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The Complexities of the Problem of Obesity
The Complexities of the Problem of Obesity ROSEMARY MURPHY, M.D.
THE treatment of obesity, one of the serious problems of medicine, is, more often than not, baffling to the clinician. The reason for this, to a considerable degree, is that obesity has been considered a simple problem with a simple cure. The cause has been generally accepted as overeating. The cures have been sought in the use of will power, glandular preparations, anorexigenic drugs, and finally in psychiatric analysis. Within recent years, largely as a result of the development of adequate techniques for animal experimentation, extensive study of the problem has been undertaken with results that indicate that obesity is undoubtedly a disease of multiple etiologies and of complicated metabolic disturbances. NERVOUS REGULATION
The role of the olfactory, ocular and taste senses in the control of food intake is self-evident, although often overlooked until an impairment in one or more is reflected in a loss of appetite. In addition to these three, the thought of food may increase or decrease food consumption, depending upon the ideas of pleasure or disgust which accompany it. Below the level of cortical control, nuclei in the hypothalamus appear to act as an appetite-satiety center2 probably influenced by the cerebral cortex, as well as responding to humoral, neurohumoral and other factors. The more medial and ventral of these nuclei have been considered to function as a "satiety" or "regulatory" center which inhibits the more laterally placed "appetite" or "feeding" center. Destruction of the medioventral nuclei, which removes inhibition from the lateral nuclei, results in hyperphagia and obesity, while destruction of the lateral nuclei produces anorexia. On the other hand, electrical stimulation of the latter centers leads to overeating. It would seem from experimental evidence that the control of the appetite center is not very sensitive. If so, this would correlate well with the fact that it is easier to gain than it is to lose weight. 16 It is logical to assume that the "balance" or "tone" of these hypothalamic satiety-appetite centers is controlled by some type of "feed-
439
440
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M URPHY
back" mechanism which reflects the metabolic needs of the body. These may be of a chemical, physical or neural nature. 16 Of the chemical mechanisms, the glucostatic 9 has been studied most thoroughly and some convincing evidence has been accumulated to show that the regulatory centers respond to the availability of blood glucose. Less convincing are the suggestions that the hypothalamic centers function in response to variations in amino acids and other unspecified metabolites. The physical or "thermostatic" theory proposes that the centers are sensitive to temperature changes produced as a result of the specific dynamic action of food. The neural theory, on the other hand, postulates that the central regulatory centers respond to impulses which reach them from the adipose tissue. The autonomic nervous system has been shown in experimental animals to have a tonic influence on the size of the fat stores. 17 Central nervous system representation of parasympathetic activity has been localized in the forepart of the hypothalamus, and sympathetic activity3 in the posterior part. Experiments in animalsl l suggest that increased parasympathetic activity produces an increase in the size of the adipose stores while sympathetic activity results in the opposite effect. Closely related to the latter effect is the demonstration that epinephrine produces a mobilization of fat from adipose tissue with an increase in the serum concentration of nonesterified fatty acids (NEFA)1 and a reduction in the quantity of stored fat. l l The current interest in serotonin, epinephrine, norepinephrine and related amines, important neurohumors which may influence the activity of the hypothalamic autonomic centers in controlling such functions as blood pressure, body temperature and wakefulness, naturally raises the question as to whether they might play a role in governing food intake. That this field is worthy of exploration is indicated by certain clinical observations. For example, obesity is seldom observed in patients with pheochromocytomas. On the other hand, patients receiving chlorpromazine, a drug thought by some3 to block central sympathetic centers and thus release parasympathetic activity, may develop bulimia, gain in weight, somnolence and a decrease in activity.8 This situation bears a striking similarity to the syndrome of hypersomnia, bulimia and abnormal mental states discussed by Gallinek. 4 The administration of reserpine, which releases serotonin, thought to be a chemical transmitter of the parasympathetic nervous system,3 may result in an increase in appetite and weight. A similar tendency to gain weight has been observed in patients receiving iproniazid (Marsilid) which increases the serotonin content of the brain presumably by an inhibition of monoamine oxidase. With increasing knowledge of the role of neurohumors in the control of autonomic functions, including hunger drives, it is possible to speculate that some pharmacologic agents, antagonistic to the neuro-
The Complexities of the Problem of Obesity
441
humors, may be effective in controlling those instances of obesity which are related to a central autonomic disturbance. HORMONAL AND METABOLIC REGULATION
At one period many physicians interpreted obesity as glandular in origin. Attention was focused primarily on the pituitary and thyroid. Even today, many patients are receiving injections of pituitary preparations or strikingly large doses of thyroid in an effort to control obesity. Realization that such forms of therapy have no valid physiological foundation cast considerable suspicion on any efforts to implicate a glandular cause for obesity. Nevertheless, at the present time, the role of glandular disturbances in some types of obesity is the subject of intensive investigation. Role of Insulin
Attention has been focused on the interrelationship of insulin and fat metabolism because a large percentage of adult diabetics are or have been overweight and because a rapid loss of body fat may occur at the onset of severe diabetes. In insulin deficiency, there is evidence for an increased mobilization of fat from adipose tissue, as demonstrated by an increased level of serum nonesterified fatty acids. l At the same time there is a defect in fat synthesis,14 which is corrected by the administration of insulin. Experimental animals (rats) treated with insulin develop a type of obesity characterized by an increase in the number of adipose tissue cells. This phenomenon distinguishes this type of obesity from that of hypothalamic lesions in which the deposition of fat can be accounted for almost entirely by engorgement of the fat cells without an increase in their number." Additional clues that insulin may play a role in the development of obesity are found in a number of studies which reveal islet cell hypertrophy in association with adiposity. Hausberger 5 has tabulated the various types in which islet cell hypertrophy has been found: Cushing's syndrome, steroid-produced obesity in mice and guinea pigs, castrated and old mice, hereditary-hypoglycemic-obese mice and some obese humans. It is interesting to note that in hypothalamic obesity in rats no islet cell hypertrophy is detected. Role of the Pituitary-Adrenal Factors
The association of obesity with hyperadrenocorticism in humans has suggested that the adrenal cortex may be a factor in the development of some types of obesity. Heilman and Kendall 6 demonstrated that in mice given Compound A, fat accounted for a greater proportion of the body weight than in untreated controls. Subsequently, Mayer and colleagues,1° using mice implanted with ACTH-secreting tumors, reported an increase
442
ROSEMARY
M URPHY
in the fat content of the body which was not restored to normal by weight reduction but which could be prevented by adrenalectomy. Obese animals of the hypo thalamic or gold-thioglucose type differ from the adrenotrophic tumor type in that weight reduction restores the fat content of the body to normal. Extension of these findings to an interpretation of human obesity must be made with caution, but it is of interest to note that with aging in man there is a relative increase in the fat content even when weight remains constant. 7 This suggests a similarity to the finding in the adrenotrophic type of obesity in the mouse. Hausberger's5 studies cited above support the concept that obesity when associated with hyperadrenocorticism is the result of insulin released in response to the corticosteroids. It is of some interest to speculate as to whether the increased glucose tolerance test found during the active phase of obesity in human beings may not reflect this same phenomenon. Role of Hexosemonophosphate Shunt in Lipogenesis
The problems of lipogenesis, whether of normal degree, or decreased as in diabetes and starvation, or relatively increased as in aging without gain in weight, or absolutely increased as in obesity, resolve in the last analysis to an understanding of the metabolic pathway for fat synthesis. For some time it has been known that synthesis of fat depended in some fashion upon an associated utilization of glucose, an action dependent upon insulin. With the discovery of alternate pathways for carbohydrate metabolism, the problem of fat synthesis began to be clarified. Of the various alternate pathways, two-the Embden-Meyerhof citric acid cycle (E-M) and the pen to se phosphate or hexosemonophosphate shunt (HMP)-play important roles in fatty acid synthesis. The Embden-Meyerhof glycolytic pathway provides a mechanism for the rapid production of energy. An essential cofactor for this pathway is diphosphopyridine nucleotide (DPN). The alternate hexosemonophosphate shunt pathway, on the other hand, is important for synthesis of fatty acids and steroids. This mechanism requires the presence of triphosphopyridine nucleotide (TPN). Evidence 12 • 13 has now been accumulated to support the concept that variations in the availability of diphosphopyridine nucleotide and triphosphopyridine nucleotide determine whether energy production or synthetic processes predominate. Thus, the addition of diphosphopyridine nucleotide enhances the Embden-Meyerhof citric acid pathway with moderate or no increase in fatty acid synthesis, while addition of triphosphopyridine nucleotide swings carbohydrate metabolism to the hexosemonophosphate shunt with marked increase in fatty acid formation. It is conceivable that, under certain conditions, the shunt pathway might predominate with an increase in lipogenesis. Using rat liver slices as the test material, Tepperman and Tepperman 16 studied this possibility which they termed "adaptive hyperlipogenesis."
The Complexities of the Problem of Obesity
443
Their results indicated that in starvation and diabetes the activity of the shunt pathway was minimal, but that in gold-thioglucose obese mice, in rats trained to eat the entire day's ration in one hour and in rats starved for 48 hours and then fed a high carbohydrate, low fat diet, the activity of the I5hunt was greatly increased. APPLICATION OF EXPERIMENTAL STUDIES TO PROBLEMS OF HUMAN OBESITY
The information which has accumulated from animal experimentation may be applied with profit, although certainly with caution, to the problem of human obesity. Experimental proof of multiple causes and multiple metabolic defects is now available. However, until there are diagnostic tests with which to differentiate the various etiologic types, therapy must remain nonspecific. Efforts should be made to correct the obvious defects in the habits of the obese patient; of these, the three most common faults are irregular eating (especially the "no breakfast and often no lunch" routine), high carbohydrate diets, and inactivity. The first of these represents a common defect in present-day American eating habits. The result is that food intake is limited to a small fraction of the day's hours and patients frequently assume that this actually represents "dieting." If the results of animal experimentation can be applied here, this pattern of eating causes a deviation of carbohydrate metabolism toward the hexosemonophosphate shunt with increased lipogenesis. At least it is not unusual, once a patient has been trained to eat three meals a day, that he comments that, although he is now consuming more food than before, he is actually losing weight. The second defect, that of an excessive carbohydrate intake, is also a prominent error in the American diet. With changes in the mode of living to the "quick meal" or "snacks," and the increase in the quantity of "spectator" eating while spending hours in front of a television set, the proportion of the dietary calories provided by carbohydrates has become excessive. When such a pattern of eating persists, it is possible that the pancreas secretes more insulin, resulting in a shift of the metabolic pathway from oxidation via the Embden-Meyerhof citric acid pathway to lipogenesis by the hexosemonophosphate shunt. The third error is assuming increasing importance not only because of its role in the development of obesity, but also because of its presumed deleterious effect on the vascular system. The unfortunate statement that it takes a 36 mile walk to lose a pound of weight which found its way into medical literature has given rise to the mistaken idea that exercise is of no importance whatever in weight reduction. Nothing could be further from the truth. This myth must be abolished. A walk of one mile each day is equivalent to one pound in 36 days or approximately 10 pounds in a year. When examined in this light, it is quite apparent that the decrease
444
ROSEMARY
M URPHY
in physical activity which has become a characteristic of the modern mode of living is a significant factor in the problem of overweight. Previous generations had their physical activities "built-in" to the act of living. Today, every improvement which has increased the ease and comfort of living has subtracted a fraction of physical activity in the process. Consequently, unless we are prepared to give up the results of modern "progress," it is essential that physical activity be restored to the daily routine in the form of planned physical activity, of which the easiest, most feasible and safest is walking. Nothing has been said thus far about the place of anorexigenic drugs in the treatment of obesity. The long list and great variety of such drugs in the Physicians' Desk Reference is proof enough of their failure to solve the problem. If the time comes when we are able to distinguish those problems of obesity which are caused by malfunction of certain hypothalamic centers from those which are metabolic in origin, and when we have pharmacologic agents designed to act at the involved areas in a predictable manner, then it will be proper to use drugs in selected cases. In the meantime, their use will serve only to direct the patient's attention away from correcting his mode of eating and living and, in most instances, is doomed to failure. REFERENCES 1. Bierman, E. L., Dole, V. P. and Roberts, T. N.: An abnormality of nonesterified fatty acid metabolism in diabetes mellitus. Diabetes 6: 475-479 (Nov.-Dec.) 1957. 2. Brobeck, J. R.: Neural regulation of food intake. Ann. New York Acad. Se. 63: 44-55 (July 15) 1955. 3. Brodie, B. B. and Shore, P. A.: Concept for role of serotonin and norepinephrine as chemical mediators in brain. Ann. New York Acad. Sc. 66: 631-642 (March 14) 1957. 4. Gallinek, A.: Syndrome of episodes of hypersomnia, bulimia, and abnormal mental states. J.A.M.A. 154: 1081-1083 (March 27) 1954. 5. Hausberger, F. X.: Action of insulin and cortisone on adipose tissue. Diabetes 7: 217-220 (May-Junc) 1958. 6. Heilman, F. R. and Kendall, E. C.: Influence of hormones of adrenal cortex, compounds A, Band E, on deposition of fat in mouse. Proc. Staff Meet. Mayo Clin. 31: 454-459 (Aug. 8) 1956. 7. Keys, A. and Brozek, J.: Body fat in adult man. Physiol. Rev. 33: 245-325 (July) 1953. 8. Margolis, L. H.: Pharmacotherapy in psychiatry; a review. Ann. New York Acad. Sc. 66: 698-717 (March 14) 1957. 9. Mayer, J.: Glucostatic mechanism of regulation of food intake. New England J. Med. 249: 13-16 (July 2) 1953. 10. Mayer, J., Zomzely, C. and Furth, J.: Body composition and energetics in obesity induced in mice by adrenotropic tumors. Science 123: 184-185 (Feb. 3) 1956. 11. Shapiro, B. and Wertheimer, E.: Metabolic activity of adipose tissue-review. Metabolism 5: 79-86 (Jan.) 1956. 12. Siperstein, M. D.: Glycolytic pathways; their relation to the synthesis of cholesterol and fatty acids. Diabetes 7: 181-188 (May-June) 1958. 13. Siperstein, M. D. and Fagan, V. M.: Role of glycolysis in fatty acid and choles-
The Complexities of the Problem of Obesity H. 15. W. 17.
445
terol synthesis in normal and diabetic rats. Science 126: 1012-]013 (Nov. 15) 1957. Stadie, W. C.: Ketogenesis. Diabetes 7: 173-180 (May-June) 1958. Tepperman, H. M. and Tepperman, J.: The hexose monophosphate shunt and adaptive hyperlipogenesis. Diabetes 7: 478-485 (Nov.-Dec.) 1958. Van Itallie, T. B.: Physiologic aspects of hunger and satiety. Diabetes 8: 226231 (May-June) 1959. Wertheimer, E. and Shapiro, B.: Physiology of adipose tissue. Physiol. Rev. 28: 451-464 (Oct.) 1948.
THE treatment of obesity, one of the serious problems of medicine, is, more often than not, baffling to the clinician. The reason for this, to a considerable degree, is that obesity has been considered a simple problem with a simple cure. The cause has been generally accepted as overeating. The cures have been sought in the use of will power, glandular preparations, anorexigenic drugs, and finally in psychiatric analysis. Within recent years, largely as a result of the development of adequate techniques for animal experimentation, extensive study of the problem has been undertaken with results that indicate that obesity is undoubtedly a disease of multiple etiologies and of complicated metabolic disturbances. NERVOUS REGULATION
The role of the olfactory, ocular and taste senses in the control of food intake is self-evident, although often overlooked until an impairment in one or more is reflected in a loss of appetite. In addition to these three, the thought of food may increase or decrease food consumption, depending upon the ideas of pleasure or disgust which accompany it. Below the level of cortical control, nuclei in the hypothalamus appear to act as an appetite-satiety center2 probably influenced by the cerebral cortex, as well as responding to humoral, neurohumoral and other factors. The more medial and ventral of these nuclei have been considered to function as a "satiety" or "regulatory" center which inhibits the more laterally placed "appetite" or "feeding" center. Destruction of the medioventral nuclei, which removes inhibition from the lateral nuclei, results in hyperphagia and obesity, while destruction of the lateral nuclei produces anorexia. On the other hand, electrical stimulation of the latter centers leads to overeating. It would seem from experimental evidence that the control of the appetite center is not very sensitive. If so, this would correlate well with the fact that it is easier to gain than it is to lose weight. 16 It is logical to assume that the "balance" or "tone" of these hypothalamic satiety-appetite centers is controlled by some type of "feed-
439
440
ROSEMARY
M URPHY
back" mechanism which reflects the metabolic needs of the body. These may be of a chemical, physical or neural nature. 16 Of the chemical mechanisms, the glucostatic 9 has been studied most thoroughly and some convincing evidence has been accumulated to show that the regulatory centers respond to the availability of blood glucose. Less convincing are the suggestions that the hypothalamic centers function in response to variations in amino acids and other unspecified metabolites. The physical or "thermostatic" theory proposes that the centers are sensitive to temperature changes produced as a result of the specific dynamic action of food. The neural theory, on the other hand, postulates that the central regulatory centers respond to impulses which reach them from the adipose tissue. The autonomic nervous system has been shown in experimental animals to have a tonic influence on the size of the fat stores. 17 Central nervous system representation of parasympathetic activity has been localized in the forepart of the hypothalamus, and sympathetic activity3 in the posterior part. Experiments in animalsl l suggest that increased parasympathetic activity produces an increase in the size of the adipose stores while sympathetic activity results in the opposite effect. Closely related to the latter effect is the demonstration that epinephrine produces a mobilization of fat from adipose tissue with an increase in the serum concentration of nonesterified fatty acids (NEFA)1 and a reduction in the quantity of stored fat. l l The current interest in serotonin, epinephrine, norepinephrine and related amines, important neurohumors which may influence the activity of the hypothalamic autonomic centers in controlling such functions as blood pressure, body temperature and wakefulness, naturally raises the question as to whether they might play a role in governing food intake. That this field is worthy of exploration is indicated by certain clinical observations. For example, obesity is seldom observed in patients with pheochromocytomas. On the other hand, patients receiving chlorpromazine, a drug thought by some3 to block central sympathetic centers and thus release parasympathetic activity, may develop bulimia, gain in weight, somnolence and a decrease in activity.8 This situation bears a striking similarity to the syndrome of hypersomnia, bulimia and abnormal mental states discussed by Gallinek. 4 The administration of reserpine, which releases serotonin, thought to be a chemical transmitter of the parasympathetic nervous system,3 may result in an increase in appetite and weight. A similar tendency to gain weight has been observed in patients receiving iproniazid (Marsilid) which increases the serotonin content of the brain presumably by an inhibition of monoamine oxidase. With increasing knowledge of the role of neurohumors in the control of autonomic functions, including hunger drives, it is possible to speculate that some pharmacologic agents, antagonistic to the neuro-
The Complexities of the Problem of Obesity
441
humors, may be effective in controlling those instances of obesity which are related to a central autonomic disturbance. HORMONAL AND METABOLIC REGULATION
At one period many physicians interpreted obesity as glandular in origin. Attention was focused primarily on the pituitary and thyroid. Even today, many patients are receiving injections of pituitary preparations or strikingly large doses of thyroid in an effort to control obesity. Realization that such forms of therapy have no valid physiological foundation cast considerable suspicion on any efforts to implicate a glandular cause for obesity. Nevertheless, at the present time, the role of glandular disturbances in some types of obesity is the subject of intensive investigation. Role of Insulin
Attention has been focused on the interrelationship of insulin and fat metabolism because a large percentage of adult diabetics are or have been overweight and because a rapid loss of body fat may occur at the onset of severe diabetes. In insulin deficiency, there is evidence for an increased mobilization of fat from adipose tissue, as demonstrated by an increased level of serum nonesterified fatty acids. l At the same time there is a defect in fat synthesis,14 which is corrected by the administration of insulin. Experimental animals (rats) treated with insulin develop a type of obesity characterized by an increase in the number of adipose tissue cells. This phenomenon distinguishes this type of obesity from that of hypothalamic lesions in which the deposition of fat can be accounted for almost entirely by engorgement of the fat cells without an increase in their number." Additional clues that insulin may play a role in the development of obesity are found in a number of studies which reveal islet cell hypertrophy in association with adiposity. Hausberger 5 has tabulated the various types in which islet cell hypertrophy has been found: Cushing's syndrome, steroid-produced obesity in mice and guinea pigs, castrated and old mice, hereditary-hypoglycemic-obese mice and some obese humans. It is interesting to note that in hypothalamic obesity in rats no islet cell hypertrophy is detected. Role of the Pituitary-Adrenal Factors
The association of obesity with hyperadrenocorticism in humans has suggested that the adrenal cortex may be a factor in the development of some types of obesity. Heilman and Kendall 6 demonstrated that in mice given Compound A, fat accounted for a greater proportion of the body weight than in untreated controls. Subsequently, Mayer and colleagues,1° using mice implanted with ACTH-secreting tumors, reported an increase
442
ROSEMARY
M URPHY
in the fat content of the body which was not restored to normal by weight reduction but which could be prevented by adrenalectomy. Obese animals of the hypo thalamic or gold-thioglucose type differ from the adrenotrophic tumor type in that weight reduction restores the fat content of the body to normal. Extension of these findings to an interpretation of human obesity must be made with caution, but it is of interest to note that with aging in man there is a relative increase in the fat content even when weight remains constant. 7 This suggests a similarity to the finding in the adrenotrophic type of obesity in the mouse. Hausberger's5 studies cited above support the concept that obesity when associated with hyperadrenocorticism is the result of insulin released in response to the corticosteroids. It is of some interest to speculate as to whether the increased glucose tolerance test found during the active phase of obesity in human beings may not reflect this same phenomenon. Role of Hexosemonophosphate Shunt in Lipogenesis
The problems of lipogenesis, whether of normal degree, or decreased as in diabetes and starvation, or relatively increased as in aging without gain in weight, or absolutely increased as in obesity, resolve in the last analysis to an understanding of the metabolic pathway for fat synthesis. For some time it has been known that synthesis of fat depended in some fashion upon an associated utilization of glucose, an action dependent upon insulin. With the discovery of alternate pathways for carbohydrate metabolism, the problem of fat synthesis began to be clarified. Of the various alternate pathways, two-the Embden-Meyerhof citric acid cycle (E-M) and the pen to se phosphate or hexosemonophosphate shunt (HMP)-play important roles in fatty acid synthesis. The Embden-Meyerhof glycolytic pathway provides a mechanism for the rapid production of energy. An essential cofactor for this pathway is diphosphopyridine nucleotide (DPN). The alternate hexosemonophosphate shunt pathway, on the other hand, is important for synthesis of fatty acids and steroids. This mechanism requires the presence of triphosphopyridine nucleotide (TPN). Evidence 12 • 13 has now been accumulated to support the concept that variations in the availability of diphosphopyridine nucleotide and triphosphopyridine nucleotide determine whether energy production or synthetic processes predominate. Thus, the addition of diphosphopyridine nucleotide enhances the Embden-Meyerhof citric acid pathway with moderate or no increase in fatty acid synthesis, while addition of triphosphopyridine nucleotide swings carbohydrate metabolism to the hexosemonophosphate shunt with marked increase in fatty acid formation. It is conceivable that, under certain conditions, the shunt pathway might predominate with an increase in lipogenesis. Using rat liver slices as the test material, Tepperman and Tepperman 16 studied this possibility which they termed "adaptive hyperlipogenesis."
The Complexities of the Problem of Obesity
443
Their results indicated that in starvation and diabetes the activity of the shunt pathway was minimal, but that in gold-thioglucose obese mice, in rats trained to eat the entire day's ration in one hour and in rats starved for 48 hours and then fed a high carbohydrate, low fat diet, the activity of the I5hunt was greatly increased. APPLICATION OF EXPERIMENTAL STUDIES TO PROBLEMS OF HUMAN OBESITY
The information which has accumulated from animal experimentation may be applied with profit, although certainly with caution, to the problem of human obesity. Experimental proof of multiple causes and multiple metabolic defects is now available. However, until there are diagnostic tests with which to differentiate the various etiologic types, therapy must remain nonspecific. Efforts should be made to correct the obvious defects in the habits of the obese patient; of these, the three most common faults are irregular eating (especially the "no breakfast and often no lunch" routine), high carbohydrate diets, and inactivity. The first of these represents a common defect in present-day American eating habits. The result is that food intake is limited to a small fraction of the day's hours and patients frequently assume that this actually represents "dieting." If the results of animal experimentation can be applied here, this pattern of eating causes a deviation of carbohydrate metabolism toward the hexosemonophosphate shunt with increased lipogenesis. At least it is not unusual, once a patient has been trained to eat three meals a day, that he comments that, although he is now consuming more food than before, he is actually losing weight. The second defect, that of an excessive carbohydrate intake, is also a prominent error in the American diet. With changes in the mode of living to the "quick meal" or "snacks," and the increase in the quantity of "spectator" eating while spending hours in front of a television set, the proportion of the dietary calories provided by carbohydrates has become excessive. When such a pattern of eating persists, it is possible that the pancreas secretes more insulin, resulting in a shift of the metabolic pathway from oxidation via the Embden-Meyerhof citric acid pathway to lipogenesis by the hexosemonophosphate shunt. The third error is assuming increasing importance not only because of its role in the development of obesity, but also because of its presumed deleterious effect on the vascular system. The unfortunate statement that it takes a 36 mile walk to lose a pound of weight which found its way into medical literature has given rise to the mistaken idea that exercise is of no importance whatever in weight reduction. Nothing could be further from the truth. This myth must be abolished. A walk of one mile each day is equivalent to one pound in 36 days or approximately 10 pounds in a year. When examined in this light, it is quite apparent that the decrease
444
ROSEMARY
M URPHY
in physical activity which has become a characteristic of the modern mode of living is a significant factor in the problem of overweight. Previous generations had their physical activities "built-in" to the act of living. Today, every improvement which has increased the ease and comfort of living has subtracted a fraction of physical activity in the process. Consequently, unless we are prepared to give up the results of modern "progress," it is essential that physical activity be restored to the daily routine in the form of planned physical activity, of which the easiest, most feasible and safest is walking. Nothing has been said thus far about the place of anorexigenic drugs in the treatment of obesity. The long list and great variety of such drugs in the Physicians' Desk Reference is proof enough of their failure to solve the problem. If the time comes when we are able to distinguish those problems of obesity which are caused by malfunction of certain hypothalamic centers from those which are metabolic in origin, and when we have pharmacologic agents designed to act at the involved areas in a predictable manner, then it will be proper to use drugs in selected cases. In the meantime, their use will serve only to direct the patient's attention away from correcting his mode of eating and living and, in most instances, is doomed to failure. REFERENCES 1. Bierman, E. L., Dole, V. P. and Roberts, T. N.: An abnormality of nonesterified fatty acid metabolism in diabetes mellitus. Diabetes 6: 475-479 (Nov.-Dec.) 1957. 2. Brobeck, J. R.: Neural regulation of food intake. Ann. New York Acad. Se. 63: 44-55 (July 15) 1955. 3. Brodie, B. B. and Shore, P. A.: Concept for role of serotonin and norepinephrine as chemical mediators in brain. Ann. New York Acad. Sc. 66: 631-642 (March 14) 1957. 4. Gallinek, A.: Syndrome of episodes of hypersomnia, bulimia, and abnormal mental states. J.A.M.A. 154: 1081-1083 (March 27) 1954. 5. Hausberger, F. X.: Action of insulin and cortisone on adipose tissue. Diabetes 7: 217-220 (May-Junc) 1958. 6. Heilman, F. R. and Kendall, E. C.: Influence of hormones of adrenal cortex, compounds A, Band E, on deposition of fat in mouse. Proc. Staff Meet. Mayo Clin. 31: 454-459 (Aug. 8) 1956. 7. Keys, A. and Brozek, J.: Body fat in adult man. Physiol. Rev. 33: 245-325 (July) 1953. 8. Margolis, L. H.: Pharmacotherapy in psychiatry; a review. Ann. New York Acad. Sc. 66: 698-717 (March 14) 1957. 9. Mayer, J.: Glucostatic mechanism of regulation of food intake. New England J. Med. 249: 13-16 (July 2) 1953. 10. Mayer, J., Zomzely, C. and Furth, J.: Body composition and energetics in obesity induced in mice by adrenotropic tumors. Science 123: 184-185 (Feb. 3) 1956. 11. Shapiro, B. and Wertheimer, E.: Metabolic activity of adipose tissue-review. Metabolism 5: 79-86 (Jan.) 1956. 12. Siperstein, M. D.: Glycolytic pathways; their relation to the synthesis of cholesterol and fatty acids. Diabetes 7: 181-188 (May-June) 1958. 13. Siperstein, M. D. and Fagan, V. M.: Role of glycolysis in fatty acid and choles-
The Complexities of the Problem of Obesity H. 15. W. 17.
445
terol synthesis in normal and diabetic rats. Science 126: 1012-]013 (Nov. 15) 1957. Stadie, W. C.: Ketogenesis. Diabetes 7: 173-180 (May-June) 1958. Tepperman, H. M. and Tepperman, J.: The hexose monophosphate shunt and adaptive hyperlipogenesis. Diabetes 7: 478-485 (Nov.-Dec.) 1958. Van Itallie, T. B.: Physiologic aspects of hunger and satiety. Diabetes 8: 226231 (May-June) 1959. Wertheimer, E. and Shapiro, B.: Physiology of adipose tissue. Physiol. Rev. 28: 451-464 (Oct.) 1948.