822 Special Articles intake varies with energy expenditure; and the second is that food yields a constant energy supply to the organism varying onl...

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intake varies with energy expenditure; and the second is that food yields a constant energy supply to the organism varying only with its quantity and its composition (e.g., that 1 g. fat yields just over 9 C. of available energy). We propose to examine these assumptions and to provide an alternative hypothesis.






normally remains constant Summary Body-mass variations in calorie intake and despite

The sensations of appetite and satiety probably not the main controlling mechanisms. There is no firm relationship between the energy-value of food and the energy made available to the organism: the effect of a given diet on body-mass is determined by its composition, the pattern of feeding, and hormonal energy output.


The amount of energy derived from food varies according to the metabolic pathway taken. Bodymass is probably controlled by a homœostatic mechanism which regulates metabolism in adipose tissue.



MUCH work has lately been done on nutrition, and the time has perhaps come to re-examine the mechanisms whereby the body-mass of an intact adult organism is maintained constant while its energy demands fluctuate. This is particularly true in man, in whom the energy demands vary from day to day, from weekdays to weekends, from periods of struggle to periods of affluence, and from year to year. The assumption that the constancy of bodymass and the inconstancy of energy requirements must be intimately linked is based on the first and second laws of thermodynamics, which were shown to apply to biological material 60 years ago: they are generally accepted and need not be re-examined now. CONSTANCY OF BODY-MASS "


Obviously a mammal, whether by habit a nibbler or a " meal eater ", requires energy independently of the time of its food intake; but we should examine the general proposition that body-mass remains constant in the adult. In normal adult mammals this is well documented1 2 ; and the constancy of body-mass is assumed in all toxicological testing. In man figures from the Metropolitan Life Insurance Company 34 indicate that between the ages of 35 and 54 women lose 5 lb. on average, and men gain 5 lb. In a continuous study of individual males, lasting 20 years or more, 63% showed some increase in



37%remained the

same or



These figures probably do not accurately represent the behaviour of the population as a whole, since insured persons are to some extent a selected group. Nonetheless the figures represent a stability in body-mass which is astonishing. It is calculated that, during this 20 years, the mean intake of food for each individual weighed approximately 24 tons, and the mean energy intake was 84 million C. Over short periods the daily fluctuations in body-mass (to the extent of 1-4 lb.) are so irregular that they probably represent changes in body hydration and bowel contents rather than in nutritional state. The classic concept of the way in which constancy of body-mass is balanced against changing energy expenditure is based on two assumptions: the first is that food 1. Brody, S. Bioenergetics and Growth. New York, 1945. 2. Brozek, J. Ann. N.Y. Acad. Sci. 1963, 110, 1425. 3. Metropolitan Life Insurance Company Statistical Bulletin, 4. ibid. 1966, 47 1.

1962, 43,


It is energy

commonly assumed that immediate demands for are met from existing body-stores, which are subsequently replenished by an increased intake of food. The latter is in turn achieved by alteration of the sensations of appetite and satiety, which are mainly controlled through the hypothalamus. But the sensation of appetite appears unlikely to fulfil such a function. Appetite is notoriously capricious: it is affected by emotion; it is usually diminished by the fatigue which follows heavy energy expenditure; it is decreased by illness (in which body metabolism rises); and it only responds crudely to variations in demand for energy. The sense of satiety as a controlling mechanism appears to be a more positive factor in animals5 6; and Edholm et al.’ showed that in man too a period of intense activity was followed, after a delay of some hours or days, by increased food intake. There are, however, good grounds for rejecting the sensation of satiety as an accurate regulating mechanism for energy balance; the sensation is not immediate as are most other sensations arising from disturbance of the " milieu intérieur "-e.g., in sodium deprivation or oxygen deprivation-and there is little or no suggestion of a feedback mechanism responding to energy expenditure. In addition, satiety is unlikely to be an acquired sensation ; and, if it were inborn, it would probably be unable to cope both with the needs of the growing child and with those of the adult. However, its importance seems clearly established, since experimental destruction of parts of the hypothalamus 8-10 causes the disappearance of satiety, and the animals gorge themselves and increase their carcass fat. The relevance of such experimental information to the normal control of body-mass is open to doubt on two grounds: the first is that the changes are entirely gross and bizarre; and the second is that when the animals are returned to their pre-experimental weight by food restriction analysis of their carcasses shows quite a different composition to that of their untreated littermates. The experimental procedure may apparently have done more than merely remove satiety. In man it ought to be possible to resolve the question by over-feeding experiments where the normal sensation of satiety is deliberately ignored. Since it is widely accepted that lean-body mass in the normal adult remains relatively constant11 deliberate overfeeding should only affect body-fat. If so, every extra 9 C. ingested should result in a 1 g. increase in weight. Dodds,12 Miller and Mumford,13 Durnin and Norgan,14.and Ashworth et al." were unable to demonstrate this satisfactorily. But 5. 6.

Hollifield, G., Parson, W., Crispel, K. R. Metabolism, 1955, 4, 537. Miller, N. E., Bailey, C. J., Stevenson, J. A. F. Science, N.Y. 1950, 112, 256. 7. Edholm, O. G., Fletcher, J. G., Widdowson, E. M., McCance, R. A. Br. J. Nutr. 1955, 9, 286. 8. Hetherington, A. W., Ranson S.W. Anat. Rec. 1940, 78, 149. 9. Kennedy, G. C. Proc. R. Soc. B, 1953, 140, 578. 10. Anand, B. K. Physiol. Rev. 1961, 41, 677. 11. Behnke, A. R., Jr., Osserman, E. F., Welham, W.C. Archs intern. Med. 1953, 91, 585. 12. Dodds, E. C. Proc. R. Soc. Med. 1950, 43, 342. 13. Miller, D. S., Mumford, P. Am. J. clin. Nutr. 1967, 20, 1212. 14. Durnin, J. V. G. A., Norgan, N. G. J. Physiol. 1967, 189, 26P. 15. Ashworth, N., Creedy, S., Hunt, J. N., Mahon, S., Newland, P. Lancet, 1962, ii, 685.


Passmore et al.,16 using more complicated conversion factors for relating intake to body-mass, were satisfied that the extra energy intake during overfeeding was represented by an increase in body-fat. Many have considered measurable changes in total body-water. The complexity which may enter into conversion factors employed in this type of calculation is almost limitless: some of the possibilities can be seen in the metabolic changes outlined in the last section of this paper. The danger is that these conversion factors tend to be derived from assumptions which may not be strictly correct. Another approach to the problem would be to establish whether body-mass fluctuates when food intake is at a constant level. In rats ’17 mice,!8 and humans 19 it has been shown that the amount of fat in the body can be altered by changing the pattern of food intake, without altering the type or quantity of food eaten, and that this is reflected by a change in body-mass. In a 71-day study of mice, we fed one group normally while the other group received an identical diet through stomach tubes. Oxygen consumption was similar in the two groups, suggesting that there was little difference in energy output; but the stomach-tube group put on more body-weight and more carcass-fat-a finding which was substantiated by studies of carbon retention. THE ENERGY-VALUE OF FOOD

When applying the laws of thermodynamics to nutritional problems it is usually assumed that 1 g. of carbohydrate will always yield about 4 C. of energy, and that 1 g. fat constantly makes available just over 9 C. If, however, some part of the fat is converted into ketones and other substances, and these substances are excreted in the urine, some of the 9 C. now leaves the organism as energy trapped in these molecules. In short, the assumption that fat and carbohydrate yield constant amounts of energy is only correct if they are completely degraded to carbon dioxide and water. The first need therefore is to face the fact that the laws of thermodynamics as applied to a thermodynamically " open " system-i.e., one which can freely and simultaneously exchange mass and energy with the universeneed more critical application than is customary in the more usually studied " closed " system, where only one or other can be exchanged. At this point the argument could properly be advanced that in practice the crude, and perhaps illogical, application of the two laws of thermodynamics has served well in the field of human nutrition insofar as a man taking in 2000-3000 C. maintains a constant body-mass and remains healthy. But these laws could still apply under two circumstances: first, if the amount of energy escaping (trapped in complex organic molecules) were a minute proportion of that available from food; second, if the amount of energy escaping were a constant proportion of that taken in. In the case of protein, the latter is known to be true. 1 g. of protein renders, in a bomb calorimeter, just over 51/2 C. Since the detached. amino-groups are all excreted in the form of urea, it is necessary to subtract the energyvalue of the urea (approximately I1/2 C.) which gives the energy-value of protein to the organism as about 4 C.

Fig. I-Effects of isocaloric low-calorie diets of different compositions on body-weight and carbon output of mice. N=Normal composition. F=80%fatdiet.

C =80% carbohydrate diet. We examined the validity of this assumption by means of further experiments on mice 20 21 (fig. 1). For 7-day periods groups of 5 mice were fed on isocaloric diets which were highfat, high-carbohydrate, or normal in composition. The carbon output was measured in stools, urine, and expired air. On a normal diet less than 50% of the carbon intake was degraded to carbon dioxide, while just over 50% was excreted in urine and stools as energy-containing molecules. When the diet consisted mainly of carbohydrate the amount of the food degraded to carbon dioxide rose to over 80%. What proportion of the energy intake did this represent ? We found 22 that the energy in urine and stools lost to the organism on a normal diet was some 10-12% of intake, and that it rose When carboto 18% when fat was the main calorie source. hydrate was the main source the energy loss was only 6%. In man the direct and continuous long-term measurement of carbon dioxide output presents formidable problems, but we do have information about the loss of carbon and energy in the urine and stools. We also found 23 that obese human subjects on diets similar in composition to those fed to the mice, had similar patterns of carbon output in stools and urine. The loss of carbon as carbon dioxide was probably also similar. The loss of energy locked in complex molecules varied from 6 to 16% of intake (fig. 2). The assumption that the organism obtains the full

energy-value of a diet is therefore untenable, since chang20. 21. 22. 23.

Dowsett, E. E., Kekwick, A., Pawan, G. L. S. Metabolism, 1963, 12, 213. Kekwick, A., Pawan, G. L. S. ibid. 1964, 13, 87. Kekwick, A., Pawan, G. L. S. Ann. N.Y. Acad. Sci. 1965, 131, 519. Kekwick, A., Pawan, G. L. S. in Physiopathology of Adipose Tissue (edited by J. Vague); p. 170. Amsterdam, 1969.

per g. 16.

17. 18. 19.

Passmore, R., Meiklejohn,

A. P., Dewar, A. D., Thow, R. K. Nutr. 1955, 9, 27. Cohn, C., Joseph, D. Am. J. Physiol. 1959, 197, 1347. Kekwick, A., Pawan, G. L. S. Metabolism, 1966, 15, 173.



Fabry, P., Petrasek, R., Braun, T., Bednarek, M., Horakova, E., Konopasek, E. Experientia, 1962, 18, 555.

Fig. 2-Effects of high-fat and high-carbohydrate 1000-calorie diets on the energy and carbon losses of obese subjects.


ing the composition of the diet alters the amount of available energy and, even on a normal diet, the amount of energy lost in this way is not negligible. Furthermore certain hormones have been found to affect the amount of energy lost to the organism, and the excretion of these is known to be independent of food intake. For example, thyroxine increased the carbon lost as carbon dioxide and decreased faecal loss 24 while fat-mobilising substance 25 (F.M.s.), a substance produced by fasting subjects and unobtainable from subjects on a full diet, diminished the carbon-dioxide output and increased the energy lost in urine and to some extent the stools (fig. 3). Cortisone, at certain dose-levels, also modified the pattern of carbon output in animals.26 We have found that the changes in carbon output produced by F.M.s. injections in animals are also reproducible in man.23 27 Thus, regardless of the energy-value of the food, the energy made available to the organism is constantly altered; and there is therefore no firm relationship between the energy in the food and that available to the organism.

solution, thyroxine,

and fatFig. 3-Effects of physiological saline mobilising substance on the body-weight and carbon output of


c= Saline.


F.M.S.Fat-mobilising substance.

Fig. 4-Main pathways of fatty-acid and triglyceride synthesis.

glucose is converted to palmitate, 464 g. The remaining 256 g. is lost

the organism loses only when and if the palmitate

is burned to carbon dioxide and water. If, however, there is total conversion of palmitate to, say, hydroxybutyrate (not, of course, within the fat-cell), the organism increases its mass by 160 g.

One other possibility still exists in the model. If 4 mole of glucose is converted to palmitate, and thence to hydroxybutyrate which is excreted, then the mass loss to the organism is 464+416 g.=880 g. loss, compared with 720 g. if the original 4 mole of glucose was burned to carbon dioxide and



put forward a hypothesis that homoeostasis of body-weight is achieved by changes in fat metabolism. now


Fig. 4 outlines some minute transactions in the fat cell. It shows the main pathways whereby, for example, 4 mole of glucose is converted into 1 mole of palmitate. This synthesis requires energy for its completion but, since it involves the transformation of A.T.P. to A.D.P., and since it is unlikely that the exact amount of energy necessary is released by the A.T.P.-A.D.P. transformation at any one moment,28 the transaction may provide a variable amount of energy to the organism. A similar situation is true in glycerol synthesis. The difficulties in finding satisfactory conversion factors in of energy intake into body-mass are clearly formidable. Since the organism is probably concerned with the constancy of body-mass, it is useful to consider the transactions of mass involved in the glucose-palmitate equation. If 4 mole of glucose is taken in the organism gains 720 g. in weight. If the glucose is degraded to carbondioxide and water, the mass loss when these are shed is also 720 g. If, however, the terms

24. 25. 26. 27. 28.

Kekwick, A., Pawan, G. L. S. Metabolism, 1963, 12, 222. Chalmers, T. M., Kekwick, A., Pawan, G. L. S., Smith, I. Lancet, 1958, i, 866. Kekwick, A., Pawan, G. L. S. J. Endocr. 1965, 31, 265. Kekwick, A., Pawan, G. L. S. Lancet, 1968, ii, 198. Masoro, E. J. Physiol. Rev. 1966, 46, 67.

Since the relationship between food intake and available energy is not immutable, it seems reasonable to suppose that some mechanism other than appetite and satiety may exist for maintaining a constant body-mass and for meeting variable energy demands. We suggest that such a homoeostatic mechanism could be provided by the body’s adipose tissue. Here the energy level per unit mass is twice that in any other tissue. Adipose tissue can rapidly supply free fatty acids which can be utilised as fuel by almost all tissues of the body except possibly the brain. It is known to contain or command alternative metabolic pathways; it can release fatty acids for use as fuel or for conversion to ketones, which in turn may be efficiently used as fuel or excreted by the kidneys; and it can serve as an energy store. It has a high oxygen uptake-above that of resting muscle on a per g. nitrogen basis-it is a source of heat, and its oxygen uptake varies with food intake by as much as 33% of the fasting values.29 30 The turnover-rate is constantly high,31 32 and, because adipose tissue is situated mainly under the skin, it can act as a heat producer while its physical characteristics make it, at the same time, an insulator. Finally, 29. 30. 31. 32.

Shapiro, B., Werthiemer, E. 1956. Metabolism 5, 79. Mirski, A. Biochem. J. 1942, 36, 232. Bernhard, K., Schoenheimer, R. J. biol. Chem. 1940, 133, 707, 713. Jeanrenaud, B. Metabolism, 1961. 10, 535.

825 in well-nourished persons it is large, representing in normal persons some 20% of total body-mass in males, and 30% or more in females.33 If one had to design a system to cope with variations in available energy and fluctuations in energy demand, while at the same time maintaining the body-mass constant, one could not improve on the model provided by adipose tissue. If this is indeed the main function of this tissue, then the homoeostatic mechanisms controlling the activity of fatty tissue become important and deserve more

attention from

biological scientists.

This paper was based on the 1967 Sanderson Wells lecture, delivered by A. K. We thank the clinical research committee of the Middlesex Hospital and medical school for facilities, and Mr. Maurice Turney for help with the figures. Requests for reprints should be addressed to A. K.





In a personal series of 4 cases of tubouterine implantation following sterilisation, 3 of the patients subsequently conceived. A questionary to all consultant gynæcologists in Great Britain elicited 355 replies with particulars of a series of 42 cases of tubouterine implantation following sterilisation and a series of 639 implantations for other conditions. The results showed a 27% conception-rate (17% full-term pregnancies) in the first series, and 14% conceptions (9% full-term pregnancies) in the second series. Reversal of sterilisation, in the young patient, may later be required. Reconstruction of the tubes after sterilisation may involve either tubo-uterine implantation or end-to-end anastomosis. The site of sterilisation will depend on which type of reconstruction operation is the most successful; at present this is uncertain.


Introduction THE number of sterilisations in Britain appears to be increasing and the average age at operation is probably falling. Some women who have been sterilised regret this step later. Thompson and Baird (1968) reported that 8 of 200 patients sterilised (4%) regretted the operation; McCoy (1968) 11 of 39 cases (28%); and Whitehouse (1969) 13 of 95 (14%). Of McCoy’s cases 6 had bitter regrets, and 4 would have accepted an operation to reverse the sterilisation as would 6 of the 13 cases reported by

Whitehouse. In a stable marriage, death of one or more of the children may lead a patient to regret having been sterilised. Religious or psychological factors may also predispose to serious anxiety about sterilisation. As a general rule, however, divorce from or death of a husband, with subsequent remarriage, is the commonest reason for regret. In these cases, few at the moment, the patient usually faces an impasse. She will probably have been assured that sterilisation is final and that she will never have another child. The probability is that she will not even approach her general practitioner for advice; and, even if she does, generations of medical students have been taught that sterilisation is irreversible ". That this is not so is clear from the favourable results in "


Kekwick, A. Br. med. J. 1960, ii,





dealt with

covers a


the past eleven years in this of 80,000.





The first case (1957) was a German girl, aged 35, who wished to get married, but who, at the age of 14, had been placed in a mental home in Nazi Germany and sterilised. The second (1962) and third (1963) cases were patients who had remarried and wanted further children by their second husbands. The fourth (1966) case was a patient with no children in whom abdominal hysterotomy and sterilisation had previously been performed because of increasing liver damage during the pregnancy following repeated hepatitis. Her condition was later diagnosed as acholuric jaundice. Knowing all the facts and the prognosis, she was adamant that she wanted a child. Bilateral tubo-uterine implantation was performed in all these patients, and the first 3 have been delivered of live children. The 4th patient is not yet pregnant two years later, although her tubes are patent.

Survey Since it was thought that these results, like those in many individual series, might be unduly favourable, all consultant gynaecologists in England, Wales, Scotland, and Northern Ireland were asked in a circular letter about their experience with this procedure and its results. Of 709 to whom circulars were addressed, 20 had either retired or died. Altogether 355 replies were received. 5 were discarded because of insufficient data and 1 because the operations were performed overseas and the patients were lost to follow-up, leaving a total of 349. 234 of these respondents had never performed the operation, and 130 of these had never been asked to do so. 115 had performed the operation. Information was requested particularly about the number of tubo-uterine implants performed following sterilisation and the incidence of subsequent pregnancy and tubal patency. Similar data were also requested concerning tubo-uterine implantation done for causes other than sterilisation. FINDINGS



post-sterilisation implantations and 639 implantations for other reasons. Success, as estimated by were

the pregnancy-rate, is shown in table I. For statistical purposes, in the 12 patients who had TABLE I-DATA ON