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Appet#e, 1987, 9, 217--229

Circadian Regulation of Feeding in Rats: Suprachiasmatic Versus Ventromedial Hypothalamic Nuclei ALEXANDER

G. S T O Y N E V

and OGNIAN

C. I K O N O M O V

Department of Physiology, Medical Academy, Sofia

The role of the suprachiasmatic nuclei as a major component of a specific circadian system controlling feeding periodicity is reviewed. Evidence is presented supporting the assumption that the ventromedia[ hypotha[amus and the suprachiasmatic nucleus may act as a constant ironic) regulator and a circadian modulator respeclively of feeding in rats. It is concluded that a specific circadian system differint~ /'ram the metabolic conlrol mechanism superimposes the circadian periodicity of feeding. A model is put forward for the possible /`uactional relationships between circadian and metabolic (homeostatic) control mechanisms of feeding in rats.

Periodicity is a fundamental property of living matter, although organisms possess regulatory mechanisms providing a continuous supply of nutrients to the cells. The intake of food from the outside world, necessary for the repletion of the endogeneous stores, is activated only periodically. Regulated are both the 24-hour amount of food ingested (i.e. homeostatic control) and the distribution of meals during the nycthemeron (i.e. circadian control). The investigation of relationships and interactions between circadian and homeostatic regulatory mechanisms is an important aspect of the study of feeding behaviour. The participation of the ventromedial hypothalamic nuclei (VMH) and the lateral hypotha[amic area (LH) in the homeostatic regulation of food intake in rats is well known. In accordance with a model proposed by Le Magnen (1980, 1981), VMH are also responsible for the generation of nycthemeral periodicity, while LH are responsible for the prandial periodicity of feeding. This model has been the subject of considerable debate (Le Magnen, 1981, peers' commentaries), but has been strongly supported in several subsequent reviews (Le Magnen, 1983, 1984a, b). The aim of this review is to emphasize the important role of the suprachiasmatic hypothalamic nuclei as a major component of a specific circadian system, superimposing circadian feeding periodicity in rats.

LI POGENESIS]LIPOLYSISCYCLE Diurnal fluctuation of feeding may be primarily due to influences of nycthemeral input and/or to cyclic mctabofic events which act upon feeding. However, several

We wish to thank ProfessorJacques L¢ Magncn for providing [he opportunity for A. G. S. to work in the laboratory at the Coll~g¢ de France and for the fruitful discussions theyhad on this topic which caused this

review, Requestsfor reprintsshouJdbe addressedto: AlexanderG. Stoynev,Departmen!of Physiology.Medical Academy, ! G. Sofiiski$tr., Sofia 1431,Bulgaria. 019.%6663/87/060217+ 13 $03.00[0

~ 1987 Academic Press Limited

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observations demonstrate that feeding cyclicity expresses the characteristics of a true endogenous circadian rhythm since it entrains to daily light-dark cycles and free-runs under constant lighting conditions or after blinding (Rosenwasser, Boulos & Terman, 1981; Siegel, 1961: Zucker, 1971). Rats consume more food during the night than during the day. Moreover both meal size and meal numbers are larger during the night (Danguir & Nicola'fdis, 1978; lkonomov, Stoynev & Vrabchev, 1981; Le Magnen & Devos, 1980a; Siegel, 1961; Zucker, 1971). Nocturnal hyperphagia is associated with a high rate of glucose utilization, hyperinsulinemia, lipogenesis, a low level of circulating free fatty acids FFA) and an increase in liver glycogen. Conversely, daytime hypophagia is associated with a low rate of glucose utilization, hypoinsulinemia, lipolysis, a high level of circulating FFA and a decrease in liver glycogen (Fuller & Diller, 1970; lkonomov, Stoynev, Shisheva & Tarkolev, 1981, Le Magnen, Deyos, Gaudilli6re, Louis-Sylvestre & Tallon, 1973; Le Magnen & Devos, 1980 b; Sakata, Fukushima, Tsutsui, Arase & Fujimoto, 1982). During the night a positive energy balance occurs together with lipogenesis and weight gain, whereas during the day there is a negative energy balance, with iipolysis and weight loss (Kakolewski, Deaux, Christensen & Case, 1971, for review see Le Magnen, 1981). During the day each meal begins later than would be expected from the utilization of calories ingested during the preceding meal. As shown by studies on metabolic correlates of meal onset and meal to meal energy balance, this difference reveals that it is the mobilization of fats and their utilization that covers the current metabolic expenses (Le Magnen & Devos, 1970, 1984). Insulin infusion during the day which abolishes lipolysis and induces iipogenesis elicits a nocturnal-like meal pattern (Danguir & Nicolai'dis, 1980). At night each meal starts earlier than would be predicted on the basis of the utilization of calories ingested during the preceding meal. This difference indicates'that a part of the food is used in fat synthesis to replete fat stores (Le Magnen & Devos, 1970, 1984). Epinephrine infusion during the night which abolishes lipogenesis and induces lipolysis elicits a day-like meal pattern (Danguir & Nicolai'dis, 1980). Taken together, the data cited above suggest that the different metabolic patterns by day and by night (i.e. the lipogenesis/lipolysis cycle) may determine the circadian rhythmicity of food intake.

VENTROMEDIAL HYPOTHALAMIC NUCLEI

We have been aware of the participation of the VMH in the homeostatic regulation offood intake in rats for a long time. The destruction ofthe VMH causes hyperphagia and obesity (Brobeck, Tepperman & Long, 1943; Hetherington & Ranson, 1940). Additionally, the diurnal periodicity of feeding is eliminated (Becket & Kissileff, 1974; Brooks, Lockwood & Wiggins, 1946; Danguir & NicoMidis, 1978). In VMH-lesioned rats the lypogenesis]lipolysis cycle is absent. The characteristics of nocturnal metabolism which indicate lipogenesis--hyperinsulinemia, a high rate of glucose utilization, a low. level of circulating FFA and a high respiratory quotient, are maintained throughout the nycthemeron (Le Magnen et al., 1973). Large and frequent meals are ingested during the day associated with significant postprandial correlation as normally observed at night (Becker & Kissileff, 1974; Le Magnen et al., 1973).

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Le Magnen's model postulates that the lipogenesis/lipolysis cycle and the resulting feeding cyelicity are controlled by the VMH. it has been suggested that down- and upregulation of insulin receptors in the VMH neurons could account for the circadian lipogenesis/lipolysis pattern (Le Magnen, 1980, 1981, 1983). In accordance with this hypothesis, nocturnal hyperinsulinemia renders VMH glueosensitive neurons subsensitive to insulin and thereby induces a relative glucopenia. Relative glucopenia brings about lipolysis during the succeeding light phase through the activation of VMH neurons and their descending pathways--direct sympathetic innervation of adrenals (activation of calecholamine release and inhibition of glucocorticoid secretion) and of the blood vessels in adipose tissues; the splanchnic innervation of the endocrine pancreas (inhibition ofinsulin and stimulation ofglucagon secretion) and the liver. Daytime hypoinsulinemia and related upregulation of insulin receptors may produce insulin hypersensitivity and inactivation of the VMH neurons during the alternate dark phase. The resulting decrease of the sympathetic tone and disinhibition of the parasympathetic vagal efferent pathways are the cause of the nocturnal hyperinsulinemia and lipogenesis (Berthoud & Jeanrenaud, 1979; Le Magnen, 1981, 1984a). The down-/up-regulation model of the VMH insulinoreceptors is supported only by indirect evidence (Le Magnen, 1984a). lnsulino- and gluco-receptors have been found in the brain (Ha vrankova, Brownstein & Rot,h, 1981; Oomura, 1976; Oomura & Kita, 198;, Van Houten & Posner, 1981). The blo6d-brain barrier is permeable to insulin, and cerebrospinal fluid levels of insulin follow basal plasma insulin levels (Stein el a/., 1983: Van Houten & Posner. 1981). Some data indicate the existence of insulindepefident VM H metabolism (Nicolai'dis, 1975; Panksepp & Pilcher, 1973). The downand up-regulation of the insulin receptors has been observed in human monocytes (Beck-Nielsen & Pedersen, 1978). The existence of a similar mechanism in the VMH neurons is compatible with results obtained in parabiotic rats. The pairing of a VM Hlesioned animal with an intact partner induces aphagia and weight loss resulting in the death of the latter (Fleming, 1969). The chronic hyperinsulinemia in the intact rat produced by blood coming from the lesioned animal, may induce insulin hyposensitivity in its intact VMH neurons. The persistent hypophagia and weight loss produced by chronic intrahypothalamic (Nicolai'dis, 1981), intracerebroventricular (icy) (Brief & Davis, ;984; Plata-Salaman, Oomura & Shimizu, 1986) and systemic (Larue-Archagiotis & Le Magnen, i 984) insulin administration in rats or by chronic icy insulin infusion in baboons (Woods, Lotter, McKay & Porte, 1979), might also be explained in a similar way.

DISCREPANCIES AND CONTROVERSIES

The major adaptive value of any circadian rhythm is to synchronize the organism to temporal environmental cues and particularly the day/night cycle (Rusak & Zucker, 1979).. The regulatory mechanism responsible for this synchronization must act as an endogenous pacemaker that "keeps time" independently of variations in the organism's internal milieu. A number of experimental manipulations that have distinct effects on physiological parameters and behaviors, did not exert any significant influence on the circadian pacemaker IRichtcr. 1965). Removal of the adrenals produced profound alterations in lipid metabolism such as a decrease in body fats, lowering plasma FFA and glucose levels and decrease in body weight (Dallman, 1984). Bilateral

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adrenalectomy, however, did not lead to any significant change in the feeding rhythmicity in rats fed ad libitum (Beilinger, Williams & Bernardis, 1979; Dallman, 1984; lkonomov, Stoynev, Vrabchev, Shisheva & Tarkolev, 1985), in spite of the desynchronization of the diurnal rhythm of the plasma insulin level (lkonomov et al., 1985). Obviously the circadian feeding pacemaker cannot be identified solely with the lipogenesis-lipolysis cycle and the liporegulatory mechanism because of the considerable sensitivity of the latter to metabolic and/or endocrine changes. Additionally, a recent study based on qmte a different rationale suggested that the satiating effect of nutrient infusions is not dependent on the magnitude of the metabolic signal, but is controlled by a circadian pacemaker which is entrained to the onset of light (Strubbe, Keyser, Dijkstra & Prins, 1986). The down- and up-regulation model of VMH insulinoreceptors may be subjected to criticism. For example, a very low insulin permeability of the blood-brain barrier has been reportecl (MargoJis & Altszldler, 1976; Woods & Porte, 1977) and Benoliei, Carayon, Jean-Joseph, Legrand & Cesselin, 1984 state that insulin is not detectable in the rat brain. Some data provide evidence that insulin does not act on the VMH metabolism andreceptors (DiRicco, Yeomans & Van itallie, 1980; Goodner & Berrie, 1977). This is supported by the inefficiency oficv insulin in reducing food intake in fooddeprived rats (Herberg, 1960), and by the'lack of effect of chronic intr~cerebral insulin infusion in high doses on the 24-hour food intake (Nagai, Mori, Nishio & Nakagawa, 1982). The suppressive effect of intravenous insulin infusion during nocturnal fasting on the subsequent daytime intake is noted only after the use ofhigh doses that significantly raise plasma insulin levels over the control levels in saline-treated rats (LarueAchagiotis & Le Magnen, 1984). The dose of icy administered insulin that suppressed feeding in the study of Brief& Davis (! 984) was very high, inducing a greater weight loss than would be accounted for by the decrease in 24-hour food intake. Therefore, the insulin effects observed in the last two experiments cannot be identified with the physiological effects of nocturnal hyperinsulinemia in rats. The parabiotic pairing of an obese LH-stimulated rat with a non-stimulated rat results in aphagia and weight loss until the death of the latter. However, the hyperinsulinemih in the obese animal is accompanied by a normal insulin level in the partner (Parameswaran, Steffens, Hervey & De Ruiter, 1977). Therefore, insulin most probably does not contribute to the observed satiety, although the hypersensitivity of VMH neurons of the non-stimulated rat to insulin should not be excluded. Studies on diurnal variation of insulin binding to erythrocytes in man provides evidence against the possible role of the insulinoreceptors down- and up-regulation in the generation of feeding cyclicity. As shown, changes in insulin binding do not mirror an intrinsic diurnal rhythm but are mainly re~ated to food intake, and may even reflect national feeding habits (Schulz, Greenfield & Reaven, 1983). At odds with Le Magnen's model is the finding that insulin is not the only humoral factor involved in the regulation of feeding (Hoebel, 1977; Leibowitz, 1980, 1986; Leibowitz & Shor-Posner, 1986; Morley & Levine, 1985). In addition, other hypothalamic structures other than VMH and LH also take part in the regulation of feeding--the dorsomedial nuclei (DMN) (Bernardis, 1973, 1985), and paraventricular nuclei (PVN) (Leibowitz, 1980) (for a recent review see Luiten, Ter Horst & Steffens, 1987). The effect of a number of mediators and hormones acling on feeding behavior is realized through the PVN (Leibowitz, 1980, 1986; Morley, Levine, Gosnell & K rahn, 1985). As proposed recently, a corticosterone-dependent mechanism of up- and down-regulation of ~t2-adrenergic receptors in the PVN may contribute to the

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circadian periodicity of feeding (Leihowitz, 1986; Leibowitz & Shor-Posner. 1986). In essence, this hypothesis shares several similarities with Le Magnen's model, ascribing a pacemaker property to a hormonal cycle. However this is not compatible with the persistent feeding rhythmicity in adrenalectomized rats (Bellinger et al., 1979: Dallman, 1984; lkonomov et aL, 1985). The postulated daytime activation and nocturnal inactivation of the VM H neurons is inconsistent wit h t he electrophysiologieal studies of VM H activity as in anaesthetized (Koizumi & Nishino, 1976) and in freely moving rats (lnouye, 1983). in fact activity of the VMH is higher during the night and lower during the day. Finally, the integrity of the VMH is not obligatory for t!'.e maintenance of the feeding cyclicity. Goldthioglucose implants into the VM H induce necrosis and obesity while the feeding rhythmicity persists with higher intakes at hight (Rietveld, Ten Hoot, Kooij & Flory, 1979). Such a dissociation is observed after unilateral VMH lesions (Rietveld, Ten Hoor, Kooij & Fiory, 1978), or parasagital knife-cuts (Gold, Sumprer, Ueberacher & Kapatos, 1975). Bilateral VMH lesions do not cause the complete disappearance of th.e circadian feeding behavior, though they increase food intake in the 12-hour light period to 35 per cent of the total daily intake (Nakagawa, Nagai, Kida & Nishio, 1979~. Similar results are also reported from Le Magnen's laboratory, in VMH-lesioned rats hyperphagia, obesity and elimination of the lipogenesis'/lipolysis cycle are combined with unchanged feeding rhythmicity (Le Magnen et al., 1973). In the same study VMH-lesioned rats consumed 60.49/o of their 24-hour food requirements during the night, this did not differ from the value of 61~ in intact rats reported by the same laboratory (Le Magnen & Tallon, 1966). The VMH lesions, leading to the elimination of feeding rhythmicity, are usually large and linked to concomitant injury to the anterior hypothalamus. Such lesions commonly include a destruction of the suprachiasmatic nuclei and/or the retrochiasmatic area. Moreover, in some animals without VMH lesions normophagia and elimination of circadian feeding periodicity have been observed (Becker & Kissileff, 1974). The circadian rhythm of feeding is also disrupted after the destruction of the DMN (Bernardis, 1973) or the anterior wall of the third brain ventricle (Bealer & Johnson, 1980). Therefore, it seems that VMH lesions eliminate the circadian rhythm of food intake only if accompanied by destruction or deefferentation of the suprachiasmatic nuclei.

SUPRACH1ASMATIC NUCLEI

The leading role of the suprachiasmatic nuclei (SCN) of the anterior hypothalamus as a circadian pacemaker in mammals and particularly in rats, is well documented (for details and review see Dallman, 1984; Kawamura & Ibuka, 1978; Moore, 1983; Moore & Card, 1985; Moore-Ede, 1986; Rosenwasser & Adler, 1986; Rusak & Zucker, 1979; Turek, 1985). The autonomy of the SCN as a circadian rhythm generator is demonstrated by metabolic (Schwartz & Gainer, 1977), electrophysioiogic (lnouye & Kawamura, 1979)and transplantation (Drucker-Colin, Aguilar-Roblero, GarciaHernandez, Fernandez-Cancino & Rattoni, 1984; Sawaki, Nihonmatsu & Kawamura, !984) studies. SCN activity occurs during the day whether the animal is a nocturnal rat, a diurnal squirrel monkey, or a crepuscular cat (Inouye, 1983; lnouye & Kawamura, 1979; Schwartz, Reppert, Eagan & Moore-Ede, 1983), In contrast, maximal multi-unit activity in rat brain structures outside the SCN, including the VMH, occur at night

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(Inouye, 1983). Indeed, nocturnal and diurnal atiimals differ in the phase relationship between the circadian pacemaker and the overt activity, but not in the phase relationship between the pacemaker and day-night cycle (Pittendrigh & Daan, 1976). The circadian rhythm of feeding disappears after bilateral destruction of the SCN (Nagai, Nishio, Nakagawa, Nakamura & Fukuda, 1978;Suite & Ibuka, 1983; Stoynev~ Ikonomov & Usunoff, 1982; Stoynev, Ikonomov, Vrabchev & Usunoff, 1986; Van Den Pol & Powley, 1979).The same outcome follows retrochiasmatie knife-cuts sparing the SCN integrity, but interrupting their efferent pathways (Nishio, Shiosaka, Nakagawa, Sakumoto & Satoh, 1979). Approximately equal amounts of food are ingested during the day and the night, without significant changes in 24-hour food intake. The number of meals is equal during day and night, without change in 24-hour meal number, meal size and duration, or feeding rate (Stoynev et al., 1982). Computer-assisted fine-grained morphological analysis shows that the brain region responsible for the generation of the circadian rhythm of feeding includes the SCN arid adjacent lateral and posterior areas (Van Den Pol & Powley, 1979).The disrupted circadian feeding rhythmicity after SCN lesions is not due to impaired synchronization and free-running rhythms in individual rats, as demonstrated by autocorrelation (Van Den Pol & Powley, 1979) or Fourier analysis (Saito & Ibuka, 1983; Stoynev et al., 1986). An increase of daytime food intake combined with a decrease of nocturnal food intake is observed during chronic insulin infusion into the SCN. This effect is dosedependent and occurs without changes in 24-hour food intake (Nagai, Mori, Nishio & Nakagawa, 1982). Circadian feeding rhythm is abolished during a reversible neural blockade of the SCN with colchicine (Morris & Morgenson, Note 1). Injection of antiSCN antibodies into the SCN eliminates the circadian rhythm of feeding (Nagai, Mori & Nakagawa, 1982). The lack of effect of SCN destruction on the circadian rhythmicity offeeding is also reported, while the circadian rhythms of plasma corticosterone concentration and body temperature disappear (Abe, Kroning, Grcer & Critchlow, 1979). In this study however, lesions spared the adjacent lateral and posterior areas of the SCN thus leaving intact parts of the crucial region responsible for the generation of the circadian feeding rhythmicity (V0n :Den Pol & Powley, 1979). This dissociation of effects on different circadian rhythms might be explained by a topological presentation of circadian functions in different oscillatory units of the SCN oscillatory complex, as already suggested (Abe et al., 1979; Rusak, 1977; Moore & Card, 1985). Note should also be taken that the conclusions of Abe et al. (1979) are based on the results from the study of only six rats during a single 24-hour cycle. These results have never been confirmed in investigations using larger numbers of animals followed up during several consecutive days and weeks (Nagai et al., 1978; Saito & Ibuka, 1983; Stoynev et al., 1982; Van Den Pol & Powley, 1979). Briefly, morphological, functional and immunological manipulations blocking the functioning of the SCN, eliminate the circadian rhythmicity of feeding without unduly disturbing the 24-hourly amount of food ingested. This is in agreement with the assumption that the VMH may act as a constant (tonic) regulator, and the SCN as a cyclic circadian modulator of feeding in the rat (Armstrong, I980). The effector pathways used by the SCN to control circadian rhythms have not yet been studied thoroughly. The intermediolateral cell column of the spinai cord is a structurereceiving SCN efferents and provides sympathetic innervation regulating circadian pineal functions (Klein, 1979; Moore & Klein, 1974). SCN efferents also reach the VMH, LH, DMN and PVN (Swanson & Cowan, 1975, for review see Moore, 1983).

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This finding may easily explain the disappearance of the circadian feeding rhythm after ¥MH and DMN lesions, which destroy not only the VMH or DMN neurons, but also interrupt the SCN efferents. Furthermore retroehiasmatic knife-cuts as mentioned above, eliminate feeding rhythmicity "(Nishic) et al., 1979). A direct functional link between the SCN and VMH neurons is confirmed using intracellular recordings in vitro (Kita, Shibata, Oomura & Ohki, 1982) and extracellular single-unit recordings in vivo (Oomura et al., 1979). One may conclude that VMH lesions cause hyperphagia and obesity as a specific effect and disappearance of feeding cyclicity as a non-specific one, due to lhe concomitant injury of the SCN efferents. Here, one may also expect the elimination of circadian rhythms of other functions. In fact, the rhythms of eorticosterone secretion (Dallman, 1984) and locomotor activity (Inouye, 1983) disappear after VMH lesioning. This effect is again associated with the destruction of the retrochiasmatic area (Inouye, 1983). The model presented in Fig. I includes a component of a specific circadian system. It is based on the presumption that the circadian pacemaker is most probably a complex structure and not a single nucleus, in accordance to the system approach in neurobiology of feeding behavior (Morgan', .1979). The SCN are genetically programmed to generate circadian rhythmicity independent of the presence or lack of internal and external periodic events. They are also responsible for the rhythms' synchronization with the light-dark cycle using a specialized visual pathway--the retinohypothalamic tract, i.e. for the setting of the endogenous period of the pacemaker at 24 hours via a process ofentrainment. The VMH are responsible for the coupling of the effector feeding system with the circadian cycle given by the SCN. Thus the light{dark cycle tunes the circadian pacemaker in favor of either lipolysis or lipogenesis respectively. In the absence of the endogenous circadian generator (SCN lesions) the internal synchronizer (VMH) may be influenced by periodic events related to neurohumoral and/or metabolic changes accompanying feeding. Elaborating further on the interrelations presented so far, one may predict that SCN lesions will be succeeded by a disappearance of the lipogenesis/lipolysis cycle (i.e. a lack of circadian variation in food intake, plasma insulin and FFA levels, rate of glucose utilization, respiratory quotient etc.), which is observed after VMH lesions. The circadian rhythmicity of food intake and plasma insulin level in accordance with this supposition are eliminated in SCN-lesioned rats, without concomitant hyperphagia. and obesity (Stoynev, lkonomov, Tarkolev & Shisheva, 1980; Stoynev et al., 1982). Circadian rhythms of oxygen consumption and respiratory quotient are also abolished after SCN lesions (Nagai, Nishio & Nakagawa, 1985). It should be noted however, that the scheme presented does not pretend to give a comprehensive explanation of all possible factors involved in the modulation of feeding periodicity. Thus the conditioned reflex activity which is superimposed on the metabolic cycle is not commented upon. Such reflex activity might explain for example the abrupt beginning of feeding observed in laboratory rats within a few minutes of switching off the light. Finally, the participation of other neural or neuroendocrine efferent circuits cannot be excluded, although the necessary experimental support is not sufficient at present. One may tentatively conclude that a specific circadian system, other than the metabolic (homeostatic) control mechanism, acts to regulate the circadian periodicity of food intake in rats, as has been established for other functions (Borbtly & Tobler, 1985).

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A. G. STOYNEV AND O. C. IKONOMOV External synchronizer Afferent system

Light

I_

.,j,

Other factors

Circoclian

generator Circadian paclmaker I'nternal

Synchronizer

Efferent system

¥ogus +

Sympolhlcus .t-

7_

AOrenals

cA

Insulin

[

Llpo~en.e.sis/lipolysls cycle

I

FIGUR~ I. Model ofthe circadian regulation of food intake. Question mark indicates that this relationship is only hypothesized. Eviden~ is cited in the text for all other relationships, a2, pancreatic ~2-adrenergic receptors; CA, catecholamines; CS, corticosterone; Psymp, parasympathetic; RHT, retinohypothalamic tract; SCN, suprachiasmatic nuclei; Symp, sympathetic; VMH, ventromedial hypothalamic nuclei; +, stimulatory effect, - , inhibitory effect. Only the dominant inhibitory effect of adrenal medulla epinephrine on insulin secretion via pancreatic az-adrenergic receptors is shown.

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Received 20 September 1986, revision 8 July 1987