June 19661 NUTRITION REVIEWS 187

25 clays than a t four days, and was most notable in those mice of lowest body weight. These observations suggest that the magni- tude of the change in distribution of body nitrogen is correlated with the severity of the secondary disease, since this syndrome is a t its peak after four days and is charac- terized by loss of body weight.

In view of these results, the authors offer n tentative explanation for the failure to gain weight or the loss of weight associated with homologous disease, even with an in- creased positive nitrogen balance. They sug- gest that during the homologous reaction nitrogen is deposited in a noncellular in- tegumentary compartment a t the expense of other body tissues. If th is material contain- ing nitrogen had a lower nitrogen-to-body- weight conversion ratio than the tissues from which nitrogen was diverted, a loss in

EXAGGERATED DEPRESSED

body weight could occur while nitrogen re- tention was increased. This could be the re- sult of deposition of nitrogen in antibody- antigen complexes upon the surfaces of skin cells. Antibody protein has been riemon- strated on the surface of homografts and host cells during rejection (E. B. Hager, M. P. DuPuy, and D. F. H. Wallach, Ann. A T . 1’. Acad. Sci. 120, 447 (1964)) and the skin is known to be damaged histologically in homologous disease.

Further investigation will undoubtedly be carried out to define more precisely the site of increased nitrogen deposition in the skin of animals with homologous disease and the chemical nature of the material con- taining nitrogen which is formed. Such stud- ies might well lead to clarification of ques- tions of fundamental importance regarding the nature of the graft-versus-host reaction.

FOOD INTAKE INDUCED BY GLUCOSE IN HYPOTHALAMIC HYPERPHAGIC RATS

Intraperitoneal injections of glucose caused greater reduction of food intake in hyperphagic rats with lesionr of the ventromedial nuclei than in intact rats, thus suggesting glucoreceplow fiinctioning extmventromedially .

Food intake can be regulated, or rather perhaps depressed from some maximum, by many interrelated factors: physiological, biochemical, psychological, pathological, and environmental. In the normal subject, many of these factors are assumed to be of little importance, and a “normal” regulation is studied. J. Mayer (New Engl. J . Med. 249, IS (1953)) has suggested a glucostatic regulatory mechanism. This mechanism, widely accepted as playing a significant role in normal food intake regulation, acts by monitoring the utilization rate of blood glu- eosc. Mayer suggests that this is done by glucoreceptors in the ventromedial nuclei of the hypothalamus, the satiety center. There is much evidence for the existence of such receptors (Mayer, Australasian Ann. Med. 13,282 (1964) ) .

B. K. Anand e t al. (see A’utrition Reviews

23, 174 (1965)) demonstrated that the rate of glucose utilization affects the activity of single neurons in the ventromedial nuclei ; the lateral areas, the “feeding” centers, maintain an activity in balance with the “satiety” center. When blood glucose utili- zation increases ventromedial nuclei activ- ity increases, and lateral area activity de- creases. Thus, in effect, hunger is a t least partially a function of the rate of glucose utilization.

R. W. Reynolds and J. Kimm ( J . Comp. Physiol. Psychol. 60, 438 (1965)) studied the effects of a glucose load on male rats, weighing 340 to 450 g., with hypothalamic hyperphagia. Lesions were caused electro- lytically in ventromedial nuclei of the hypo- thalamus. Nine unoperated and ten oper- ated rats were studied.

During a 28 day postoperative period,

188 S U ' I R I T I O S REVIEWS [Vol. 24, N o . 6

the ratq were fed ad libitum. During a fol- lowing 17 day period, rats mere allowed food only one-half hour per day. They mere then injected 15 minutes prior to the feeding interval with one of two glucose treatments, and on alternate days with 1 ml. normal saline. Each rat was given four injections of 375 mg. glucose in 1 1111. normal saline, and one injection of 750 mg. glucosr in 2 1111. normal saline. RIayer and H. W. Bates (Am. J. Physiol. 168,812 (1959)) described rats, of an unspecified weight, which showed a brief hpperglycemia varying from 140 to 170 mg. per 100 ml. within the first hour when injected subcutaneously with 375 mg. glucose. Blood glucose levels returned to normal values within three hours.

At the end of the present experiments histological studies were done to determine the extent of the brain lesions.

Following surgery, eight rats with lesions gained between 4.4 and 9.2 g. per day for an unspecified time. The control group gained between 1.0 and 2.3 g. per day. The so-called hyperphagics appeared to be hy- perphagic, although the interval during which the increased growth rate was main- tained, not mentioned by the authors, is a useful criterion.

The 375 mg. glucose caused a 24 per cent depression in the food intake of hyper- phagics in the following half-hour feeding, ns compared with their food intake follom- ing injection of normal saline. This is in contrast to a 16 per cent depression of food intake of the control rats. When twice the amount of glucose was injected, the food intake was depressed 55 per cent for the hyperphagics and 26 per cent for the con- trols.

In general, the hyperphagics that had R

greater tjhan average response to the first glucose treatment, reacted the same to the second. There were extreme variations in the elicited responses of both controls and hyperphagics. Food intake data on the con- trol rats were not reported; therefore, the

variation of response from saline injection!: cannot be compared.

Differences between the means of the t n o groups for both groups were said to be sig- nificant (P < 0.05). The hyperphagics var- ied in food intake change from -0.88 t o 50.00 per cent, and 6.7 t o 82 per cent respec- tively for the 375 mg. and 750 mg. injec- tions of glucose. The control group changc varied from 8.3 to 27 per cent, a.nd -3 to 85 per cent for the same two treatments. The variation of the response of the hyper- phagics did not appear to be related to the extent of destruction of the ventromedial nuclei.

No absolute amounts of food intake arc given, so that i t is impossible to determine normal food intake levels of the two group:: during the half-hour feeding, or what effect the saline injection had on food intake. Since no body weight curves are sho~vn, i t is also impossible to determine whethpr lesioned rats were still in a dynamic state of growth during injection treatments, or whethcr they had returned to a more nor- mal growth rate.

The hyperphagic rats demonstrated greater food intake depression after saline injections than the controls when glucose was injected intraperitoneally. This is not the reaction that would be expected if the ventromedial nuclei c,ontain glucoreceptore.

The authors attempted to explain the es- aggeration of the response to glucose I)? suggesting that electrolytic lesions sensit.ize other neural structures, either through re- lease from inhibition or by irritation. There- fore, if some of these sensitized structures included glucoreceptors, a.nd if increased activation of these cells led to behavior dc- pressing food intake, the exaggeration of the induced depression of food intake could he explained. But if these glucoreceptorr: can cause such a food intake depression upon glucose injection, i t would seem the? would also have been excited by blood glu- cose elevation brought about by the cs-

June 19661 NUTRITION REVIEWS 189

cessive amount of food that caused the hy- perphagia.

Since the glucose load was not adjustecl to body weight, assuming the controls were of a similar age and had therefore appreciably less body weight than the hyperphagics a t the time of the experiments, the blood glu- cose change could have been considerably

less for the hyperphagics than for t,he con- trols. Therefore, i t is possible that had the blood glucose changes been the same, the hyperphagics' food intake response would have been much greater. The mechanism of action, as suggested by the authors, may not explain how the lesioned rats could be- come hyperphagic.

DIETARY FAT AND CIRRHOSIS IN THE RAT

Recent sludies showing a n effect of certain types of dietary jut on ja t t y cirrhosis in the rat almost reverse earlier studies. Saturated fa t ty acids, particularly palmitic and stearic, appeared to induce a more severe cirrhosis than unsaturated or shoitei chain saturated fa t ty acids.

Several studies have been reported in re- cent years suggesting that polyunsaturated fatty acids are responsible for an increased degree of fibrosis in rats on diets deficient in choline and low in protein, Studies by .I. J, Patek, N. M. deFritsch, F. E. Kendall, and R. L. Hirsch have shown that animals on diets which produce cirrhosis show a greater degree of liver damage when 10 per cent corn oil is incorporated into the diet than when a similar amount of coco- nut oil is present (see hrutf-ition Reviews 23, 349 (1965)). Additional studies by these workers have shown that the same changes can be seen when hydrogenated corn oil is compared with unprocessed corn oil. Animals on the regular corn oil diet Jiow the most severe signs of liver damage.

When rats are given diets deficient in cho- line for short periods of time fat accumu- lation increases in the liver (A. A. Benton, A. E. Harper, and C. A. Elvehjem, J . Biol. Chem. 218, 693 (1956)). Recently, F. G. Zaki, F. 1%'. Hoffbauer, and F . Grande (..lrch. Path. 80, 323 (1965)) reported on the effect of feeding several fats to rats in a basic hypolipotropic diet containing G per cent casein, 6 per cent soy protein, niid 20 per cent fat. The rest of the calories wre supplied by sugar, and approprinte

salt and vitamin mixtures were incorporated into the diet. L-Cystine was also added.

Previous studies have shown that this diet produces cirrhosis in the rat. Red palm oil, lard, a commercial vegetable fat, cottonseed oil, and safflower oil were used. Their total saturated fatty acid content ranged from approximately 10 to 75 per cent.

Two experiments were carried out, one using young rats weighing 50 to 75 g. and a second using older rats weighing 100 to 120 g. Each experimental group consisted of 12 animals. The aninials were on the diet for a period of 20 weeks. A grading system was used to determine development of fatty cirrhosis in the liver. Lipid and collagen in the liver were also determined; fatty acids of liver triglycerides were determined by gas-liquid chromatography.

In the initial experiment with young rats, most animals in each experimental group developed fatal hemorrhagic renal necrosis. Animals fed the control diet, which consisted of the experimental diet plus 0.4 per cent choline chloride, showed very little damage and showed no changes character- istic of cirrhosis.

The studies with older animals produced specific changes, which could be associated with the diets. The liver lipid content of all control groups was in the normal range,