THE METABOLIC RATE AND RESPIRATORY QUOTIENTS OF RATS ON A FAT-DEFICIENT DIET

BY LAURENCE G. WESSON AND GEORGE 0. BURR

(From the Department of Pharmacology, Vanderbilt University School of Medicine, Nashville, and the Department of Botany, Uniaersity of

Minnesota, Minneapolis)

(Received for publication, January 19, 1931)

In 1929 and 1930, Burr and Burr (1, 2) described a deficiency disease produced in rats by a fat-deficient, but otherwise balanced diet. This disease is superficially characterized by an arrest of growth, emaciation, scaliness of the feet, tail, and skin, excessive intake of water, hemorrhagic and necrot,ic tail, prolapse of the penis, bloody urine, and death of the animal. A careful study by Jackson has shown that the organs of these rats are practically free from fatty tissue. He has also described a characteristic degeneration of the kidneys (3). The disease is characterized by the fact that apparently complete cures are accomplished by relatively small amounts of the highly unsaturated acids, linolic and probably linolenic acids.

It was desired to determine the respiratory quotients and meta- bolic rate of these animals as part of a larger study of the metabolic and structural changes produced in the rats by the fat-deficient diet. In this connection, the work described in this paper attempts to ascertain whether or not animals on the fat-deficient diet are able to form fat from carbohydrate and, if so, whether fat is formed when a limited amount of carbohydrate is fed in t’he fasting condition, in which case, it is an abnormal metabolism of carbohydrate. It was also desired to ascertain whether or not the carbohydrate metabolism of these rats is affected by linolic acid which cures the deficiency disease, and by liver lipoids which have been shown by Wesson (4) to restore an apparently abnormal carbohydrate metabolism to normal. It was desired, as well, to learn whether the metabolic rate, both basal and carbohydrate assimilatory, is normal or abnormal in the diseased and cured rats.

525

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526 Studies on Fat-Deficient Diet

In order to accomplish this, carbohydrate was fed to rats in various stngts of t.he disease before and after curing, and the metabolic rate and respiratory quotients obtained following this carbohydrate test meal were cornpared with those obtained by Wesson (5) using the same procedure with normal rats. As nearly as possible t’he same uniform condit’ions of temperature, available metabolites, and previous environment were obtained. The animals, maintained since weaning at a temperature of 26-27” were, after 14 hours of fasting, given the calculated amount of dextrin required for 12 hours of normal metabolism, and the respiratory quotients and metabolic rate determined at 28” at approximately hourly periods for 12 hours following. They were then returned to their accustomed diet for 5 to 10 days before another series of determinations.

Diets

At weaning the rats were placed on a basic diet consisting of sucrose, purified casein, and 3.8 per cent salts (McCollum’s Salt Mixture 185). Daily doses of 0.66 gm. of ether-extracted yeast and the unsaponifiable material from 72 mg. of cod liver oil (Patch), and from 36 mg. of wheat germ oil were added to the diet.

The drinking water contained 0.27 mg. of KI per liter, and the mixed diet about 0.1 mg. of KI per kilo. It being assumed that t,he average rat eats 10 gm. of fo.od and drinks 20 cc. of water per day its daily KI intake would be about 0.006 mg. of KI. This amount of iodine is not far from an ordinary normal intake. The fat content of the diet was between 0.01 and 0.1 per cents.

The rats that were used in this series may be grouped as follows: Group A, High Carbohydrate Diet-Sucrose 84.2 per cent, casein

12 per cent, and salts 3.8 per cent were supplemented by vitamins A, B, D, and E, as outlined in the preceding paragraph.

Group B, “Treated’‘-These rats, maintained on the high carbo- hydrate diet described under Group A, were given daily 3 drops of a mixture of equal parts of methyl linolate and methyl linolenate when symptoms of the fat-free disease had become pronounced. The curative unsaturated acids were fed from April 29 to August 4, and then discontinued. At the time the respiratory determina- tions were made (October and November) the animals were slowly reverting to the diseased condition.

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L. G. Wesson and G. 0. Burr 527

Group C, High Protein Diet--Sucrose 31.2 per cent,, casein 65 per cent, and salts 3.8 per cent were supplemented by vitamins A, B, D, and E as for Group A. One rat (Rat W 30036) of this group was reared on a casein, salt, and vitamin mixture containing no sucrose.

Group D, Tung Oil with High Carbohydrate Diet-5 drops of tung oil daily were added to the high carbohydrate diet of Group A. Tung oil contains a minimum amount of linolic and linolenic acids, but a high percentage of eleostearic acid, isomeric with linolic acid.

Respiratory Metabolism Determinations

Since the rats of this series were more or less emaciated, the

modified formula of Lee (6) (

S = 10.76 X W”.61 X y >

(in

which S is surface area measured in sq. cm., W is weight in gm., and N, the degree of emaciation) was used in calculating the sur- face areas. This formula includes a correction factor for the degree

of emaciation N F - ( I”>

(in which L is the length in cm. from

nose to anus) originally derived by Cowgill and Drabkin (7). Lee, on the basis of his series of emaciated, normal, and obese rats, ascribes the value 0.310 to N for the average rat of normal proportions.

The body weights that were used as a basis for the calculations of surface area were obtained immediately before the beginning of the preliminary fasting period.

The weight of the carbohydrate test meal was based on the calories required by an average normal rat of the same surface area for 12 hours. As the amount required per sq. cm. of body surface by the average rat for 12 hours on the basis of 800 calories per sq. m. per 24 hours is 0.04 calories, and as 0.009734 gm. of dextrin will furnish this amount of energy, the product of surface area in sq. cm. by 0.009734 gives the weight of dextrin required for the test meal (5).

The test meal of dextrin, made into a thin paste with water, was usually eaten readily by the rat within 10 to 15 minutes. The rat was then placed in the chamber of the closed circuit respiratory calorimeter (5), and the respiratory quotients and metabolic rate

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TABL

E I

Met

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Rat

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th

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. 0.

90

0.91

0.89

0.88

0.85

0.82

0.79

0.79

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orie

s 10

72

1 83

3 I

777

1 72

8 I

768

I 76

4 I

765

I 73

2 I

0.77

0.78

728

I 79

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0.77

0.77

770

I 77

5 I

R.Q

. B

asal

av

erag

e 0.

733

Cal

orie

s 71

8

cn

E

1 w

3013

9

2 3 w

3015

3

Nov

. 14

, 11

6 gm

. N

ov.

19,

116

gm.

Nov

. 9,

132

gm.

Nov

. 13

, 13

4 gm

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ov.

21,

144

gm.

Nov

. 24

, 14

5 gm

.

+++

++

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G

30

R.Q

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orie

s 30

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37

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1.06

0.99

0.85

0.84

0.81

0.79

0.79

0.

78

0.78

0.77

“

“ 84

7 81

3 69

3 82

6 77

0 80

8 80

1 76

6 79

3 83

0 82

5 85

5

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L. G. Wesson and G. 0. Burr 533

were then determined at 28” in the same manner as described elsewhere (5).

The time interval is measured from the beginning of the test meal to the average time of the period for which a determination is made. For example, if the interval is 1.0 to 1.9 hours, it is considered as the 1st hour for the purposes of tabulation.

Results

In comparing with each other (Table I) the results of this series of determinations of the metabolic rate and respiratory quotients of rats in various stages of the fat-deficiency disease, weight should be put not only on the severity of the skin symptoms (expressed by +), but also on the percentage of emaciation (E), which is derived as follows: The most severely emaciated rats of our series had an emaciation coefficient (N) of 0.240. Lee’s coefficient for the average rat of normal proportions is 0.310. We have used the difference between these coefficients, 0.070, for calculating the percentage of emaciation on the assumption that a rat is 100 per cent emaciated when the emaciation coefficient is 0.240. Therefore, the percentage emaciation (E) used in Table I expresses the degree of emaciation of our animals as the per cent of total emaciation obtained. For example, an animal with an emaciation coefficient of 0.240 is 100 per cent emaciated, and one with a coefficient of 0.310 is 0 per cent emaciated.

The metabolic rate should also be taken into consideration in connection with the rapidity with which the respiratory quotients fall from the initially high values after the carbohydrate meal.

Respiratory quotients above unity are observed in all groups especially with those rats whose emaciation is more rapidly increas- ing or decreasing as in Runs 5, 12, 18-20, 22, 25-27, 32, 35, 40, 64, and 65.

Runs 1 to 17 were made upon rats 43 months old that, had been upon the carbohydrate diet for nearly 4 months, while Runs 18 to 28 were made upon rats 9 months old that had been 8 months upon the same diet. It is to be noticed that the metabolic rate, both assimilatory and basal, is exceptionally high in the fir t series of runs (Runs 1 to 17), compared with the average normal value, and is normal or subnormal in the second series (Runs 18 to 28) just mentioned.

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534 Studies on FabDeficient Diet

The metabolic rate is also normal or subnormal for the rats of the other groups. The effect of methyl linolate in general is to increase the metabolic rate especially where the emaciation is decreased by the methyl linolate as in Runs 13, 26, 27, 34, 35, and 65.

The rectal temperatures measured with a mercury thermometer, of thirty-one individuals of various groups of rats on the fat-free diet ranged between 37.0 and 38.7”, average 37.7”, while those of normal rats under the same conditions of temperature for 3 days or more varied between 37.5 and 38.0”, average 37.6”. The differ- ence is too small to be considered of significance.

DISCUSSION AND CONCLUSIOX3

Formation of Fat from Carbohydrate-The formation of fat from carbohydrate is a normal process of well fed animals whose glyco- gen stores are practically filled. This conversion of carbohydrate to fat represents a mode of utilization of the excess of ingested carbohydrate in a form that can no longer be retained as such. In the present series of rats, as well as with normal rats with which comparison is made, the carbohydrate stores are presumably no longer full after the preliminary fasting period of 14 or more hours. If normal rats are fed a moderate meal of dextrin under these circumstances, the highest respiratory quotient reached is 1.00, and the average 0.91. Although it is believed that respiratory quotients ranging from 0.90 to 1.00 may represent some degree of fat combustion (S), quotients above 1.00 according to our present knowledge may be taken to definitely indicate the formation of fat from carbohydrate, which proceeds simultaneously with the normal combustion of carbohydrate, protein, and possibly fat. In the present series, judging from the respiratory quotients that are in many cases well above 1.00, we have the conversion of carbohydrate into fat despite the preliminary fasting period. This condition may therefore be considered abnormal.

The diseased animals in their emaciated condition are becoming progressively free from stores of fat in spite of the generous intake of food. As they lose weight on the fat-deficient diet, their loss of fat is excessive. Under the influence of linolic or linolenic acids they gain weight, and the gain in fatty tissue is excessive. It is shown by the respiratory quotients that this fat, at least in part,

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L. G. VC’esson and G. 0. Burr 535

is produced from carbohydrate. It is a matter of great interest, however, that linolic or linolenic acids apparently do not result from t’his conversion, eit.her in the primary stage of formation of fat or in the secondary stage of utilization of this fat, since linolic or linolenic acids from sources outside the body are a,pparently required to cure the characteristic symptoms of these diseased rats. If they were formed, it would be expected that symptoms cured by linolic and linolenic acids would not develop.

This formation of fat from carbohydrate even after methyl linolate or liver lipoids has been given is not.eworthy, since Wesson (4) found under conditions different from those described above a marked although t,emporary reduction in abnormal fat-forming quotients following the feeding o,f small amounts of liver lipoids.

Metabolic Rate-The examination of the metabolic rate of these diseased rats comprised the second object of this investigation. This question derived increased interest because of a suggestion put forward by Chidester (9) and by Chidester and Wesson (10) based on bhe work of others (11-20) that the factor of hyperthy- roidism might be found to exist in a condition in which animals were fed a fat-deficient diet for a long period if they received at the same time normal, or even minute amount,s of inorganic iodine. The experimental work upon which this suggestion was based supports in a manner the hypothesis that a physiological antago- nism between unsaturated acids and the thyroid exists, and that, with the lack of unsaturat,ed acids in the diet, the effect of the thyroid becomes accentuated, or, vice versa, with an excess of unsaturated acids in the diet, the effect of the thyroid on the body becomes markedly diminished.

The results of these metabolism experiments are in many respects indicative of the correct.ness of the surmise mentioned above, although certain features are difficult to reconcile with the conditions that might be expected in hyperthyroidism. In sup- port of the theory of hyperthyroidism as applied t.o this series of rats may be mentioned the high metabolic rate observed in some cases. This is seen to be present in a pronounced degree in rats just entering the condition recognizable as characteristic of the deficiency disease, and apparently is not connected with the activity of the animal while in the respiratory calorimeter. This, judging from observation, was normal over t,he 12 hours

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Studies on Fat-Deficient Diet

duration of the run. Here the assimilatory and basal metabolic rate reached a value 25 per cent or more above the normal value obtained under very similar conditions, although the animals were not receiving what would ordinarily be an excessive amount of iodine.

The difference between the carbohydrate assimilatory rate and the basal rate is also found to be unusually high in the series of animals just entering the diseased condition. If the difference in this case may be said to be due to the specific dynamic action of the carbohydrate, it may, because of its magnitude, be compared with the high specific dynamic action that has been obtained from carbohydrate in cases in which hyperthyroidism was definitely known to exist (18, 19). On the other hand, unlike Miyazaki and Abelin (18) who reduced this high specific dynamic action by fat feeding, we were unable to detect a reduction after feeding unsat- urated acids with the diet for a number of days. Furthermore, the high basal metabolic rate is not reduced by methyl linolate or liver lipoids. These facts, together with the fact that other workers have not found the need for highly unsaturated acids to produce their thyroid effects, renders it difficult to accept the suggestion as to the possible participation of a condition of hyperthyroidism in the rats, at least with respect to the unsaturated acids-iodine hypothesis as restated by Chidester (9) and Chidester and Wesson (10). McCarrison (15) and Mellanby and Mellanby (17) found butter most effective, Abelin, Goldener, and Kobori (20) found that oleic acid and mixtures of oleic acid with stearic and palmitic acids were as effective as any other oils, while Burr and Burr (2) found that butter and the saturated acids are ineffective in curing the low fat disease. The development of the symptoms of the fat-free disease by rats on Diet D that includes the highly unsaturated eleostearic acid of tung oil also speaks against the validity of this hypothesis as applied to this disease.

On the other hand, the subnormal metabolic rate found in the case of many of the older animals would indicate a condition of possible hypothyroidism that is consistent with the findings of Gray and Loeb (21) and Gray and Rabinovitch (22) that the feeding of iodides results first of all in a period of hyperactivity of the thyroid followed by a prolonged period of hypoactivity. The effect of excess inorganic iodide feeding on the activity of the thy-

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L. G. Wesson and G. 0. Burr

roid of animals is discussed by a number of workers (12, 14,2l-30). It should be pointed out, however, that Gray and Rabinovitch (22) found no marked changes in the thyroid until 10 mg. of 1~1 were fed daily (2000 times our doses), and, except for histological changes in the thyroid, the animals were perfectly normal. Their experiments were done with guinea pigs and extended over a period of 108 days. This work would indicate that none of the symptoms of the fat-deficiency disease can be produced by HI feeding.

The abnormal formation of fat from carbohydrate (respira- tory quotients above unity) has been found by Miyazaki and Abelin (18) in the case of rats in a condition of hyperthyroidism. Whether fat is formed from carbohydrate also in the case of emaciated animals with a known subnormal thyroid activity has not been determined, so far as we are aware.

Emaciation (31-34), cessation of growth (35), hemorrhage (33, 34), sterility (36), excessive consumption of water, high food in- take (31, 33, 37), and the lack of apparent nervousness or tend- ency to excessive activity (38), are features of the condition of these rats that are compatible with what would be expected in a condi- tion of hyperthyroidism. A difference of opinion is found in the literature as to body temperature in hyperthyroidism (31, 34, 39, 40).

The contradictory evidence as to the thyroid phase, if any, of the fat-deficiency disease awaits elucidation from other angles. This work is now being undertaken as a part of the larger problem mentioned in the introductory paragraphs.

SUMMARY

1. The metabolic rate and respiratory quotients following a carbohydrate test meal have been determined in the case of rats maintained for some time on a fat-deficient diet, and are compared with those obtained on normal rats and under approximately the same conditions.

2. The respiratory quotients in the 1st hours following the carbohydrate feeding are in many cases well above unity, definitely indicating the formation of fat from carbohydrate by these rats in various stages of the fat-deficiency disease.

3. The fact that no relief is obtained from the symptoms of the fat-deficiency disease by the fat thus formed from carbohydrate

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538 Studies on Fat-Deficient Diet

indicates that the curative linolic and linolenic acids are not formed by the rat from the carbohydrate or from the fat.

4. The basal and assimilatory metabolic rate in the case of rats showing the early symptoms of the fat-deficiency disease was well above the normal value, while the metabolic rate in the later stages of the disease was normal or subnormal.

5. The possible relationship of thyroid activity to several phases of the fat-deficiency disease is discussed.

BIBLIOGRAPHY

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32. Fordyce, A. D., Edinburgh Med. J., 9,55 (1912). 33. Farrant, R., Brit. Med. J., 2, 1363 (1913). 34. Kunde, M., Am. J. Physiol., 82, 195 (1927). 35. Cameron, A. T., and Carmichael, J., J. Biol. Chem., 46, 35 (1921). 36. Gudernatsch, J. F., Am. J. Physiol., 36, 370 (1915). 37. Schafer, E. A., Quart. J. Ezp. Physiol., 5,203 (1912). 38. Carlson, A. J., Rooks, J. R., and McKie, J. F., Am. J. Physiol., 30, 129

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Laurence G. Wesson and George O. BurrON A FAT-DEFICIENT DIET

RESPIRATORY QUOTIENTS OF RATS THE METABOLIC RATE AND

1931, 91:525-539.J. Biol. Chem. 

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