acid oxidation in control of eating, at lea,;t when considerable amounts of fat are ingested. Finally, hepatic amino acid sensors responding to alanine, arginine and leucine have been identified (107,108). Hepatic vagal afferents responded to intraportal amino acids with an increased firing rate (108). The mechanism of this increase and the possible interactions between amino acid sensitive and glucosensitive neurons remain to be clarified. Nevertheless, the existence of hepatic amino acid sensors is interesting because intraportal or intraperitoneal administration of amino acids has been shown to inhibit eating (e.g. 83). In summary, hepatic branch vagotomy attenuates at least some of the changes in food intake observed in response to various manipulations that alter hepatic metabolism of fuels other than glucose. Although the hepatic branch of the vagus does not only innervate the liver and is not the only afferent neural connection between liver and brain (81), these results indicate that metabolic cues, which are sensed in the liver and conveyed to the brain through afferent nerves, affect eating. Moreover, some of these changes in liver

147 metabolism occur in relation to meal-taking and may well provide the physiological basis for the hepatic contribution to the metabolic control of eating. NATURE OF HEPATIC METABOLIC SENSORS

The effects of inhibitors of glucose utilization and fatty acid oxidation on eating and other findings (see 57) indicate that utilization of metabolites is sensed in the liver and affects eating. Reports of an increase in food intake after administration of the fructose analogue 2,5-anhydro-mannitol (2,5-AM) (112) fit the hypothesis that ATP availability plays a major role in this sensory process. In addition to inhibiting gluconeogenesis and glycogenolysis (46), 2,5-AM has been shown to decrease the cytosolic ATP/ADP ratio in isolated hepatocytes (101). The hyperphagic effect of 2,5-AM originates in the liver because: (1) rats began eating sooner and ate more food during hepatic portal than during intrajugular infusion of 2,5-AM (113); (2) hepatic branch vagotomy blocked the eating response to 2,5-AM (113); and (3) after adminstration of radioactive 2,5-AM, significant quantities of radioactivity were found in the liver but not in the brain (113). A most recent study using 31p nuclear magnetic resonance showed that 2,5-AM is rapidly phosphorylated in the liver, trapping hepatic phosphate and decreasing ATP also in vivo (82); these changes occur in a time frame that parallels the eating response. ATP drives the sodium pump and, hence, affects membrane potential, which may be linked to afferent nerve activity. Experimental manipulation of sodium pump activity also affects eating: we have shown several years ago that ouabain stimulates eating after intraperitoneal injection in rats (56). The hyperphagic effect of ouabain was blocked by hepatic branch vagotomy, but not by peripheral anticholinergic blockade with atropin (56), indicating that hepatic afferents are involved in the hyperphagic effect of ouabain. Further support for the assumption that the hyperphagic effect of ouabain originates in the liver is derived from recent studies, showing that remotely controlled infusion of ouabain stimulated spontaneous eating in ad lib fed rats when given into the portal vein, whereas equivalent infusions of ouabain into the inferior vena cava had no significant effect on eating (Table 1).

TABLE 1 DIFFERENTIAL EFFECTS OF HEPATIC PORTAL AND VENA CAVA INFUSION OF O U A B A I N ON FOOD INTAKE Ouabain (2mg/kg b.wt.)

Hepatic portal infusion Vena cava infusion

Saline

2h Food intake (g) 1.9±0.4" 0.6±0.3 1.1±0.4 1.0±0.3

Data are means ± SEM of 8 rats. Remotely controlled hepatic portal and vena cava infusions of ouabain or vehicle (saline) were given in the middle of the bright phase of the 12/12h dark/light cycle in ad libitum fed rats. *Significantly (/7<0.05) higher than corresponding control intake.

148

LANGHANS TABLE 2 EFFECTS OF VARIOUS SUBSTANCESON HEPATOCYTE MEMBRANEPOTENTIAL AND VAGAL AFFERENT ACTIVITY Substance

Hepatocyte membrane potential

Afferent nerve activity

glucose

increase (mouse, 5-10min)(65) no effect (rat, 25-30min)(19) increase (mouse)(65) increase (rat/mouse)(19,65) increase (rat)(19) increase (rat)(31) increase (rat)(19)

decrease (guinea pig)(70) increase (guinea pig)(72) no effect (guinea pig)(71) decrease (guinea pig)(72) increase (rat)(108) increase (rabbit)(77)

decrease (mouse)(88)

n.d.

2-deoxy-glucose fructose pyruvate alanine palmitate FAO inhibitors (together with palmitate)

FAO = fatty acid oxidation. References in parentheses, n.d. = not determined

What is the morphological substrate of the hepatic metabolic sensors implied by behavioral studies? Russek assumed that hepatic glucosensors are hepatocytes which are hyperpolarized by some metabolite of the glycolytic chain, related both to liver glycogen content and glucose uptake (91,92). Glucose has in fact a short-term hyperpolarizing effect on hepatocyte membranes (65), but this effect is independent of intracellular glucose utilization because the nonmetabolizable glucose antagonist 2-DG also hyperpolarized hepatocytes (65). The previously observed failure of glucose to hyperpolarize hepatocytes after 25-30 min of perfusion (19) or after 70 min of exposure (88) is also consistent with the assumption that the hyperpolarizing effect of glucose is independent of glucose utilization. Alternatively, an opening of K÷-channels due to osmotic cell swelling and the ensuing efflux of K ÷ may contribute to the short-term effect of glucose and 2-DG on hepatocyte membrane potential (65). In liver perfusion studies, Niijima showed that the discharge rate of hepatic vagal afferents decreased when D-glucose was added to the perfusion medium (70). In contrast, 2-DG increased the firing rate of hepatic vagal afferents (72), and the effect of glucose on the spike frequency of hepatic vagal afferents was blocked by ouabain (70-72). The opposite effects of glucose and 2-DG on eating and afferent nerve activity together with the similar effects of both substances on hepatocyte membrane potential clearly argue against a role of hepatocytes as glucosensors in the control of eating. Rather, the results strongly indicate that vagal afferents respond directly to glucose and 2-DG and represent the hepatic glucosensors that affect eating by monitoring their own rate of glucose utilization, as originally proposed by Niijima (70). If there is a connection between hepatocytes and the glucosensitive neurons, the response of these glucosensors might be modulated by the hyperpolarization of hepatocytes induced by monosaccharides. The direct response of the vagal glucosensors to glucose could thus be amplified by the hyperpolarization of hepatocyte membranes induced by glucose, whereas the direct effect of 2-deoxy-Dglucose on afferent nerve activity could be antago-

nized by the hyperpolarization of liver cell membranes (65). This antagonism may contribute to the absence of a hepatic component in the eating response to 2D G observed in several studies (e.g. 93,96). As many of the vagal afferents terminate in the wall of the hepatic portal vein (11), hepatic glucosensors seem to be well suited to monitor the incoming supply of glucose, and feed this information into the CNS circuitry that controls eating. Glucose is the preferred metabolic fuel for peripheral nerves, but it is questionable whether other metabolites are utilized and sensed directly by vagal afferents. As hepatocytes are able to oxidize almost all fuels and rely in particular on fatty acid oxidation (98) for ATP generation, hepatocytes may contribute to the metabolic control of eating by sensing the oxidation of fuels other than glucose. In liver perfusion studies hepatocyte membranes were also hyperpolarized by palmitate, pyruvate, lactate, alanine, and fructose (19,31,65,88) (Table 2). The hyperpolarizing effect of pyruvate was reversed by ouabain, indicating that it depends on a pyruvate-induced increase in sodium pump activity (19). Pyruvate also decreases afferent nerve activity (72), and its hypophagic effect is presumably related to its hepatic oxidation (51,53). Taken together, these data fit the idea that hepatocellular oxidation of pyruvate inhibits eating through an increase of hepatocyte membrane potential that somehow decreases afferent nerve activity. On the other hand, fructose decreases food intake when injected into the portal vein (110), and increases hepatocyte membrane potential (19,65), but it does not seem to affect the spike frequency in afferent nerves (72). This is hard to reconcile with the assumption that hepatocyte membrane potential modulates afferent nerve activity. Alanine also inhibits eating after parenteral administration in rats (unpublished results) and increases hepatocyte membrane potential (19,31) and afferent nerve activity (108). The hyperpolarizing effect of alanine does not seem to be exclusively coupled to a stimulation of sodium pump activity (18,31). Rather, some evidence implicates a volume-regulatory efflux of K ÷ in the hyperpolarizing effect of alanine (31). Finally, oxidation and sodium pump activity are probably involved in the hyperpolar-

HEPATIC METABOLIC C,ONTROL OF EATING

149

hepat~rc vagal afferents

membrane potential

close contact ?

D spike frequency

[

I

satiety

ne~iromodulator? membrane potential

/ ,

opening of potassium channels

sodium pump activity l ATP oxidation

hepatocytes

~ /

various metabolites FIG. 1. Hypotheticalcoding mechanism for hepatic metabolicsensors involvedin eating control. See text for further details.

izing effect of palmitate on liver cell membranes, because this effect is atte,nuated by inhibitors of fatty acid oxidation and ouabain (88,95). Palmitate has been reported to increase afferent nerve activity (77). It should be mentioned, however, that the effect of palmitate on spike frequency disappeared when albumin was added to the perfusion medium (77). This casts some doubt on the physiological relevance of the effect of palmitate on afferent nel~ze activity. It is presently also unknown whether fatty acid oxidation inhibitors block any effect that palmitate may have on afferent nerve activity. All in all, metabolites may affect hepatocyte membrane potential through mitochondrial oxidation, cytosolic ATP and sodium pump activity or through potassium efflux due to cell swelling and the ensuing opening of potassium channels (31,65). The latter possibility may also apply to glucose that is derived from hepatic glycogenolysis o1' to ketone bodies resulting from enhanced fatty acid oxidation (88). Main features of this hypothetical coding mechanims of hepatocytes are shown in Fig. 1. Clearly, however, further studies are necessary to explain the discrepancies between the effects of various substrates on hepatocyte membrane potential and afferent nezve activity (see Table 2), and to answer the closely related question of how the metabolic information is transferred from hepatocytes to hepatic afferent nerves. Using anterograde tracing of the hepatic vagal innervation, Berthoud et al. (11) failed to detect afferent nerve endings in rat liver parenchyma. More recently, however, the neurofilament protein 200 was detected immunohistochemically

in close association with hepatocytes in certain areas of rat liver (33), suggesting that rat liver parenchyma is innervated. Yet, this technique cannot differentiate between efferent and afferent nerve fibers. If there is no connection between hepatocytes and afferent nerves, hepatocytes might perhaps release some as yet unidentified modulator of nerve activity (95). This possibility has not yet been investigated. In summary, utilization of various metabolic fuels in hepatocytes and the ensuing changes in hepatocyte membrane potential or another as yet unidentified mechanism relaying the information to afferent nerves may be integrated with the effects of glucose utilization within hepatic nerves. The integration seems to occur mainly on a higher level, perhaps in the hindbrain and in the lateral hypothalamus. This assumption is also consistent with several findings indicating that the utilization of glucose and other metabolites, in particular fatty acids, exert a coordinated control over eating behavior (12,30,37,43). Such findings lend strong support to theories suggesting that some general measure of energy flow in metabolism rather than changes in the utilization of a particular fuel controls eating (14,36,51,68). In addition to the possible functioning of hepatic metabolic sensors outlined above, there may be another mechanism involved in the effect of hepatocellular metabolism on eating. Besides producing ATP through oxidative phosphorylation, oxidation of metabolic fuels is always thermogenic. The concomitant rise in liver temperature might provide an

150 additional link between stimulation of hepatic oxidative metabolism and inhibition of eating. The hepatic vagus nerve has been shown to contain thermosensitive fibers, which respond to slight increases in liver temperature with an increase in spike frequency (2). Moreover, artificial heating of rat liver within physiological limits decreased food intake (26) and this effect appeared to be mediated by afferent nerves (27). In a more recent study in which liver temperature of ad lib fed rats was continuously recorded, liver temperature invariably and independent of meal size or ambient temperature increased to just above 39°C during meals taken in the dark phase of the lighting cycle (25). The meal-end liver temperatures represented the highest values recorded. Similar results were reported by others (1). As liver temperature also increases prior to meal onset (25), an hepatic thermostatic mechanism clearly cannot be involved in the maintenance of satiety. However, prandial hepatic thermogenesis may be sensed by thermosensitive afferents and contribute to satiation, providing some kind of safety mechanism that limits meal size when a threshold temperature is reached.

LANGHANS release (40,44). In short, the question of whether an hepatic glucosensitive mechanism contributes to glucagon-induced satiation or not remains open to discussion. Besides stimulating hepatic glycogenolysis and gluconeogenesis, glucagon activates hepatic oxidative metabolism (32,120), in particular fatty acid oxidation and ketogenesis (32,63), and increases hepatocyte membrane potential (29,38,78). Stimulation of hepatic mitochondrial respiration or fatty acid oxidation by glucagon may contribute to glucagon's satiating effect at least under some conditions. Alternatively, glucagon may hyperpolarize hepatocytes directly by stimulating sodium pump activity or by increasing membrane K ÷permeability (38,49,78). Similarly, the question of whether or not hepatic afferent nerves possess glucagon receptors, which might be involved in the decrease of the spike frequency in hepatic vagal afferents by glucagon (72), needs to be answered. In summary, most data indicate that glucagon-induced satiation originates in the liver, but the exact mechanism of glucagon's effect on eating remains to be elucidated.

Insulin ROLE OF GLUCAGON AND INSULIN IN THE HEPATIC METABOLIC CONTROL OF EATING

Glucagon Because of its well-known hyperglycemic effect, glucagon has been employed for studies of eatingcontrol early on. We showed more than 10 years ago that intraperitoneal injection of antibodies to pancreatic glucagon increases meal size and meal duration (60). Today, the most compelling evidence for a physiological satiating effect of glucagon that originates in the liver is derived from the observation that hepatic branch vagotomy blocked the inhibition or stimulation of eating after remotely controlled hepatic portal infusion of glucagon and glucagon antibodies, respectively (42). It was originally proposed that glucagon signals satiety by stimulating hepatic glucose production (100). Glucagon-induced satiation in fact sometimes appeared to be linked to its glycogenolytic and hyperglycemic effects (41,60,116). Moreover, Ritter and her colleagues (87) showed that intraportal injection of subdiabetogenic doses of alloxan abolished glucagoninduced satiation, whereas intrajugular injection of the same alloxan dose had no effect on glucagon-induced satiation (87). Alloxan is toxic to glucosensitive cells and its effect seems to be limited to the liver under the conditions tested (87). The data therefore suggest that hepatic glucosensors are necessary for glucagoninduced satiation. Indirect support for the idea that hepatic glucosensors are involved in the satiating effect of glucagon is derived from the fact that glucagon, like glucose, decreased the spike frequency in hepatic vagal afferents (72). Yet, several dissociations regarding the effects of glucagon on food intake and hepatic glucose production have been reported (40,44,52,58,116), and glucagon's potency to inhibit eating sometimes appeared to be inversely related to hepatic glucose

Insulin is released in relation to eating (e.g., 10,20,21,61,104) and is essential for the entry and metabolism of ingested nutrients in most tissues. Administration of low doses of insulin by various routes has often been shown to inhibit eating in various species (3,117,118). Several reports of hypophagia and body weight loss in response to intracerebroventricular infusions of insulin (15,80,119) indicate that insulin inhibits eating by acting directly in the brain. Moreover, intrahypothalamic administration of insulin also reduced food intake (64,67) and intrahypothalamic injection of antibodies to insulin increased food intake in rats (102). Circulating insulin might act rapidly on neurons of brain areas that lack a functioning blood-brain barrier. Another important and possibly fast passage for insulin from blood to brain sites that are involved in food intake regulation seems to be via specific insulin receptors in the brain capillary endothelial walls (28). Yet, when administered directly into the cerebrospinal fluid, a clear reduction of food intake by insulin was not apparent in the first meal (119), indicating that insulin's central effect on eating is mainly long-term. As basal insulin secretion and plasma levels of insulin are directly proportional to the level of adiposity (16), insulin may actually be involved in the control of eating by body fat. In addition, prandially released pancreatic insulin appears to have an immediate satiating effect, as has been advocated for many years by Vanderweele (117,118). Most recently, Vanderweele showed that intraportal infusion of insulin reduced meal size in rats (115). In our hands, remotely controlled hepatic portal infusions of various doses of insulin, given during spontaneous meals, did not affect meal size generally and meal duration in rats (Table 3) (59). However, under the same conditions hepatic portal infusion of insulin antibodies (in vitro binding capacity 20-50 mU rat insulin) increased meal size (Table 3) (59). These data indicate that normal

HEPATIC METABOLIC CONTROL OF EATING

151

TABLE 3 EFFECTS OF HEPATIC PORTAL INFUSION OF INSULIN AND INSULIN ANTIBODIES ON MEAL DURATION AND MEAL SIZE

Meal size (%) Meal duration (%)

Insulin (mU/meal.)

Insulin antibodies

45+6 -16±8

+29±10" +13±11

Data are means SEM of 20 (insulin) and 9 (insulin antibodies) rats. Remotely controlled hepatic portal infusions of insulin (mU/meal) and insulin antibodies (in vitro neutralizing capacity 50mU rat insulin) were given during the first spontaneous nocturnal meal in ad libitum fed rats. *Significantly (p<0.05) greater than control meal size, which was about 3 g. Control meal duration was 10-12 min.

prandial insulinemia is a necessary part of satiation during spontaneous mealIs in the rat. So far, however, the question of whether or not pancreatic insulin

affects meal size also through an hepatic action cannot be answered satisfactorily. It is also not known whether hepatic afferent nerves possess insulin receptors. CONCLUDING REMARKS

There is ample evidence that the liver plays a major role in the control of eating. Hepatic glucosensors and hepatic metabolic sensors which continuously monitor the utilization of glucose and various other fuels are presumably connected to the brain by afferent nerves and provide information about fuel reserves and the currently oxidized fuel mixture for the central controller. Whereas the coding mechanism of the hepatic glucosensors seems to be rather clear, several questions remain to be answered concerning the putative sensory function of hepatocytes in the metabolic control of eating. The same applies to the mechanisms that underlie the satiating effects of glucagon and insulin.

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