non-production of hypothalamic obesity in the rat by lesions rostral or dorsal to the ventro-medial...

NON-PRODUCTION O F HYPOTHALAMIC OBESITY I N THE RAT BY LEISIONS ROSTRAL OR DORSAL TO THE

VENTRO-MEDIAL HYPOTHALAMIC NUCLEI

A. W. HETHERINGTON Institute of Neurology, Northwestern University Medical School, Chioago, Illinois

SIX FIGURES

Thc production of hypothalamic obesity in the rat is an easy mat- ter, requiring only that certain definite regions on both sides of the hypothalamus be destroyed. Work in this laboratory has been directed toward the identification of the precise structures, either nuclei or fiber groups, destruction of which is followed by adiposity. The view was finally advanced (Hetherington and Ranson, ’42) that obesity is caused by “lesions which occupy the medial hypothalamus, particularly the region of the ventromedial hypothalamic nucleus, or are placed in the caudal hypothalamus in a position to interrupt a large number of descending fibers from the hypothalamic cell group& ” The mammillary nuclei, and probably also the premammillary nuclei, the mamillothalamic tract, the fornix, and the periventricular and suprachiasmatic nuclei were considered to be unconcerned in the syndrome.

The question which arose next was to what extent the hypothalamic outflow of fibers controlling fat metabolism was contributed to by fibers originating in cell groups lying more rostrally than those pre- viously destroyed. Admittedly, large lesions in the central and caudal hypothalamus probably interrupt many fibers travelling caudally from regions lying rostral to the ventromedial hypothalamic nuclei (viz., the anterior hypothalamic and preoptic areas and the cell groups of the basal olfactory forebrain). The influence of such hypothalamic lesions in producing obesity might not depend entirely - or even at all -upon their destruction of local cell bodies, but rather upon their severance of the connections between more rostral centers and the lower brain-stem. Such an assumption is unquestionably true in the case of the most caudal obesity-producing hypothalamic lesions. Ob-

Aided by a grant from the Committee on Research in Endocrinology of the National Research Council.

33

34 A. W. HETHERINGTON

viously, the capacity of large lesions lying entirely ahead of the ventromedial hypothalamic nucleus to bring about adiposity had to be tested.

METHODS

The technique of placing lesions in the hypothalamus of the rat with the Horsley-Clarke instrument has been described by Clark ( '39) and Hetherington and Ranson ( '40). In the present series of animals bilateral electrolytic lesions of various sizes were placed either near the base of the brain and at levels progressively rostral to the ventromedial hypothalamic nucleus, or in the dorsal hypothalamus a t several rostrocaudal levels near that nucleus. When lesions were placed dorsal to the ventromedial hypothalamic nucleus the procedure of placing them was altered to the degree that, instead of lowering the electrode to the base and then raising it the required distance above that plane, the distance down to the dorsal hypothalamus was measured from the cortex above. Thus the basal structures were spared even the slight damage incidental to electrode passage. The rostral lesions were distributed all the way from slightly behind the chiasma to points ahead of the anterior commissure. All were planned to go to the base, and were made by introducing the electrode from one t o three times on each side - the electrolyzed points on either side being close enough to each other to fuse together. At each point of insertion, a current of 2 m. a. was applied for 20 seconds.

The animals were maintained under the identical dietary and cag- ing conditions used with previous series of rats. As is customary, they were weighed at intervals, and at the conclusion of the experiment they were anesthetized, measured, and killed by decapitation. The lesions in the brains were studied histologically in Weil and cresyl violet sections.

RESULT 8

Lesions of the nature described were placed in the brains of twenty- two animals. When these brains were examined histologically it was found that the electrolytic destruction was distributed in the following manner: In three rats the anterior hypothalamic areas had been se- verely damaged or entirely eliminated, and in three more this same result had been accomplished, togetlier with extensive destruction of the medial preoptic areas. Two other animals displayed large lesions of the medial preoptic areas which extended forward to involve the medial portions of the diagonal band of Broca. Two rats had sustained severe damage to the lateral preoptic areas and the immediately ros-

HYPOTHALAMIC OBESITY 35

tral structures, including the tuberculum olfactorium and the nucleus accumbens. I n six animals tremendous lesions had been, inflicted which eliminated practically all the cell groups lying between the anterior commissure and the rostra1 edge of the median eminence, between the base and the dorsal limits of the hypothalamus, and between the internal capsule on each side. The remaining six rats had damage to the dorsal hypothalamus varying in extent and exact location.

I n determining whether or not a rat is fat it is usually only necessary to inspect it and compare it with its control, since the obesity induced by properly placed hypothalamic lesions is marked. In general, however, the degree of obesity is correlated with the degree to which the critical structures are damaged (though it is apparently essential that the injury be bilateral), and occasionally only low grades of obesity are obtained. In evaluating the slighter degrees of adiposity the “nu- tritive correction factor” of Lee (’29) has been found useful as an index to describe an animal’s nutritional state. This is the ratio of the cube root of the rat’s body weight in grams to its nose-anus length in centimeters. Normal male animals of our colony which are 6 to 8 months of age may afford ratios as high as 0.302; the upper limit for normal females of this age is probably somewhat lower, being somewhere between 0.295 and 0.300. Operated rats, therefore, which display ratios higher than this must usually be considered as showing a tendency to obesity. A figure lower than this, even if the operated animal seems to be in an appreciably better nutritional state than its control, makes a diagnosis of adiposity questionable.

Applied to the present series of rats, the nutritional index reveals only one operated animal, a male (index: 0.304), which might be considered slightly fat. The remaining twenty-one were definitely non- obese, as judged,both by inspection and by their indices. The excep- tional animal was one which, besides having large lesions of the medial preoptic and anterior hypothalamic areas on both sides, showed much damage to the supraoptic, filiform, and ventromedial hypothalamic nuclei on one side, and sheared along the lateral borders of the latter two nuclei for a considerable distance on the other side. Lesions in- volving the more centrally located ventral hypothalamic cell groups are well known to cause adiposity. It should, perhaps, be emphasized again that none of the other rats got fat. A more detailed study of the brain damage present in several representatives of the non-obese animals having lesions of various types will serve to make the results more explicit.


Lesions of the preoptic areas. Figure 1 is a drawing of a transverse section through the caudal halves of the lesions on both sides of the basal forebrain in rat Re-55 (non-obese male; index: 0.282). I n this animal two symmetrical lesions began at the base on each side in the medial portion of the tuberclum olfactorium. As the lesions spread caudally and dorsally through the diagonal band of Broca they assumed a more lateral disposition and destroyed large portions of the lateral preoptic area. They went dorsally almost as far as the anterior commissure ; caudally they stopped a t roughly the rostral limits of the lateral hypothalamic area.

Figure 2 shows a transverse section through the center and greatest diameter of the lesion in Re-59 (non-obese female ; index : 0.273). The lesions, which were fused across the midline from the beginning, began rostrally a t the base in the

Fig. 1 Transverse section through the preoptic area at the level of the caudal border of the anterior commissure in rat Re-55. The lesions in this and the following diagrams are bordered by a band of fine parallel lines. The boundaries of nuclei in the transverse sections are shown with heavy, dashed lines. Abbreviations for all figures are as follows: A, anterior commissure; AHA, anterior hypothalamic area; Arc, arcuate nucleus; BP, basis pedunculi; CF. column of fornix; DM. dorsomedial hypothalamic niieleus ; E, entopeduncnlar nucleiis : F, fornix; Fill paraventricular nucleus; IC, internal capsule; LHA, lateral hypothalamic area; LPA, lateral preoptic area; ME, median eminence; MFB, medial forebrain bundle; MPA, medial preoptic area; MT, mammillo-thalamic tract; 0, nucleus suprachiasmatieus ; OC, optic chiasma; OT, optic tract ; SM, stria medullaris ; SO, supraoptic nucleus ; ST, stria terminalis ; TO, tuberculum olfactorium ; VM, ventromedial hypothalamic nucleus ; ZI, zona incerta ; 11, optic nerve; 111, third ventricle.

Fig. 2 Transverse section through the preoptic area a t the level of the caudal border of the anterior commissure in rat Re-59.

most medial portions of the nuclei of the diagonal bands on both sides. They quickly spread dorsally, doing slight damage to the anterior commissure, and caudally, destroying almost all of the medial preoptic area on each side. The chiasma was considerably injured, as were also the rostral halves of the anterior hypothalamic areas. The lesions finally disappeared at the base at the caudal edge of the optic chiasma.

I n these two cases the two principal divisions of the preoptic areas, medial and lateral, were very largely eliminated without inducing obesity. I n five other animals similar results were obtained, and in several of these even the ventral portions of the septa1 area were included among the structures damaged.


Lesions of the anterior hypothalamic area. Among the non-obese rats reported by Hetherington and Ranson ( '42) were several (Re-13, -14, -16) having small or fair-sized lesions of this area. I t was not felt, however, that these lesions were sufficiently large to justify the conclusion that destruction of the anterior hypothalamic area does not cause adiposity. Indeed, in one case (Re- 20) destruction of a good portion of the area, as well as of the rostral parts of the ventromedial hypothalamic nuclei did bring about a mild degree of fat deposition. In figure 3 is shown a transverse section through the greatest diameter of the lesion in Rb-50 (non-obese male; index: 0.293). This rat had syin- metrical lesions beginning in the media4 preoptic areas at the level of the caudal border of the anterior commissure. The lesions spread quickly to the base and laterally, as well as of course caudally, destroying the caudal portion of the medial preoptic areas, all of the anterior hypothalamic areas, and even the

Fig 3

Fig. 3 Transverse section through the anterior hypothalamic area just rostral to the

Fig. 4 Transverse section through the hypothalamus in the plane of the middle third plane of the paraventricular nuclei in rat Rb-50.

of the ventromedial hypothalamic nucleus in rat Re-64.

rostral tips of the ventromedial hypothalamic nuclei on both sides. There was some cell loss in the paraventricular nuclei, but the lesions stayed out of them, though bounding them closely on their ventrolateral aspects. The lesions also encroached upon the lateral hypothalamic area on each side at this level.

Five other rats in addition to this one had large lesions of the anterior hypothalamic area, wi'th or without damage to the medial preoptic area besides, and only one of these gained weight even slightly in excess of normal. This was the animal (discussed in the third paragraph of the results) having damage also in the region of the ventromedial hypothalamic nuclei.

h'eparatiofi of the hypothalamus from the basal forebrain. The huge lesion presenbin Rb-46 (non-obese female ; index : 0.287) is shown in transverse section in figure 6, and in horizontal projection on the hypothalamus and preoptic area in figure 5. The lesion in this rat began in the ventral portion of the septa1 region slightly rostral t o the anterior commissure, and expanded rapidly t o the base and laterally. The commissure was extensively damaged, and the medial and lateral preoptic areas, and the anterior hypothalamic areas along with the suprachiasmatic nuclei are destroyed practicaly in their entirety. The lateral


hypothalamic area on each side, and the rostral portion of the thalamus underwent widespread damage. The lesion then receded dorsally from the base as i t proceeded caudally and only clipped the rostral poles of the ventromedial hypothalamic nuclei, but completely eliminated the paraventricular nuclei. I n addition, the rostral parts of the dorsomedial hypothalamic nuclei were injured, and all this was done without the appearance of obesity.

Six rats in all were operated in this manner and kept alive until they were killed 24 to 4 months later. One other animal had damage reaching just as far caudal as in the one described above; in the other four the lesions ended at a slightly more rostral level, sparing at least part of the paraventricular nucleus.

Fig 5 F L ~ 6 Fig. 5 Diagram showing rostrocaudal extent of the lesion in rat Rb-46. This figure is a

reconstruction in the horizontal plane of the principal structures lying in the ventral part of the hypothalamus and in the preoptic area, seen from the dorsal side.

Transverse section through the anterior hypothalamic area probably just rostral to the plane of the paraventricular nuclei in rat Rb-46.

The latter lesions were, however, just as extensive from side to side and dor- soventrally, and apparently interrupted all the possible fibers which might be flowing caudally from the ventral forebrain through the region of the ventromedial hypothalamic nucleus. None of the rats showed any sign of growing fat.

Lesions of t h e dorsal hypothalamus. I n general, the evidence gained from preceding series of rats has indicated that it is bilaterally symmetrical damage nearer the base of the hypothalamus in the region of the ventromedial hypothalamic nucleus which is correlated with the highest levels of adiposity. Nevertheless, in most instances lesions in the ventromedial nucleus have tended to expand dorsally along the electrode track into the dorsomedial hypothalamic nucleus, damaging it considerably. I n figure 4 is shown a lesion purposely placed in the dorsomedial nucleus, destroying it completely on both sides in Re-64 (non- obese female; index: 0.294). The damage also extended caudally into the posterior hypothalamic areas. No obesity resulted, either in this animal, or in five others which had lesions placed in the same general region.

Fig. 6

DISCUSSION

From the evidence which has been presented it seems likely that the cell groups rostral or dorsal to the ventromedial hypothalamic nuclei


make little if any contribution to the regulation of fat metabolism. Whatever the disordered mechanism may be, the inference appears unavoidable that the anatomical basis of the syndrome of hypothalamic obesity consists of destruction of the cells in or near the ventromedial nucleus, or of their descending fibers in the brain-stem.

Limiting the hypothalamic control of fa t metabolism solely to the cells of the ventromedial hypothalamic nucleus is perhaps premature with the evidence at present available. Dr. J. R. Brobeck (’43) in a personal communication to the author has remarked that he has been impressed by the frequency with which the tissue lying just laterally to the ventromedial nucleus is involved by the lesions in the obese rats which he and Dr. Tepperman have been studying. This observation squares with the findings of Hetherington and Ranson ( ’42), who sug- gested that destruction of the capsule of tissue around the ventromedial nucleus, “especially on its lateral and ventrolateral aspect,’’ might well be important. Though it remains to be shown that lesions of this small region alone will suffice to cause adiposity, it is quite possible that fibers leaving the nucleus may travel in considerable numbers via this route, and perhaps even establish connections with other nearby neurons, before turning down into the brain-stem.

It is of much interest that Vidal and de Robertis (’43) have likewise found in mice showing spontaneous hypothalamic obesity clear indications of pathological change in the region of the ventromedial hypothalamic nucleus. These cases were characterized by diminution in number of cells, particularly in the rostral and middle thirds of the nuclei ; by signs of chronic cellular lesions, especially in the dorsomedial divi- sion of the ventromedial nucleus ; and by diminution of the number of myelinated fibers in the lateral zone of the capsule of the nucleus.

These interesting findings seem to agree with the results of destruc- tire procedures, which have indicated that elimination of the more rostral portions of the ventromedial nucleus and the tissue neighboring it laterally is sufficient to bring about obesity. Hetherington and Ran- son (’42) pointed out that some of their lesions destroyed only the rostral two-thirds to three-quarters of the nucleus. Furthermore, Dr. George Clark has occasionally produced adiposity in the rat by transverse section of the hypothalamus during the course of his study of sexual behavior (Clark, ’42). The transverse lesion in the brain (of a fat rat) which was presented to the author appears to cut across the hypothalamus to the base behind the level of the paraventricular nucleus, through the rostral portion of the dorsomedial


nucleus, and across approximately the middle, or slightly ahead of the middle of the ventromedial nucleus.

Although the results which have been obtained in the rat seem thus fairly definite and consistent, in other species they have not been so clear cut. Biggart and Alexander (’39) commented that “it seems probable that fat metabolism is controlled in some way by the anterior hypothalamic group of nuclei.” They noted that in their obese dogs the lesions were so placed as to interrupt any fibers passing from the paraventricular nuclei to the hypophysis, but did not indicate that they believed this fact to be crucial. They did definitely state that six of the ten dogs gaining weight had damage to the ventromedial hypothalamic nuclei; and a study of the illustrations of the lesions presented for three of the remaining four animals suggests that the existence of injury to that nucleus, even if only indirect, was not unlikely. In appraising injury to hypothalamic cell groups one should at all times take into consideration such matters as cell loss, as well as of simple gross destruction.

Heinbecker and White ( ’42) have expresed the opinion that obesity in the dog is caused by degeneration or destruction of the paraventricular nuclei, particularly of their caudal parts, and is still more marked when there exists also damage of the supraoptic nuclei. The photomicrograph of the hypothalamus of an obese dog which they submit as evidence does indeed seem to show that the paraventricular nuclei had disappeared. A comparison of this picture with another made of a section through the hypothalamus of a non-obese dog will strongly tempt one to believe, however, that the paraventricular nuclei were not the only cell group to disappear in the fa t animal; there appears also to be a striking paucity of nerve cells in all parts of the anterior hypothalamus at the level shown, and close scrutiny even suggests the presence of some increased vascularity. It may yet prove true in the dog, as in the rat, that the ventromedial hypothalamic nucleus is involved in the regulation of fat metabolism.

It is certainly worth noting that in the rat, at least, the presence or degree of obesity has not been correlated with the amount of damage which had been done to the paraventricular nuclei. In the series of animals reported by Hetherington and Ranson ( ’40, ’42) the paraventricular nuclei in some of the non-obese rats showed the greatest cell loss and injury found, whereas in some of the fattest rats this nucleus was in an excellent state of preservation. Two of the animals in the present series which had enormous lesions of the anter-


ior hypothalamic and preoptic areas (figs. 5 and 6) underwent complete elimination of the paraventricular nuclei without becoming fat.

In the monkey adiposity has only recently been reported. Ranson, Fisher, and Ingram ('38) reported a single case of obesity i n this species, but were reluctant to attribute the animal's remarkable fat- ness to its hypothalamic lesion. In this paper the authors emphasized three points: (1) the bilateral lesions in the fat monkey were very asymetrical; ( 2 ) the lesions in this animal resembled those found in other, but non-obese, monkeys; (3) on the basis of 28 non-obese monkeys having lesions of various nuclei, there is no hypothalamic nucleus whose complete integrity is essential for proper regulation of €at metabolism. Strictly speaking, these statements can be regarded as correct. Unfortunately, however, they have been taken to mean (Newburgh, '42) that obesity cannot be produced in the monkey by hypothalamic lesions, and this inference is almost certainly unjustified.

The author has had the privilege of examining all the microscopic material and most of the protocols on which Ranson, Fisher, and In- gram based their paper, and believes that in the light of the present more specific knowledge about the hypothalamic structures destruction of which causes obesity in the lower forms it is now necessary to clarify and qualify some of the earlier conclusions regarding the monkey. Insofar as the particular fat monkey (M36) reported in the earlier paper is concerned, the following may be added : It is recorded in the description of the lesion found with the protocol, and confirmed by microscopic examination of the sections of the hypothalamus that the medial portions of the hypothalamus were damaged on both sides. On the right side a large part of the medial hypothalamus (including all of the ventromedial nucleus) was destroyed. On the left a broad band of neuron-free gliosis extended medially from the large lesion in the lateral hypothalamic area to the ventricle; this band of gliosis lay squarely across the ventromedial hypothalamic nucleus, and in its broadest extent left only a few of the most dorsal and ventral cells on each side of it. Thus, although the hypothalamic damage as a whole was quite asymmetrical, both ventromedial hypothalamic nuclei were involved.

No other case of marked obesity in the monkey was observed in this laboratory; nevertheless, a re-study of the animals of the series reported by Ranson ( '39) provides some suggestive material. The lesions in all these animals were reviewed, and when one was found which it was believed should have caused the animal to become obese because of the similarity of the damage to the effective lesions in the


rat, the protocol for the monkey was consulted for further information. The larger number of animals were found to have died, or to have been killed iii from a few days to 2 weeks. Four, however, were discovered which were permitted to live up to 32 days. Of MC21 it is recorded in the protocol (on the 30th postoperative day): “Eats well . . . Is sleek and fat. ” MC21 had bilateral, symmetrical lesions which destroyed about the caudal one-third of the ventromedial hypothalamic nuclei, the premammillary nuclei, and the mammillary body, and spread out into the posterior and lateral hypothalamic areas to some extent. Of MC37 it is said (21st day) : “Eats food avidly . . . I s getting very fat.” The brain of MC37 was prepared by the Marchi method, and the hypothalamic nuclei cannot be made out. The lesion on the left began over the chiasma in a position where it should have eliminated the anterior hypothalamic and paraventricular nuclei on that side. On the right the lesion came down from the ventral thalamus into the dorsomedial hypothalamic region and lateral hypothalamic area. On both sides the lesions approached the base and ventricle closely enough so that both ventromedial hypothalmic nuclei should have been almost completely destroyed. Of MC41 it is said (19th day) : “Looks as if he were getting fat.” In MC41 a large lesion destroyed all the ventromedial nucleus and the medial one-half to two-thirds of the lateral hypothalamic area on the right side. In the left side a lesion at the level of the mammillary body destroyed most of the lateral hypothalamic area and extended up into the H field. These lesions, curiously enough, correspond to the hypothetical asymmetrical lesions proposed by Hetherington and Ranson (’42) as probably being capable of causing adiposity in the rat. The fourth animal, MC11, was described by Ran- son (’39, monkey 11). In this monkey the lesions began over the optic chiasma beside the ventricle and destroyed bilaterally the paraventricular nuclei, the dorsomedial hypothalamic nuclei, and about the rostra1 two-thirds of the ventromedial hypothalamic nuclei. On the nineteenth postoperative day, the protocol states, “Is getting fat -has big appe- tite. Objects to being touched anywhere. Does not move actively.” The description of this monkey would fit exactly that of a rat with a similar lesion. In Ranson’s paper the monkey is said to have gained only 140 gm. - but this increase was only a little under 10% of its original weight, and according to measurements in the protocol was unaccompanied by any growth in body length. So the increase in weight might well have been adipose tissue.

Later, the protocols of all the other animals whose lesions had been rejected as non-conducive to adiposity were examined. Significantly,


not a single reference to any sign of obesity in these monkeys was found.

The protocols of the monkeys studied by Ingram, Fisher, and Ranson ('36) could not be located, but the slides of these animals have been examined, and their paper reveals that the only three (MD1, MD3, MD4) which would have been likely to grow! fat were observed for only 15 to 21 days after the operation-whereupon they were presumably autopsied. This period is hardly long enough to be certain these monkeys would not have become obese. Nor would the conditions of the experiment, under which food intake was kept as nearly constant as possible (and therefore evidently limited in quan- tity) have favored the early appearance of pronounced adiposity. The lesions in the other monkeys were judged to be either too asymmetrical, or too close to the base to damage the ventromedial nucleus very much bilaterally.

The latest reports of adiposity in the monkey are those of Brooks, Lambert, and Bard ('42) and Ruch, Patton, and Brobeck ('42). The former workers observed adiposity in six of twelve monkeys after lesions were made in the suprachiasmatic areas and in the tuberal region of the hypothalamus. As yet a detailed description of nuclear and fiber damage in these animals has not appeared. Weight gain became apparent in the six animals 3 weeks after the operation. They gained at a rate varying between 50 and 150 gm. per week until their body weights more than doubled. Ruch, Patton, and Brobeck obtained several obese monkeys by making lesions in the medial posteroventral region of the thalamus and the adjacent mesencephalic tegmentum. Dr. Rrobeck has informed the author that these lesions went as far ventrally as the H fields, and it seems quite possible the lesions interrupted the pathway which has been presumed to lead from the hypo,thalamic cell groups regulating fat metabolism into the brain-stem. This pathway it could be predicted would spread with the other fibers traveling in the lateral hypothalamic area through a good part of the tegmental region.

Obesity, then, can be produced in the monkey, as well as in the rat and the dog, by making hypothalamic lesions. The evidence so far available is not sufficient to show conclusively which group of cells in the hypothalamus of the dog and monkey must be destroyed to bring about excessive fat deposition, but the indications are that they map be more or less the same as those in the rat ; viz., the ventromedial hypothalamic nuclei, and possibly those cells lying closest to them.


These neurons exercise their influence upon fat metabolism via path- ways descending through the brain-stem, most likely through the tegmentum.

SUMMARY

Bilateral electrolytic lesions of various sizes made with the Horsley- Clarke instrument have been placed in the ventral septa1 region, the olfactory tubercle, the diagonal band of Broca, the medial and lateral preoptic areas, and the anterior hypothalamic area of rats. In some animals only one of' these regions was damaged; in others several in combination were destroyed; and in six the lesions were so large the entire region between the anterior commissure and the rostral edge of the median eminence, between the base and the dorsal limits of the hypothalamus or the anterior commissure, and between the internal capsule on each side, was eliminated. I n two of this third group the paraventricular nuclei also were destroyed. I n addition, bilateral lesions of the dorsomedial hypothalamus at the rostrocaudal level of the ventromedial hypothalamic nucleus were made. None of these series of animals became obese.

It is, therefore, assumed that cell groups of the basal forebrain rostral to the ventromedial hypothalamic nucleus make little if any contribution to regulation of fat metabolism. Whatever the mechanism, it is destruction of the cells in or near that nucleus, or of their descending fibers in the brain-stem, which causes the syndrome.

The hypothalamic lesions of a large number of monkeys which have been operated in this laboratory over a period of years have been re-examined and compared with the protocols of the corresponding animals. It is believed that indications were found that the hypothalamic lesions which cause obesity in the monkey may be about the same as the effective lesions in the rat.

LITERATURE CITED

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the mwkey (Macaca mulatta). Fed. Proc. (Am. Physiol. Soe.), vol. 1, part 11,

The use of the Horsley-Clarke instrument on the rat. Science, vol. 90, p. 92. Sexual behavior in rats with lesions in the anterior hypothalamus. Am. J.

HEINBECKER, P., AND H. L. WHITE 1942 Experimental obesity in the dog. Proc. SOC.

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1942 Effect of early hypophysectomy on hypothalamic obesity. Endocrinology,

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NEWBURCIH, L. H. RANSON, S. W. 1939 Somnolence caused by hypothalamic lesions in the monkey. Arch.

Neurol. and Psychiat., vol. 41, pp. 1-23. RANSON, S. W., C. FISHER AND W. R. INQRAM Adiposity and diabetes mellitus in a

monkey with hypothalamic lesions. Endocrinology, vol. 23, pp. 175-181. RUOH, T. C., H. D. PAWON AND J. R. BROBEC~ 1942 Hyperphagia and adiposity in rela-

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non-production of hypothalamic obesity in the rat by lesions rostral or dorsal to the ventro-medial...

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