Glucocorticoids and hypothalamic obesity

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  • Neuroscience & Biobehavioral Reviews, Vol. 12. pp. 29--37. Pergamon Press plc, 1988. Printed in the U.S.A. 0149-7634/88 $3.00 + .00

    Glucocorticoids and Hypothalamic Obesity

    BRUCE M. KING

    Department of Psychology, University of New Orleans, Lakefront, New Orleans, LA 70148

    Received 3 August 1987

    KING, B. M. Glucocorticoids and hypothalanlic obesity. NEUROSCI BIOBEHAV REV 12(1) 29-37, 1988.--Recent studies have demonstrated a role for adrenal glucocortico~d hormones in the hyperphagia and obesity which follow lesions of the ventromedial hypothalamus (VMH). Although VMH lesions elevate morning plasma corticosterone levels, it is concluded that this contributes little to the development of obesity. More importantly, animals with VMH lesions appear to be hyperresponsive to very low levels of circulating glucocorticoids. The overeating and obesity are both prevented and reversed by either complete adrenalectomy or complete hypophysectomy (i.e., resulting in plasma corticosterone levels of less than 1.0 p.g/dl) and restored by dosages of glucocorticoids that have no effect on feeding behavior and weight gain in nonlesioned adrenalectomized animals. Mineralocorticoid hormones have no effect on hypothalamic obesity. Judging by the time course of effects on feeding behavior in VMH-damaged mice of a single intracerebroventricular injection of a low dose of glucocorticoid, which has no effect when administered intraperitoneally, it is concluded that glucocorticoids exert their effect centrally in a permissive, rather than a regulatory, manner. Stimulation of the neighboring paraventricular nuclei (PVN) with norepinephrine or neuropeptide Y produces a rapid feeding response which is also abolished by adrenalectomy and restored with administration of glucocorticoids. However, it is unlikely that the PVN is the site at which glucocorticoids exert their effect in animals with VMH lesions, for PVN lesions or knife-cuts, or combination VMH-PVN lesions, also result in hyperphagia and obesity. It is concluded that adrenal glucocorticoid hormones exert their permissive effects on feeding behavior at brain sites other than the medial hypothalamus. The septo-hippocampal complex is suggested as a possible site.

    Ventromedial hypothalamus Paraventricular nuclei Feeding behavior Obesity Adrenal glands

    Pituitary Glucocorticoid hormones

    DAMAGE to the area of the basomedial hypothalamus re- sults in obesity in a variety of species [3, 12, 15]. Obesity in humans resulting from tumors or injury in this region was first described in 1840 [88] and later became known as Frrhlich's syndrome [44]. It was initially attributed to an endocrine imbalance due to impaired pituitary function, but this was questioned by several investigators who observed obesity in humans or animals with hypothalamic, but no di- rect pituitary, damage [5, 38, 109]. In one of the first experi- ments to use the stereotaxic instrument after it was modified for use with rats, Hetherington and Ranson [59] reported that lesions of the ventromedial hypothalamus (VMH) were most effective in producing obesity. The abnormal weight gains resulting from such lesions were generally attributed to a disinhibition of feeding behavior [118] and the role of the endocrine system was minimized.

    Later studies found that rats with VMH lesions gained more weight and/or fatty tissue than control animals during food restriction or pair-feeding [53, 54, 56], thus demonstrat- ing a primary (i.e., lesion-induced rather than feeding- induced) metabolic deficit. When VMH-lesioned rats were found to have greatly exaggerated levels of plasma insulin [52], even when pair-fed with controls [23, 48, 55], a hor- monal role in hypothalamic obesity was once again empha- sized. In fact, several investigators attributed VMH obesity almost entirely to exaggerated vagally-mediated insulin re- sponses [23, 66, 67, 96]. However, alterations in inter- mediary metabolism which enhance lipogenesis and lead to excessive fat accumulation had been demonstrated following VMH lesions even in a state of insulin deficiency [49]. In

    addition, animals with VMH lesions made diabetic by pan- createctomy or injection of alloxan or streptozotocin were found to gain more weight than nonlesioned animals during controlled insulin administration [43,127, 133]. These results suggested that insulin was not the only factor important in lipid deposition in the VMH-iesioned animal. Based on results with vagally-transected animals, King and Frohman [73] concluded that hyperinsulinemia could account for only 40 percent of the weight gain after VMH lesions.

    Adrenal glucocorticoids, which are also involved in carbohydrate metabolism, have long been known to be associated with various obesity syndromes. Hyperad- renocortical activity is associated with the hyperphagia and obesity in Cushing's syndrome [25], whereas adrenocortical insufficiency is associated with anorexia and weight loss in Addison's disease Ill2]. Elevating glucocorticoid levels in rodents has been found to produce abnormal weight gain and/or increased carcass fat, and increased gluconeogenesis and insulin production [62,86]. Genetically obese mice (ob/ob) and rats (fa/fa) and diabetic mice (db/db) have all been found to have elevated serum corticosterone levels [13, 20, 35, 57, 93, 94, 136], while adrenalectomy in these obese rodents slows or normalizes food intake and weight gain [11, 19, 100, 113, 114, 134].

    Despite this abundance of evidence with other models of obesity, glucocorticoid hormones have only recently been implicated in hypothalamic obesity. In fact, adrenalectomy appears to have an even more dramatic effect in animals with VMH lesions than in genetically obese animals, resulting in a complete reversal of the obesity rather than just a slowing of

    29

  • 30 KING

    the abnormal weight gain [18, 28, 30, 31, 71, 75]. This paper reviews the results of these studies and explores the possible mechanism(s) and site(s) at which glucocorticoids exert their effect.

    VMH LESIONS AND ADRENOCORTICAL ACTIVITY

    Nearly all vertebrate species display a circadian rhythm in adrenocortical activity. In rodents, which are nocturnal animals, plasma corticosterone levels reach their zenith within four hours of the transition to the dark phase of a 12 hour light/dark cycle and are at their nadir during the first few hours of the light phase of the cycle [129]. Rodents dis- play most of their physical activity and food and water in- gestion during the dark portion of the cycle, When main- tained under conditions of constant light or dark, corticoste- rone levels free-run (i.e., are not entrained to light-dark) with a period of about 24 hours unless the animals are kept on a restricted feeding schedule, in which case hormone levels become entrained around the presentation of food [76,92]. Plasma corticosterone levels rise during food presentation, or in anticipation of the presentation of food, and then rapidly decline during the course of a meal [21, 61, 129].

    Complete isolation of the mediobasal hypothalamus re- sults in disruption of the diurnal rhythm in corticosterone secretion [95] and inhibits the adrenocortical response to some, but not all stimuli [40, 50, 95]. Several early experi- ments reported that lesions of the mediobasal hypothalamus which included the median eminence impaired the pituitary- adrenocortical response to stress [16, 32, 45, 63, 87, 107]. There were no abnormal weight gains reported in any of these experiments, however, so it remained unknown whether typical hyperphagia-inducing VMH lesions affected pituitary-adrenocortical activity. A few subsequent experi- ments reported that obesity-inducing VMH lesions resulted in a significant reduction in adrenal weights [8, 9, 58, 130], but several others found no change [15, 17, 68, 85, 110, 119].

    The critical factor appears to be whether or not VMH lesions extend into the median eminence. Szent~gothai et al. [124] reported that damage to the median eminence that produced adrenal atrophy could impair the development of obesity in rats with medial hypothalamic lesions. King, Levine and Grossman [74] found that not only did rats with obesity-inducing VMH lesions which spared the median eminence have normal adrenal weights, but that the animals had significantly higher a.m. (i.e., first few hours of the light phase) plasma corticosterone levels. The adrenocortical re- sponse to shock-induced stress was normal. Several subse- quent experiments have also found that VMH lesions result in greater than normal a.m. plasma corticosterone levels [22, 72, 77, 99, 105]. Mice made obese by administration of gold thioglucose were reported not only to have markedly ele- vated corticosterone levels, but significantly larger adrenal weights as well [105].

    It is important to note that the lesion-induced elevations in plasma corticosterone are not observed throughout the day and night, but only in the first few hours of the light portion of the cycle (i.e., when levels in normal rats are at their nadir). VMH lesions appear to disrupt the diurnal rhythm in corticosterone levels [6,77], with glucocorticoid concentrations remaining relatively flat throughout the 24- hour cycle (i.e., intermediate between the zenith and nadir observed in normal animals). Dallman [26] has proposed that this is the result of the lesions interrupting fibers from the suprachiasmatic nuclei, lesions of which also abolish the cir-

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  • GLUCOCORTICOIDS AND HYPOTHALAMIC OBESITY 31

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    FIG. 2. Mean body weight (g-+SE) of 8 groups of female rats (n=6/group) with combinations of adrenalectomy (ADX) or sham-adrenalectomy (SADX) and ventromedial hypothalamic lesions (VMH) or sham lesions (SVMH). (Reproduced from Bruce, King, Phelps and Veitia ll8].)

    cadian rhythmicity of corticosterone in ad lib fed animals [1,91]. The role of the VMH in adrenocortical activity can not simply be inhibitory, however, for this does not adequately explain the less than normal p.m. corticosterone levels observed in VMH-lesioned rats [6,77].

    Unlike normal rats, or animals with suprachiasmatic le- sions, rats with VMH lesions on a restricted feeding schedule do not show a phase shift in activity or peak corti- costerone levels to the presentation of food [65,77]. Nor do they display the usual rapid decline in serum corticosterone levels with consumption of a meal [22]. It appears, therefore, that the VMH is the anatomical locus which mediates the circadian response to food synchronization [77].

    The critical question, of course, is just how important is the lesion-induced increase in a.m. plasma corticosterone levels to the hyperphagia and/or weight gain? King et al. [72] found the corticosterone elevations to be equally great in food-restricted (to normal body weight) and ad lib fed VMH rats on postoperative days 2 through 25 (see Fig. 1). It was concluded that the elevation in plasma glucocorticoids ob- served in VMH rats was a primary effect of the lesion and was independent of food intake or initial weight gain. There is some evidence that morning corticosterone levels return to normal after many weeks of food ad lib [74]. Obesity- inducing parasagittal knife cuts alongside the paraventricular nucleus have recently been reported to cause a decrease, rather than an increase, in corticosterone levels [121]. Ad- ministration of adrenocorticotropin (ACTH) reversed the ad-

    renal deficit, but had no effect on food intake or weight gain [123]. Plasma concentrations and diurnal rhythmicity of cor- ticosterone have been reported to be normal in genetically obese rats [135]. It is concluded, therefore, that while the increase in a.m. corticosterone levels after VMH lesions may promote gluconeogenesis and abnormal weight gain, it is not essential for the development of obesity.

    VMH LESIONS AND ADRENALECTOMY

    Until recently, there had been very little attention de- voted to the effects of adrenalectomy on ventromediai hypo- thalamic obesity. In 1965, Bernardis and Skelton [8] reported that adrenalectomy had little or no effect on food intake and weight gain in weanling rats with VMH lesions. York and Bray [ 132] later claimed that adrenalectomy also had no effect in adult rats with VMH lesions, but the weight gains were uncommonly low for animals with hypothalamic lesions (about 85 g/42 days). Although a subsequent experiment by Mook, Fisher and Durr [90] reported that adrenalectomy partially suppressed abnormal weight gain in rats with VMH lesions, it was generally believed that the presence of adrenal corticosteroids was not essential for the development of hy- pothalamic obesity [1 I, 14].

    In the early 1980's, however, two independent series of experiments demonstrated that VMH obesity was critically dependent on adrenal glucocorticoids. Debons and his co- workers [28, 30, 31] reported that adrenalectomy completely

  • 32 KING

    prevented the development of obesity in mice treated with gold thioglucose, while King and his colleagues [18, 71, 75] found that removal of the adrenals completely prevented and reversed hyperphagia and obesity in rats given electrolytic VMH lesions (see Fig. 2). Adrenalectomy did not affect other motivated behaviors such as lever pressing for electri- cal stimulation of the brain [75]. Both groups of researchers verified completeness of adrenalectomy by directly measur- ing plasma levels of corticosterone. Adrenalectomies were considered to be complete by King eta / . [71,75], for exam- ple, only when stress-induced corticosterone levels were less than 1.0/zg/dl of plasma. Moderate weight gains were ob- served when corticosterone levels exceeded this criteria (see next section). Previous studies utilized only indirect verifi- cation tests, but residual adrenal tissue or accessory adrenal glands are common in rodents [111], which may account for the weight gains that were observed in these early experi- ments.

    Hyperphagia and rapid weight gains were restored in both adrenalectomized gold thioglucose-treated mice and ad- renalectomized electrolytic lesioned rats by doses ofcortisol or corticosterone that did not affect food intake or body weight in normal control animals [18, 28, 30, 71]. Mineralocorticoids, which have been found to elevate body weight and food intake in nonlesioned adrenalectomized rats [33], did not restore the overeating and obesity in VMH animals with adrenalectomy ([30]; Lynn Devenport, per- sonal communicaton). A previous study reported that ad- renal demedullation also did not affect the development of hypothalamic obesity [90]. Thus, it was established that it was the glucocorticoids that were critical for the manifesta- tion of obesity. A recent study by Debons et al. [31] demon- strated that a single intracerebroventricular injection of cor- tisone, corticosterone, or dexamethasone, at a dosage so low that it had no effect when administered intraperitoneally, restored the hyperphagia in adrenalectomized gold thioglu- cose-treated mice (see Fig. 3).

    In addition to elevated levels of corticosterone, rats and mice with VMH lesions are also hyperinsulinemic [73], and the plasma concentrations of the two hormones were found to be related in lesioned animals fed ad lib [72]. Adrenalec- tomy not only prevented the development of hyperphagia and obesity in VMH-lesioned rats, but hyperinsulinemia as well [71]. The postabsorptive, but not basal, hyperin- sulinemia was restored by administration of corticosterone. Debons et al. [29] found that the resistence of the VMH to gold thioglucose-induced necrosis caused by alloxan- induced diabetes was abolished by adrenalectomy, and then restored again by administration of cortisone. These studies suggest that the hormones involved in carbohydrate metabo- lism interact to influence the effects of lesions on food intake and weight gain.

    It should be noted that all of the studies by the Debons and King groups used a standard high-carbohydrate diet. It has recently been reported, however, that adrenalectomy in ob/ob mice completely eliminates abnormal energy gains on a high-carbohydrate, but not a high-fat, diet [108]. The early study by Mook, Fisher and Durr [90], in which moderate weight gains in VMH-adrenalectomized rats were observed, employed a high-fat diet. The criterion for completeness of adrenalectomy in both of these studies, however, was less stringent than that employed by the Debons and King groups. Further work is needed, therefore, to determine whether the effects of adrenalectomy on hypothalamic obe- sity are diet dependent.

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  • GLUCOCORTICOIDS AND HYPOTHALAMIC OBESITY 33

    results are due to a species difference, because adrenalec- tomy produces the same effect on VMH lesion obesity in both rats and mice [18, 28, 30, 71]. Instead, there appears to be greater difficulty in producing hypophysectomies (using the criterion of plasma corticosterone levels of less than 1.0 /zg/dl) in rats than mice. Many of the rat st,dies obtained their hypophysectomized animals from commercial suppliers [24, 54, 55, 78, 132], but King and Smith [75] found even these surgeries to be incomplete by the criterion previously used for adrenalectomy. Earlier rat studies attempted to verify the completeness of their hypophysectomies by anatomic inspection of the sella [24, 54, 55, 60, 70] and/or measurement of body weight change [24, 54, 55, 70], but it has been found that stress-induced plasma ACTH levels often return to 80% of normal by eight weeks after surgery even when residual pituitary tissue cannot be found by visual inspection of the sella [89].

    GLUCOCORTICOIDS: A CRITICAL MINIMAL LEVEL REQUIRED FOR DEVELOPMENT OF OBESITY

    King and Smith [75] found that their hypophysectomized- VMH lesioned female rats obtained a moderate degree of obesity (weight change of +83.9 g/20 days compared to -12.3 g for hypophysectomized-sham lesioned animals) even though mean stress-induced plasma corticosterone levels were only 1.7/zg/dl. VMH-lesioned animals with ad- renalectomies resulting in plasma corticosterone levels of less than 1.0 p.g/dl failed to gain more weight than sham operated controls (27.0 g vs. 38.6 g, respectively). Whenever adrenalectomies were found to be incomplete (eight animals with mean stress-induced corticosterone levels of 2.7/~g/dl), a moderate obesity resulted (+97.3 g/20 days) similar to that found with hypophysectomized-VMH lesioned animals. Thus, except for occasional increases in the first few days after lesions [75], adrenalectomized- or hypophysectomized- VMH lesioned animals have never displayed abnormal weight gains when plasma corticosterone levels were less than 1.0/.~g/dl [18, 27, 28, 30, 31, 71, 75]. Whenever cortico- sterone levels have just barely exceeded 1.0/zg/dl plasma, however, the result has been obesity, albeit to a lesser de- gree than in lesioned animals with sham adrenalectomies or sham hypophysectomies.

    Akana, Cascio, Shinsako and Dallman [2] found that the body weights of male adrenalectomized rats (no lesions), which were considerably lower than unoperated controls, were partially restored by a subcutaneous corticosterone implant which clamped plasma corticosterone at relatively fixed levels. A significant increase in food intake and body weight was noted when mean plasma corticosterone levels were as low as 1.8 p.g/dl. Body weight was seldom restored to normal, however, at any dosage of corticosterone. This suggests the possibility that VMH-lesioned animals, which show abnormal weight gains when mean stress-induced cor- ticosterone levels are as low as 1.7 /xg/dl plasma [75], are hyperresponsive to glucocorticoids as has been found for genetically obese rodents [41,42]. A single intracerebroven- tricular injection of glucocorticoids, which has only a slight effect on food intake in adrenalectomized control mice, produces hyperphagia lasting several days in adrenalec- tomized gold thioglucose-treated mice [31]. With complete adrenalectomy (plasma corticosterone less than 1.0/~g/dl), gold thioglucose mice not only fail to maintain normal body weight, but become anorexic and die [28]. It appears, there- fore, that there is a critical level of plasma corticosterone in

    the vicinity of 1.0 /zg/dl, below which overeating and the development of obesity are prevented, and above which the lesioned animals are supersensitive to circulating glucocor- ticoids.

    MECHANISM(S) OF ACTION

    A role for adrenal glucocorticoid hormones in hypotha- lamic obesity is now firmly established. The manner by which these hormones influence feeding and/or the devel- opment of obesity, however, is less clear. Several possibilities will be discussed.

    One possibility is that the loss and restoration of glucocorticoids might influence hypothalamic obesity by their effects on intermediary metabolism (i.e., peripherally). Glucocorticoids promote gluconeogenesis and hepatic lipogenesis, and thus adrenalectomy leads to a reduction in plasma glucose levels. The effects of adrenalectomy are par- ticularly marked in nutritionally stressed animals [7,69] and Dallman [26] has proposed that the VMH-iesioned animal with its abnormal feeding pattern can be viewed as nutri- tionally stressed. Adrenalectomy in animals with VMH le- sions does not merely abolish overeating and weight gain, but often causes a subnormal insulin response to glucose [71], prolonged anorexia and subsequent death [28]. Recent evidence suggests, however, that glucocorticoids primarily influence feeding behavior and subsequent weight gain by their effects in the brain rather than peripherally.

    A second possibility is that the ventromedial hypothala- mus influences food intake and/or weight gain via direct ef- fects on adrenocortical secretions. A direct neural pathway from the adrenal gland to the ventromedial nucleus was first suggested by Halfisz and Szent~gothai in 1959 [51]. Unilat- eral adrenalectomy caused enlargement of the cell nuclei in the contralateral VMN and shrinkage in the ipsilateral nu- clei. A later autoradiography study revealed a much higher concentration of tritiated ieucine into the contralateral VMN than in the ipsilateral side following unilateral adrenalectomy [46]. When the compensatory adrenal growth which follows unilateral adrenalectomy was found to be prevented by spi- nal hemisection [37] or unilateral VMH lesions ipsilateral, but not contralateral, to the side of adrenalectomy [36], a neural loop from the adrenal gland through the hypothalamus to the other adrenal gland was suggested. The most effective lesions for prevention of compensatory adrenal growth were in the dorsal lateral part of the VMH [36] and recent studies have reported similar results with parasagittal knife cuts alongside the paraventricular nucleus [121,122]. It was suggested that the hypothalamic damage interfered either with the ventral noradrenergic bundle [36] or corticotropin- releasing factor (CRF) axons as they exit the PVN [123]. It must be emphasized, however, that while there may be neural pathways through the hypothalamus involved in com- pensatory adrenal growth, as of yet there is no evidence that this pathway is involved in feeding behavior or body weight regulation. In fact, it has recently been found that the im- paired adrenal growth caused by obesity-inducing parasagit- tal knife cuts alongside the paraventricular nucleus could be reversed by ACTH administration, but that the ACTH had no effect on body weight gain or food intake [123]. Thus, there is an abundance of evidence (see previous section on adrenocortical activity) that hypothalamic obesity is not mediated simply via circulating glucocorticoid levels.

    Work by Leibowitz and her colleagues suggests a third possibility, i.e., that glucocorticoids have a direct effect on

  • 34 KING

    feeding behavior by affecting cq-noradrenergic receptors in the paraventricular nucleus (PVN) of the hypothalamus. The PVN is the major site of corticotropin releasing factor neurons which project to the median eminence [120,126] and is a projection site of noradrenergic and adrenergic afferents from the brainstem [101]. The PVN is the most effective site for acute noradrenergic induced feeding [80] and the in- creased intake is mainly in the form of carbohydrates [125] (a recent study, however, found that marked obesity resulted when NE was chronically infused into the VMH, but not the PVN [103]). There is a periodicity in the effectiveness of PVN-injected norepinephrine on feeding behavior which corresponds to the diurnal rhythm in corticosterone [10].

    Similar to VMH lesion-induced obesity, feeding induced by noradrenergic stimulation of the PVN is abolished by complete adrenalectomy and restored by subcutaneous ad- ministration of corticosterone, but not by deoxycortico- sterone [83]. In animals with incomplete adrenalectomy, the strength of the feeding response to norepinephrine was posi- tively correlated with plasma levels of corticosterone. More recently, it has been reported that injection of neuropeptide Y into the PVN, VMH, or lateral hypothalamus elicits an even stronger feeding response than PVN injections of nor- epinephrine [115], and that this too is suppressed by ad- renalectomy and restored by subcutaneous corticosterone [116]. Acute PVN injections of both norepinephrine and neuropeptide Y cause a dose related release of corticoste- rone [34,81], but only norepinephrine increased glucose levels (the effects on insulin have not yet been studied, but noradrenergic stimulation of the adjacent lateral hypothala- mus is known to enhance insulin secretion [102]).

    Since PVN stimulation causes an increase in both corti- costerone and food intake, does this mean that glucocor- ticoids have a direct regulatory role in feeding behavior? Not necessarily, for lesions of the PVN or parasagittal knife cuts next to it both markedly suppress plasma corticosterone levels [104, 121, 122], but paradoxically cause overeating just as does PVN stimulation, leading to obesity [4,82]. Adminis- tration of ACTH restores corticosterone levels without further affecting food intake [123], while adrenalectomy in these animals with already suppressed plasma corticosterone levels abolishes the overeating and obesity [47]. It is more likely, therefore, that some minimal level of corticosterone is required to obtain an overeating response after either stimu- lation or lesion. It is thus likely that glucocorticoids exert their effect in a permissive manner. By permissive, it is meant that rather than directly inducing a feeding response,

    glucocorticoids exert their effect tonically by altering recep- tor responsivity to another hormone(s) or neurotransmit- ter(s) (see [64]). The study by Debons et al. [31], you recall, demonstrated that just one intracerebroventricular microin- jection of glucocorticoid restored overeating for several days in adrenalectomized gold thioglucose mice (and that the ef- fect often did not begin until after several days). Glucocor- ticoids are known to act permissively with catecholamines to promote gluconeogenesis and glycogenolysis in the river [39,131].

    The neuroanatomical site at which glucocorticoids exert their permissive effect in animals with VMH lesions has yet to be determined. It is unlikely that it is the paraventricular nucleus, for a recent study by Sims and Cox [106] found that large bilateral lesions of both the VMH and PVN resulted in marked obesity. If glucocorticoids exerted their effect at the PVN, then elimination of the PVN should have had the same effect on VHM obesity as adrenalectomy. It is possible that the critical site is not even in the hypothalamus. A recent study by Reul and de Kloet [98] found two receptor systems for corticosterone: mineralocorticoid-like receptors that are restricted predominantly to the lateral septum and hippocam- pus, and glucocorticoid receptors in the lateral septum, nu- cleus tractus solitarii, central amygdala, PVN, locus coeruleus and raphe. Mineralocorticoid-like receptors were nearly fully occupied by endogenous ligand when plasma corticosterone levels were at their morning trough levels (1.4 /zg/dl) and after a subcutaneous dose of 1 /zg corticoste- rone/100 g body weight. Glucocorticoid receptors, on the other hand, were only 50% occupied after a subcutaneous dose of 50-100/zg corticosterone/100 g body weight (result- ing in plasma corticosterone levels of 25/zg/100 ml), suggest- ing that these receptors become occupied only when plasma corticosterone levels are at their zenith at night or after stress. Reul and de Kloet concluded that corticosterone's action via mineralocorticoid-like receptors "'may be in- volved in a tonic (permissive) influence on brain function with the septo-hippocampal complex as the primary target." Presumably, the extremely low levels of plasma corticoste- rone (1.0-3.0 /zg/dl) which allowed a moderate obesity in VMH-lesioned rats with incomplete adrenalectomies or hypophysectomies [74] would exert their effect primarily via the mineralocorticoid-like receptors. Investigators might be advised, therefore, to start looking at extra-hypothalamic sites (the lateral septum and hippocampus in particular) as the possible locus at which glucocorticoids exert their per- missive.effects.

    REFERENCES

    I. Abe, K., J. Kroning, M. A. Greer and V. Critchlow. Effects of destruction of the suprachiasmatic nuclei on the circadian rhythms in plasma corticosterone, body temperature, feeding and plasma thyrotropin. Neuroendocrintdogy 29: 119-131, 1979.

    2. Akana, S. F., C. S. Cascio, J. Shinsako and M. F. Dallman. Corticosterone: narrow range required for normal body and thymus weight and ACTH. Am J Physiol 249: R527-R532, 1985.

    3. Anand, B. K., S. Dua and K. Shoenberg. Hypothalamic con- trol of food intake in cats and monkeys. J Physiol (Lond) 127: 143-152, 1955.

    4. Aravich, P. F. and A. Sclafani. Paraventricular hypothalamic lesions and medial hypothalamic knife cuts produce similar hyperphagia syndromes. Behav Neurosci 97: 970-983, 1983.

    5. Bailey, P. and F. Bremer. Experimental diabetes insipidus. Arch Intern Med 28: 773-803, 1921.

    6. Bellinger, L. L., L. L. Bernardis and V. E. Mendel. Effect of ventromedial and dorsomedial hypothalamic lesions on circa- dian corticosterone rhythms. Neuroendocrinology 22:216--225, 1976.

    7. Berdanier, C. D., R. Wurdeman and R. B. Tobin. Further studies on the role of adrenal hormones in the responses of rats to meal feeding. J Nutr 106: 1791-1800, 1976.

    8. Bernardis, L. L. and F. R. Skelton. Failure to demonstrate a functional connection between the adrenal gland and ven- tromedial hypothalamic nuclei with regard to control of food intake. Experientia 21: 36-37, 1965.

    9. Bernardis, L. L. and F. R. Skelton. Growth and obesity follow- ing ventromedial hypothalamic lesions placed in female rats at four different ages. Neuroendocrinology 1: 265-275, 1965/1966.

  • GLUCOCORTICOIDS AND HYPOTHALAMIC OBESITY 35

    10. Bhakthavatsalam, P. and S. F. Leibowitz. t~2-Noradrenergic feeding rhythm in paraventricular nucleus: relation to cortico- sterone. Am J Physiol 250: R83-R88, 1986.

    11. Bray, G. A. Endocrine factors in the modulation of food intake. Proc Nutr Soc 37: 301-310, 1978.

    12. Bray, G. A. and T. F. Gallagher. Manifestations of hypotha- lamic obesity in man: a comprehensive investigation of eight patients and a review of the literature. Medicine 54: 301-330, 1975.

    13. Bray, G. A. and D. A. York. Genetically transmitted obesity in rodents. Physiol Behav 51: 598-646, 1971.

    14. Bray, G. A. and D. A. York. Hypothalamic and genetic obesity in experimental animals: an autonomic and endocrine hypoth- esis. Physiol Rev 59: 71%809, 1979.

    15. Brobeck, J. R., J. Tepperman and C. N. H. Long. Experi- mental hypothalamic hyperphagia in the albino rat. Yale J Biol Med 15: 831-853, 1943.

    16. Brodish, A. Diffuse hypothalamic system for the regulation of ACTH secretion. Endocrinology 73: 727-735, 1963,

    17. Brooks, C. McC. and E. F. Lambert. A study of the effect of limitation of food intake and the method of feeding on the rate of weight gain during hypothalamic obesity in the albino rat. Am J Physio/ 147: 695-707, 1946.

    18. Bruce, B. K., B. M. King, G. R. Phelps and M. C. Veitia. Effects of adrenalectomy and corticosterone administration on hypothalamic obesity in rats. Am J Physiol 243: EI52-EI57, 1982.

    19. Castonguay, T. C., M. F. Dallman and J. S. Stern. Corticoste- tone prevents body weight loss and diminished fat appetite following adrenalectomy. Ntttr Behav 2:115-125, 1984.

    20. Coleman, D. L. and D. L. Burkhart. Plasma corticosterone concentrations in diabetic (db) mice. Diabetologia 13: 25-26, 1977.

    21. Coover, G. D., B. R. Sutton and J. P. Heybach. Conditioning decreases in plasma corticosterone level in rats by pairing stimuli with daily feedings. J Comp Physio/Ps.vchol 97: 716-- 726, 1977.

    22. Coover, G. D., S. Welle and R. P. Hart. Effects of eating, meal cues and ventromedial hypothalamic lesions on serum cortico- sterone, glucose and free fatty acid concentrations. Physiol Behav 25: 641-651, 1980.

    23. Cox, J. E. and T. L. Powley. Intragastric pair feeding fails to prevent VMH obesity or hyperinsulinemia. Am J Physiol 240: E556--E572, 1981.

    24. Cox, V. C., J. W. Kakolewski and E. S. Valenstein. Effects of ventromedial hypothalamic damage in hypophysectomized rats. J Comp Physiol Psychol 65: 145-148, 1968.

    25. Cushing, H. The basophil adenomas of the pituitary body and their clinical manifestations (pituitary basophilism). Bull Johns Hopkins Hosp 50: 137-195, 1932.

    26. Dallman, M. F. Viewing the ventromedial hypothalamus from the adrenal gland. Am J Physio/246: RI-RI2, 1984.

    27. Debons, A. F., C. Das, B. Fuhr and E. Siclari. Inhibition by hypophysectomy of the hyperphagia and obesity following gold thioglucose. Physiol Behav 29: 695-699, 1982.

    28. Debons, A. F., K. C. Das, B. Fuhr and E. Siclair. Anorexia after adrenalectomy in gold thioglucose-treated obese mice, Endocrinology 112:1847-1851, 1983.

    29. Debons, A. F., 1. Krimsky, A. From and H. Pattinian, Diabetes-induced resistence of ventromedial hypothalamus to damage by gold thioglucose: reversal by adrenalectomy. Endo- crinology 95: 1636-.1641, 1974.

    30. Debons, A, F., E. Siclari, K. C. Das and B. Fuhr. Gold thio- glucose-induced hypothalamic damage, hyperphagia and obe- sity: dependence on the adrenal gland. Endot:rinology 110: 2024--2029, 1982.

    31. Debons, A. F., L. D. Zurek, C. S. Tse and S. Abrahamsen. Central nervous system control of hyperphagia in hypotha- lamic obesity: dependence on adrenal glucocorticoids. Endo- crinology 118:1678-- 168 I, 1986.

    32. DeGroot, J. and G. W. Harris. Hypothalamic control of the anterior pituitary gland and blood lymphocytes. J Physiol (Lond) 111: 335-346, 1950.

    33. Devenport, L. D., A. Torres and C. G. Murray. Effects of aldosterone and deoxycorticosterone on food intake and body weight. Behav Neurosci 97: 667-669, 1983.

    34. Diaz, S., D. Eidelmann, L. Spencer and S. F. Leibowitz. Noradrenergic stimulation of the paraventricular nucleus causes a release of corticosterone. Paper presented at the 57th annual meeting of the Eastern Psychological Association, New York, New York, April, 1986.

    35. Dubuc, P. Basal corticosterone levels of young ob/ob mice. Horm Metab Res 9: 95-97, 1977.

    36. Engeland, W. C. and M. F. Dallman. Compensatory adrenal growth is neurally mediated. Neuroendocrinology 19: 352-362, 1975.

    37. Engelend, W. C. and M. F. Dallman, Neural mediation of compensatory adrenal growth. Endocrinology 99: 165%1662, 1976.

    38. Erdheim, J. Ober Hypophysenganggeschwulste und Hirnchol- estacatome S.-B. Akad Wiss Wien 113: 537-726, 1904.

    39. Exton, J. H. Regulation ofgluconeogenesis by glucocorticoids. In: Ghwocorticoid Hormone Action (Monographs on Endocri- m~/ogy, Vo/ 12), edited by J. D. Baxter and G. G. Rousseau. New York: Springer Verlag, 1979, pp. 535-546.

    40. Feldman, S., N. Conforti, I. Chowers and J. M. Davidson. Pituitary-adrenal activation in rats with medial basal hypotha- tamic islands. Acta Endocrim~l 63: 405-414, 1970.

    41. Freedman, M. R., T. W. Castonguay and J. S. Stern. Effect of adrenalectomy and corticosterone replacement on meal pat- terns of Zucker rats. Am J Physiol 249: R584-R594, 1985.

    42. Freedman, M. R., B. A. Horwitz and J. S. Stern. Effect of adrenalectomy and glucocorticoid replacement on develop- ment of obesity. Am J Physiol 250: R595-R607, 1986.

    43. Friedman, M. I. Effects of alloxan diabetes on hypothalamic hyperphagia and obesity. Am J Physio/222: 174--178, 1972.

    44. Frrlich, A. Dr. Alfred Froehlich stellt einen Fall von Tumor der Hypophyse ohne Akromegalie vor. Wein KI#l Rdsch 15: 883, 1902.

    45. Ganong, W. F., A. M. Nolan, A. Dowdy and J. A. Luetscher. The effect of hypothalamic lesions on adrenal secretion of cor- tisol, corticosterone, l l-deoxycortisol and aldosterone. Endo- c'rinology 68: 168-171, 1961.

    46. Gerendai, I., J. Kiss, J. Moln~ir and B. Hal~isz. Further data on the existence of a neural pathway from the adrenal gland to the hypothalamus. Cell Tissue Res 153: 55%564, 1974.

    47. Gold, R. M. The effects of obesifying hypothalamic knife cuts on adrenal growth and secretion. Paper presented at the 57th annual meeting of the Eastern Psychological Association, New York, New York, April, 1986.

    48. Goldman, J. K., L, L. Bernardis and L. A. Frohman. F~od intake in hypothalamic obesity. Am J Physio/227: 88--91, 1974.

    49. Goldman, J. K., J. D. Schnatz, L. L. Bernardis and L. A. Frohman. Effects of ventromedial hypothalamic destruction in rats with preexisting streptozotocin-induced diabetes. Metab- olism 21: 132-136, 1972.

    50. Hal~isz, B., M. A. Slusher and R. A. Gorski. Adrenocortico- trophic hormone secretion in rats after partial or total deaffer- entation of the medial basal hypothalamus. Neuroendocrinol- ogy 2: 43-55, 1967.

    51. Hal~isz, B. and J. Szent~igothai. Histologischer Beweiseiner nerv6sen Signalfibermittlung yon der Nebennierenrinde zum Hypothalamus. Z ZellfiJrsch Mikroski Anat 50: 297-306, 1959.

    52. Hales, C. N. and G. C. Kennedy. Plasma glucose, non- esterified fatty acid and insulin concentrations in hypothala- mic-hyperphagic rats. Biochem J 90: 620-624, 1964.

    53. Han, P. W. Hypothalamic obesity in rats without hyperphagia. Trans NY Acad Sci 30: 22%243, 1967. t,

    54. Han, P. W. Obesity in force-fed, hypophysectomized rats bear- ing hypothalamic lesions. Proc Sot" Exp Biol Med 127: 1057- 1060, 1968.

  • 36 K ING

    55. Han, P. W. and L. A. Frohman. Hyperinsulinemia in tube-fed hypophysectomized rats bearing hypothalamic lesions. Am J Physiol 219: 1632-1636, 1970.

    56. Han, P. W. and A.-C. Liu. Obesity and impaired growth of rats force fed 40 days after hypothalamic lesions. Am J Physiol 211: 22%231, 1966.

    57. Herberg, L. and H, K. Kley. Adrenal function and the effect of a high fat diet on C57BL/6J and C57BL/6J ob/ob mice. Horm Metab Res 7: 410--415, 1975.

    58. Herrero, S. Radio-frequency current and direct-current lesions in ventromedial hypothalamus. Ant J Physiol 217: 403-410, 1969.

    59. Hetherington, A. W. and S. W. Ranson. The relation of various hypothalamic lesions to adiposity in the rat. J Comp Neurol 76: 475-499, 1942.

    60. Hetherington, A. W. and S. W. Ranson. Effect of early hy- pophysectomy on hypothalamic obesity. Endocrinology 31: 30-34, 1942.

    61. Heybach, J. P. and J. Vernikos-Danellis. Inhibition of ad- renocorticotrophin secretion during deprivation-induced eating and drinking in rats. Neuroendocrinology 28: 32%338, 1979.

    62. Hollifield, G. and W. Parson. Body composition and in vitro synthesis of lipids by adipose tissue of II-dehydro- corticosterone-treated mice. Am J Physiol 197: 105-107, 1959.

    63. Hume, D. M. and D. H. Nelson. Effect of hypothalamic lesions on blood ACTH levels and 17-hydroxycorticosteroid secretion following trauma in the dog. J Clin Endocrinol Metab 15: 83% 840, 1955.

    64. Ingle, D. J. Permissibility of hormone action. A review. Acta Endocrinol (Copenh) 12: 172, 1954.

    65. Inoue, S. I. Ventromedial hypothalamic lesions eliminate anticipatory activities of restricted daily feeding schedules in the rat. Brain Res 250: 183-187, 1982.

    66. Inoue, S. and G. A. Bray. An autonomic hypothesis for hypo- thalamic obesity. Lift, Sci 25: 561-566, 1979.

    67. Jenrenaud, B. Hyperinsulinemia in obesity syndromes: its metabolic consequences and possible etiology. Metabolism 27: 1881-1892, 1978.

    68. Joseph, S. A. and K. M. Knigge. Effects of VMH lesions in adult and newborn guinea pigs. Neuroendacrinology 3: 30% 331, 1968.

    69. Kaul, L. and C D. Berdanier. Effect of pancreatectomy or adrenalectomy on the responses of rats to meal feeding. J Ntttr 105: 1176--1185, 1975.

    70. Kennedy, G. C. and D. M. Parrott. The effect of increased appetite and of insulin on growth in the hypophysectomized rat. J Endocrinol 17: 161-166, 1958.

    71. King, B. M., A. R. Banta, G. N. Tharel, B. K. Bruce and L. A. Frohman. Hypothalamic hyperinsulinemia and obesity: role of adrenal glucocorticoids. Am J Physiol 245: E 194-E 199, 1983.

    72. King, B. M., C. B. Calvert, K. R. Esquerrr, J. H. Kaufman and L. A. Frohman. Relationship between plasma corticoste- rone and insulin levels in rats with ventromedial hypothalamic lesions. Physiol Behav 32: 991-994, 1984.

    73. King, B. M. and L. A. Frohman. The role of vagally-mediated hyperinsulinemia in hypothalamic obesity. Neurosci Biobehat' Rev 6: 205-214, 1982.

    74. King, B. M., S. Levine and S. P. Grossman. Pituitary- adrenocortical response to shock-induced stress in normal and hypothalamic hyperphagic rats. Physiol Behav 22: 753-757, 1979.

    75. King, B. M. and R, L. Smith. Hypothalamic obesity after hy- pophysectomy or adrenalectomy: dependence on corticoste- rone. Am J Physiol 249: R522-R526, 1985.

    76. Kreiger, D. T. Regulation of circadian periodicity of plasma corticosteroid concentrations and of body temperature by time of food presentation. In: Biological Rhythms attd Their Central Mechanisms, edited by M. Suda, O. Hayaishi and H. Nakagawa. Amsterdam: Elsevier/North-Holland, 1979, pp. 247-255.

    77. Kreiger, D. T. Ventromedial hypothalamic lesions abolish food-shifted circadian adrenal and temperature rhythmicity. Endocrinology 106: 649-654, 1980.

    78, Kurtz, R. G., P. Rozin and P. Teitelbaum. Ventromedial hypo- thalamic hyperphagia in the hypophysectomized weanling rat. J Comp Physiol Psychol 80: 1%25, 1972.

    79. LaQuer, G. L., S. M. McCann, L. H. Schreiner, E. Rosem- berg, D. McK. Rioch and E. Anderson. Alterations of adrenal cortical and ovarian activity following hypothalamic lesions. Endocrinology 57: 44-54, 1955.

    80. Leibowitz, S. F. Paraventricular nucleus: A primary site mediating adrenergic stimulation of feeding and drinking. Pharmacol Biochem Behav 8: 163-175, 1978.

    81. Leibowitz, S. F., S. Diaz and L. Spencer. Adrenergic and neuropeptide Y systems in the hypothalamic paraventricular nucleus affect circulating levels of corticosterone and glucose. Soc Neurosci Abstr 12: 782, 1986.

    82. Leibowitz, S. F., N. J. Hammer and K. Chang. Hypothalamic paraventricular nucleus lesions produce overeating and obesity in the rat. Physiol Behav 27: 1031-1040, 1981.

    83. Leibowitz, S. F., C. R. Roland, L. Hor and V. Squillari. Noradrenergic feeding elicited via the paraventricular nucleus is dependent upon circulating corticosterone. Physiol Behav 32: 856-864, 1984.

    84. Martin, R. J., P. J. Wangsness and J. H. Gahagan. Diurnal changes in serum metabolites and hormones in lean and obese Zucker rats. Horm Metab Res 10: 187-192, 1978.

    85. Mayer, J., R. G. French, C. F. Zighera and R. J. Barrnett. Hypothalamic obesity in the mouse. Production, description and metabolic characteristics. Am J Physh~l 182: 75-82, 1955.

    86. Mayer, J., C. Zomzely and J. Furth. Body composition and energetics in obesity induced in mice by adrenotropic tumors. Science 123: 184--185, 1956.

    87. McCann, S. M. Effect of hypothalamic lesions on the adrenal cortical response to stress in the rat. Am J Physiol 175: 13-20, 1953.

    88. Mohr, I~. Hypertrophie der Hypophyse cerebri und dadurch bedingter Druck auf die Hoehengrundflaeche insbesondere auf die Sehnerven, dass Chiasma derselben, und dem laengseitigen Hoehenschenkel. Wochenschr Ges Heilkunde 6: 565-574, 1840.

    89. Moldow, R. and S. W. Yalow. Extrhypophysial distribution of corticotropin as a function of brain size. Proc Natl Acad Sc'i USA 75: 994-998, 1978.

    90. Mook, D. G., J. C. Fisher and J. C. Durr. Some endocrine influences on hypothalamic hyperphagia. Horm Behav 6: 65-79, 1975.

    91. Moore, R. Y. and V. B. Eichler. Loss of a circadian adrenal corticosterone rhythm following suprachiasmatic lesions in the rat. Brain Res 42: 201-206, 1972.

    92. Morimoto, Y. and Y. Yamamura. Regulation of circadian ad- renocortical periodicities and of eating fasting cycles in rats under various lighting conditions. In: Biological Rhythms attd Their Central Mechanisms. edited by M. Suda, O. Hayaishi and H. Nakagawa. Amsterdam: Elsevier/North-Holland, 1979, pp. 178--188.

    93. Naeser, P. Function of the adrenal cortex in obese- hypothalamic mice (gene symbol ob). Diabetologia 10: 44% 453, 1974.

    94. Naeser, P. Adrenal function in the diabetic mutant mouse (gene symbol dbm). Acta Physiol Scand 98: 395-399, 1976.

    95. Palka, Y., D. Coyer and V. Critchlow. Effects of isolation of medial basal hypothalamus on pituitary-adrenal and pituitary- ovarian functions. Neuroendocrinology 5: 333-349, 1969.

    96. Powley, T. L. The ventromedial hypothalamic syndrome, sa- tiety, and a cephalic phase hypothesis. Psychol Rev 84: 8%126, 1977.

    97. Redding, T. W., C. Y. Bowers and A. V. Schally. Effects of hypophysectomy on hypothalamic obesity in CBA mice. Proc Soc Exp Biol Med 121: 726-729, 1966.

  • GLUCOCORTICOIDS AND HYPOTHALAMIC OBESITY 37

    98. Reul, J. M. H. M. and E. R. de Kloet. Two receptor systems for corticosterone in rat brain: microdistribution and differen- tial occupation. Endocrinology 117:2505-2511, 1985.

    99. Saito, M. and G. A. Bray. Diurnal rhythm for corticosterone in obese (ob/ob) diabetes (db/db) and gold-thioglucose-induced obesity in mice. Endocrinology 113: 2181-2185, 1983.

    100. Saito, M. and G. A. Bray. Adrenalectomy and food restriction in the genetically obese (ob/ob) mouse. Am J Physiol 246: R20--R25, 1984.

    101. Sawchenko, P. E. and L. W. Swanson. The organization of noradrenergic projections from the brainstem to the paraven- tricular and supraoptic nuclei in the art. Brain Res Rev 4: 275- 325, 1982.

    102. Shimazu, T. Central nervous system regulation of liver and adipose tissue metabolism. Diabetologia 20: 343-356, 1981.

    103. Shimazu, T., M. Noma and M. Saito. Chronic infusion of nor- epinephrine into the ventromedial hypothalamus induces obe- sity in rats. Brain Res 269: 215-223, 1986.

    104. Shor-Posner, G., A. Azar and S. F. Leibowitz. Electrolytic paraventricular nucleus (PVN) lesions and feeding behavior: relation to food restriction, drugs and corticosterone. Sot" Neurosci Abstr 10: 302, 1984.

    105. Siclari, E. and A. F. Debons. Enhanced adrenal activity in hypothalamic obesity. Fed Proc 40: 906, 1981.

    106. Sims, J. S. and J. E. Cox. Ventromedial hypothalamic and paraventricular nucleus lesions damage a common neural sys- tem to produce obesity. Sot" Neurosci Abstr 12: 594, 1986.

    107. Slusher, M. A. Dissociation of adrenal ascorbic acid and corti- costerone responses to stress in rats with hypothalamic lesions. Endocrinology 63: 412-419, 1958.

    108. Smith, C. K. and D. R. Romsos. Effects of adrenalectomy on energy balance of obese mice are diet dependent. Am J Physiol 249: RI3-R22, 1985.

    109. Smith, P. E. The disabilities caused by hypophysectomy and their repair. The tuberal (hypothalamic) syndrome in the rat. JAMA 88: 158-161, 1927.

    I10. Snapir, N., M. Yaakobi, B. Robinzon, H. Ravona and M. Perek. Involvement of the medial hypothalamus and the septal area in the control of food intake and body weight in geese. Pbarmacol Biochem Behav 5: 60%615, 1976.

    111. Softer, L. J. The anatomy, morphological structure and em- bryology of the adrenals. In: Disease of the Adrenal Glands, edited by L. J. Softer, J. L. Gabrilove and A. R. Sohval. Philadelphia: Lea and Febiger, 1956, p. 189.

    112. Softer, L. J., R. I. Dorfman and J. L. Gabrilove. The Human Adrenal Gland. Philadelphia: Lea and Febiger, 1961, pp. 266-- 269.

    113. Solomon, J., G. Bradwin, H. Cocchia, D. Coffey, T. Condon, W. Garrity and W. Grieco. Effects of adrenalectomy on body weight and hyperglycemia in 5 month old ob/ob mice. Horm Metab Res 9: 152-156, 1977.

    114. Solomon, J. and J. Mayer. The effect of adrenalectomy on the development of the obese-hyperglycemic syndrome in ob/ob mice. Endocrinology 93: 510-513, 1973.

    115. Stanley, B. G., A. S. Chin and S. F. Liebowitz. Feeding and drinking elicited by central injection of neuropeptide Y: Evi- dence for a hypothalamic site(s) of action. Brain Res Ball 14: 521-524, 1985.

    116. Stanley, B. G., D. Lanthier, A. S. Chin and S. F. Leibowitz. Feeding elicited by paraventricular nucleus injection of neuropeptide Y: a role for circulating corticosterone. Sot" Neurosci Abstr 16: 592, 1986.

    117. Steele, R. Influences of corticosteroids on protein and carbo- hydrate metabolism. In: Handbook of Physiology. Endocrinol- ogy Adrenal Gland, vol VI, sect. 7. Washington, DC: Am. Physiol. Soc., 1975, pp. 135-167.

    118. Stellar, E. The physiology of motivation. Psychol Rev 61: 5--22, 1954.

    119. Stevenson, J. A. F. Effects of hypothalamic lesions on water and energy metabolism in the rat. Recent Prog Horm Res 4: 363-394, 1949.

    120. Swanson, L. W., P. E. Sawchenko, J. Rivier and W. W. Vale. The organization of ovine corticotropin releasing factor (CRF)-immunoreactive cells and fibers in the rat brain: an im- munohistochemical study. Neuroendocrinology 36: 165-186, 1983.

    121. Sylvan, A., J. Fecko, R. M. Gold and J. McElroy. Adrenal suppression following hypothalamic knife-cuts that produce obesity. Sot" Neurosci Abstr l h 56, 1985.

    122. Sylvan, A., J. M. Fecko, J. S. Meyer, R. M. Gold and J. M. Watt. Effects of hypothalamic knife cuts on adrenal growth and secretion. Paper presented at the 57th annual meeting of the Eastern Psychological Association, New York, New York, April, 1986.

    123. Sylvan, A., J. M. Watt, J. S. Meyer, R. M. Gold, S. Gath and L. Crevier. Reversal of adrenal deficits by ACTH does not reverse hypothalamic knife-cut obesity. Soc Nearosci Abstr 12: 1452, 1986.

    124. Szent,'lgothai, J., B. Flerk6, B. Mess and B. Halfisz. Hypotha- lamic Control of the Anterior Pituitary. Budapest: akademai Kiado, 1962.

    125. Tretter, J. R. and S. F. Leibowitz. Specific increase in carbo- hydrate consumption after norepinephrine (NE) injection into the paraventricular nucleus (PVN). Soc Neurosci Abstr 6: 532, 1980.

    126. Vale, W., J. Speiss, C. Rivier and J. Rivier. Characterization of a 41-residue ovine hypothalamic peptide that stimulates secre- tion of corticotropin and fl-endorphin. Science 213: 1393-1394, 1981.

    127. Vilberg, T. R. and W. W. Beatty. Behavioral changes following VMH lesions in rats with controlled insulin levels. Pbarmacol Biochem Behav 3: 377-384, 1975.

    128. Wilkinson, C. W., J. Shinsako and M. F. Dallman. Daily rhythms in adrenal responsiveness to adrenocorticotropin are determined primarily by the time of feeding in the rat. Endocri- nology 104: 350-359, 1979.

    129. Wilkinson, C. W., J. Shinsako and M. F. Dallman. Rapid de- creases in adrenal and plasma corticosterone concentration after drinking are not mediated by changes in plasma ad- renocorticotropin concentration. Endocrinology 110: 159% 1606, 1982.

    130. Wilson, C. Some effects ofventromedial hypothalamic lesions, adrenalectomies, and corticosterone replacement therapy on energy expenditure in rats. Behav Biol 21: 380-392, 1977.

    131. Wolfe, B. B., T. K. Harden and P. P. Molinoff. fl-adrenergic receptors in rat liver: effects of adrenalectomy. Proc Natl Acad Sci USA 73: 1343-1347, 1976.

    132. York, D. A. and G. A. Bray. Dependence of hypothalamic obesity on insulin, the pituitary and the adrenal gland. Endo- crinology 90: 885-894, 1972.

    133. Young, T. K. and A. C. Liu. Hyperphagia, insulin and obesity. Chin J Physiol 19: 247-253, 1965.

    134. Yukimura, T. and G. A. Bray. Effects of adrenalectomy on body weight and the size and number of fat cells in the Zucker (fatty) rat. Endocr Res Commun 5: 18%198, 1978.

    135. Yukimura, Y., G. A. Bray and A. P. Woifsen. Some effects of adrenalectomy in the fatty rat. Endocrinology 103: 1924-1929, 1978.

    136. Zucker, L. M. Hereditary obesity in the rat associated with hyperlipemia. Ann NY Acad Sci 131: 447-458, 1965.