Acta med. scand. Vol. 1%, pp. 145-147, 1974

EDITORIAL

RENAISSANCE OF A NEW FRONTIER IN OBESITY RESEARCH

All who have treated severe obesity by conven- tional therapeutic measures aiming at a negative caloric balance know how extremely difficult this is. This is also massively documented in the litera- ture. The successful treatment of a patient with severe obesity, defined as a maintained body weight within the limits of approximately normal, is probably seen very seldom. After having tried to treat several hundred such patients the ex- perience of the author is that when severe, hyper- plastic obese patients continue to reduce weight on an outpatient basis and approach the normal body weight, then there is some additional factor contributing to weight decrease, and occult malig- nant disease should be remembered.

Why, then, is severe obesity so difficult to treat in practice, when the theory seems so easy? Are there factors which we still do not know suffi- ciently well and, if so, which may such factors be?

Energy balance

The first law of thermodynamics does, of course, apply also to severely obese subjects. Why, then, do they not decrease to normal body weight in spite of high motivation and hard trying? This must be because they are not in a negative caloric balance, signifying that caloric intake is suffi- ciently reduced in relation to caloric output or that the caloric output is smaller than anticipated. Usu- ally, in practice, the main emphasis is placed on the caloric intake side, the patient being more or less openly suspected to have a hidden caloric in- take. This side of the equation is, however, easy to check; there are precise methods to determine the caloric equivalents of dietary intake and to assure that these calories have indeed been re- moved from the gastrointestinal tract.

The first factor on the caloric output side of the equation is, of course, physical activity. Obese subjects have been found often to be physically

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inactive. There is, however, also another factor which is not directly associated with physical ac- tivity, and which might cause a variation in caloric output. This is the caloric expense for other pur- poses than muscle work, and here the methodo- logical difficulties are much greater than when caloric intake is measured. Particularly for long- time purposes these methods are very imprac- ticable. This fact alone implies that it might be worthwhile to search for unknown factors which may explain the enigma of the failure of treatment of severe obesity.

Technical errors in measuring caloric output Let us take some striking examples of the lack of precision of the methods applied for measurements of the caloric output due to other factors than physical activity. The accepted “normal” varia- tion of f 10% in basal metabolic rate allows varia- tion of oxygen uptake in absolute terms which may differ between comparable individuals by a factor of 2. This methodological error could ac- count for several kg fat per year.

Another more genuine methodological difficulty is to estimate the caloric contents remaining in the body, a factor necessary to know when evalu- ating caloric balance. One kg adipose tissue con- tains at least ten times more calories than one kg lean tissue. Furthermore the caloric content of water is zero, a fact which frequently seems to be forgotten in obesity treatment practice. Clearly, then, body weight is not a sufficient measure; one needs to know the exact amounts of body fat, body water and lean body weight. The possibility of obtaining exact measurements seems best for body water but is considerably less for body fat. A shift of weight of several kg from lean tissue to fat tissue, corresponding to several tens of thou- sands of calories, might well escape notice with the presently available techniques. This means that

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experiments with energy balance measurements have to be performed over sufficiently long pe- riods. Instead, unfortunately, difficulties in meas- urement of the lost calories then appear. To meas- ure heat production or oxygen uptake accurately over long periods seems, in fact, impossible with available techniques.

These methodological difficulties have probably prevented meaningful conclusions within this field. The clinical problem of obesity does not become smaller through the fact that weight increase is often a very slow process. In order to trace the reason for a weight increase of 5 kg per year, one needs to be able to measure differences of the order of 100 calories per day. This is probably beyond the capacity of our presently available methods.

The Vermont study Recent studies by a group in Vermont, USA (6), have in a most dramatic way brought this question into focus. These studies are impressive because the time axis is so long that the methodological problems mentioned are probably of minor im- portance. These investigators overfed young men with more than 5 OOO calories per day for several months, causing an excess of more than 1 mill. calories in some cases. In spite of this magnificent overfeeding under controlled conditions, some of the volunteers did not increase in body weight. This might be the reverse situation to the unsuc- cessful, unhappy dieting patient, who does not reduce weight in spite of reduction of caloric in- take. This points clearly to the fact that there is yet much to learn about energy regulation, and within this field of ignorance the explanation of the enigma of the unsuccessful dieting patient may well be hidden. Let us therefore look into some more arguments within this field of obesity re- search, which has in fact attracted the interest of several recent international congresses.

Old and recent information on caloric expenditure The phenomenon of the subject who can eat whatever he wants without increasing in weight is well known. This empirical fact was recorded at the beginning of this century by Neumann ( 5 ) in studies on himself. Neumann noted that he could eat a wide range of calories, but his body weight remained constant. It could be argued that he did not know his body composition before and after

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the dietary periods. A shift in lean and fat body mass could explain missing calories. Furthermore his physical activity was not know. This is true, but the observation periods were so long that these errors probably cancel out.

These were the first attempts to document the empirical observations. The Vermont study (6) and other studies referred to below then constitute a renaissance of an old frontier in obesity research.

Miller (3) reviewed some of these aspects in a recent congress in the following way. Careful studies of the caloric intake in a given population at a given body weight reveal that there is indeed a large variation. Actually some adults seem to manage to keep their body weight constant on the same caloric consumption as babies. The implica- tion is, according to Miller, that caloric intake has comparatively little to do with the resulting body weight.

Another example taken by Miller to demonstrate the potential possibilities within this field is the variation of basal metabolic rate mentioned above. Obviously, when the method is so crude, large differences could easily be hidden during long periods. Nevertheless, careful measurements of absolute oxygen uptake rates in different experi- mental situations have revealed small differences which, when multiplied by the time factor, become most important.

Basal metabolic rate is the oxygen uptake after sleep, in the fasting and in resting state. Possible differences between different situations of interest are most likely minimized by these ambitions to standardize the situation examined. It seems more logical to perform the measurements after a stand- ardized work load in the non-fasting state. Then the caloric expenditure is increased and potential differences between situations of interest should be accentuated. When performing these experiments Miller et al. (4) found that the energy output (oxygen uptake measurements) increases in sub- jects fed a hypercaloric diet, which might explain the lack of increase in body weight in some of these subjects. When measuring oxygen uptake over whole days, it seems possible to explain satisfactorily the extra output of calories.

Is there a regulation of caloric expenditure? It is obvious that within this field very small dif- ferences in caloric intake and output play a large role over a year or more in terms of kg body fat.

Editorial 147

It is therefore surprising that the caloric intake of different weight-constant subjects differs so vastly, also under strictly controlled conditions during long periods. This leads Miller and others to be- lieve that the regulation of body weight and body fat resides mainly on the caloric output side, the caloric intake playing a comparatively minor role. The output regulation is mainly due to the effi- ciency of handling calories, directing them to heat o r to body fat.

Careful measurements have thus given experi- mental support to the idea that, in fact, there is probably a regulatory mechanism on the caloric output side. The next question is then how this can be explained on the biochemical and/or per- haps endocrine basis. Several theoretical explana- tions remain. These could be such phenomena as uncoupling of oxidative phosphorylation, or more specific energy leaking pathways of carbo- hydrate, protein and lipid metabolism. None has so far been convincingly demonstrated, but here too the possibilities of exact evaluation are limited.

This, of course, leaves us with the potential pos- sibility that obesity is caused not so much by over- eating but by a deficient system for disposing extra calories. “Luxus Konsumtion”, a term coined by the early German workers, signifying the potential to get rid of extra, “luxus”, calo- ries, is not at work in subjects tending to become obese. They become obese by accumulating more ingested calories than do subjects without a ten- dency to obesity. From this point of view, ac- cordingly, it is normal to dispose of some ingested calories, and abnormal to be too efficient in saving calories.

Adipose tissue cellularity and energy expenditure The recent development of the cellular concept of adipose tissue and its relation to obesity seems to have a potential to create a better understanding of obesity. These observations may help mainly to distinguish different subgroups of obesity, and therefore different possibilities for, among other things, pathogenesis. The hyperplastic obese pa- tients are those who are most difficult to reduce to a normal body weight by introduction of a negative

caloric balance ( I ) . Furthermore, when subjected to physical training, their weight reduction is ab- normally slow (2). Weight decrease seems to cease at a certain fat cell size and seems actually pos- sible to predict approximately when fat cell size is known at the start of treatment ( I ) . These ob- servations imply that there may be some associa- tion between adipose tissue cellularity and the possible caloric expenditure regulation.

The new information briefly reviewed here is still fairly preliminary in spite of the fact that the observations are old both empirically and in re- search. Nevertheless, it may open up means to solve a dilemma which most obesity treating doc- tors. not to mention the poor obese patient, have experienced as most frustrating, namely why some people increase in weight while others do not, and why is conventional treatment of obesity very seldom successful.

Per Bjorntorp, Clinical Metabolic Laboratory, Medical Department I, Sahlgren’s Hospital, Gothenburg, Sweden

REFERENCES I . Bjorntorp. P., Carlgren, G., Isaksson, B., Krot-

kieuski. M.. Larsson, B. & Sjostrom, L.: The results of treatment of obese women with caloric restriction in relation to adipose tissue cellularity. In press 1974.

2. Bjhtorp. P., de Jounge, K., Sjostrom, L. & Sulli- van. L.: The effect of physical training on insulin production in obesity. Metabolism 19: 631, 190.

3. Miller. D. S.: Thermogenesis in everyday life. Pro- ceedings of the Second Congress of Energy Balance in Man. Lausanne, March 14-16, 1974. Excerpta Medica. In press 1974.

4. Miller. D. S., Mumford, P. & Stock, M. J.: Glut- tony. 2. Thermogenesis in overeating man. Amer. J. clin. Nutr. 1 1 : 1223, 1%7.

5. Neumann, R. 0.: Experimentelle Beitrage zur Lehre von taglichen Nahrungsbedarf des Menschen unter besonderer Beriicksichtigung der notwendigen Ei- weissmenge. Arch. Hyg. 45: I , 1902.

6. Sims. E. A. H. & Horton, E. S.: Endocrine and metabolic adaptation to obesity and stqation. Amer. J. clin. Nutr. 21: 1455, 1968.

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