Human obesity - a survey and a suggestion Obesity is a disease characterized by the excessive accumulation of adipose tissue. In all obese patients there is an increase in the amount of fat in most adipocytes; in as yet an undetermined fraction of the obese population there is also an increase in the number of fat cells.1 The excessive accumulation of adipose tissue characteristic of obesity results from prolonged positive caloric* balance. The metabolic events that link positive caloric balance to an excess of fat tissue are well known. Much less well understood, however, is why positive caloric balance develops in the first place. Stimulated by the problem of human obesity, biologists have made remarkable progress over the past 20 years m developing an understanding of the metabolism of adipose tissue. Those phenomena responsible for the deposition of lipid within the fat cell and for the mobilization of fat from this element have been delineated. It is clear that fat is deposited in the fat cell as a result of two processes: (a) the incorporation of circulating triglyceride and (b) the in situ synthesis of lipid from plasma glucose. Both of these processes are initiated by feeding and facilitated by *As with other scientific journals, CMAJ has been changing, over the last few years, to the use of units of Syst.me mr ternational d'unit.s, as recommended by the World Health Organization. By adopting the joule in place of the calorie as the unit of energy in nutrition and making other pertinent changes, we believe that we are helping the medical profession ease into the new international terminology for this field, as for others. The articles in the obesity symposium in this issue (starting on page 1401) show evidence of this practice. - Ed.
the increase in the concentration of plasma insulin that is a consequence of the ingestion of food. Mobilization of fat from adipose tissue results from activation of a tissue lipase, which breaks down stored triglyceride, releasing free fatty acid from fat tissue. This reaction is regulated by the concentration of insulin in plasma; it is activated by the reduction in the plasma insulin concentration that occurs with fasting and is inhibited by the increase in the plasma insulin concentration that occurs with feeding. Thus, prolonged positive caloric balance results in enhanced incorporation of plasma triglyceride in fat cells, enhanced de novo synthesis of lipid within adipocytes, and inhibition of fat mobilization from the adipose tissue. These events culminate in an increase in adipocyte fat content and size.2 There is less complete knowledge as to the mechanisms responsible for the control of the cellularity of adipose tissue. It is evident that a minority of obese subjects display an increased number of fat cells. Usually these patients have been obese for many years, often from early childhood.1 Animal experimentation suggests that the pattern of infant nutrition can affect fat cell number, and it is possible that the presence of fat cell hyperplasia in adult humans reflects this kind of early control. There is also evidence that the fat cell is among the more long-lived of the cellular elements in mammals. In the rat, marked depletion of total body fat by starvation does not lead to the destruction of fat cells; these cells remain intact and capable of reaccumulating lipid when feeding is resumed.3
The remarkable advances that have been made in understanding the metabolism of adipose tissue have not been accompanied by similar changes in the therapy of obesity. Obesity remains one of the most intractable disorders known to man, and the infrequency with which long-standing obesity can be reversed is well known to all physicians and to most patients. Fundamental to this lack of progress in the therapy of obesity is the fact that there is no clear understanding of why obese patients enter into the prolonged period of positive caloric balance that results in obesity. In some patients, positive caloric balance is due to overt gluttony; these individuals often have profound psychiatric abnormalities and should be treated appropriately. However, in most, obesity develops with a diet that is not greatly different from the North American norm, and in these instances positive caloric balance may result as much from an alteration in energy expenditure as from an alteration in food intake. While a number of investigators have postulated the presence of an inherited disorder of energy metabolism in patients with obesity, to date no such disorder has been found. However, there is evidence that obese subjects have a different pattern of kinetic behaviour than do normal-weight individuals. Time-motion photography has been used to demonstrate that overweight subjects display fewer spontaneous movements and move less frequently during exercise than do individuals who are of normal weight.4 Further, the infant offspring of obese patients have been described as displaying less movement than infants of normal-weight parents. Thus, it is conceivable that movement pat-
CMA JOURNAL/DECEMBER 23, 1978/VOL. 119 1383
terns are abnormal in the obese and that this abnormality is an inherited characteristic. The extent of genetic influences in the development of obesity has been explored in some detail. Despite this attention, all that is known is that genetic factors are important in the causation of the obese state; the genetic determinants that are involved have not been elucidated. All attempts to uncover an inherited metabolic abnormality fundamental to the development of obesity have been unsuccessful. The existing information suggests that the many metabolic derangements that occur with obesity are the result and not the cause of the obese state. For example, the most common metabolic derangement seen in obesity, hyperinsulinism, can be induced in normal volunteers by the simple expedient of having them overeat. Further, when obese subjects who are hyperinsulinemic are fasted, serum insulin values rapidly fall to within the normal range. Also, there is no clear evidence that genetic factors impose an inbred abnormality of eating behaviour; once again the available data suggest that these patterns are learned rather than inherited. However, it is just conceivable that there is a genetic basis for the abnormalities in kinetic behaviour previously mentioned. The data are too preliminary to allow a definitive conclusion, but this possibility is worth serious consideration. The absence of a primary, reversible, metabolic or psychiatric basis for the development of human obesity has made the treatment of the vast majority of patients unsatisfactory in the extreme. There is probably no other disease, including cancer, in which patients are more prone to the acceptance of fad or quack remedies. Compounding attempts at therapy is the fact that only a few physicians have much knowledge of human nutrition or much time and compassion for the fat patient. An alternative approach would be to direct most obese adults into treatment programs staffed by nutritionists and public health personnel. As behaviour therapy has been shown to be successful, at least in the short term, in the management of small groups of patients,5 behaviour therapists may be useful additions to this team. Physicians might concentrate
their attention on those patients in whom significant cardiovascular or metabolic complications of obesity have developed. The importance of proper control of these complications is emphasized by the recent demonstration that they, and not the degree of fatness itself, are responsible for much of the excess mortality associated with obesity. Ultimately, the public health problem posed by the fact that 10% to 15% of the North American populaion is significantly overweight can only be approached by the development of proper preventive techniques. Because of the many studies that have indicated that unless obese children are treated in an early, energetic and appropriate fashion they will mature into obese adults refractory to treatment, these preventive measures should be directed at children and their parents. At the very least, steps should be taken to improve nutrition education in the schools, including school-parent organizations, and to provide nutrition counselling services to those families with a distinct genetic predisposition to the development of the disease. These programs will require resources and, in view of our very limited success in treating adult obesity, serious consideration should be given to diverting money and manpower from adult to pediatric initiatives. C.H. HOLLENBERG, MD, FRcP[c], FACP Professor and chairman Department of medicine University of Toronto Toronto, Ont.
References 1. SALANS LB, CUSHMAN SW, WETSMANN RE: Studies of human adipose tissue. Adipose cell size and number in nonobese and obese patients. J Clin Invest 52: 929, 1973 2. HOLLENBERG CH: The fat cell and
the fat patient. Ann R Coil Physicians Surg Can 8: 119, 1975
3. HOLLENBERG CH, VosT A: Regulation of DNA synthesis in fat cells and stromal elements from rat adipose tissue. I Clin Invest 47: 2485, 1968 4. MAYER J: Obesity: Progress and remaining ignorance, chap 16, in Con-
troversies in internal Medicine, INGELFINGER FJ (ed), Saunders, Philadel-
Myeostatin Vaginal Cream plus Oral Tablets
Amost effective way to treat recurrent vaguud candidiasis. MYCOSTATIN VAGINAL CREAM MYCOSTATIN VAGINAL TABLETS Indications: Vaginal infections caused by Candida (Monilia) species. Dosage: Cream: Usual dosage is 4 g (100,000 units) once or twice daily. Tablets: Usual dosage is 1 tablet (100,000 units) once or twice daily. In most cases 2 weeks ot therapy will be sufficient but in some cases more prolonged treatment may be necessary. Administration should be continued tor at least 48 hours after clinical cure to prevent relapse. Instructions tor the patient are enclosed in each package. Supply: Cream: Tubes ot 120 g with applicator designed to deliver a 4 g dose. Each gram contains 25,000 units ot nystatin in a cream base. Tablets: Packages 0115 and 30 tablets with applicator. Each tablet contains 100,000 units 01 nystatin and 0.95 g ot lactose.
MYCOSTATIN ORAL TABLETS indications: Prevention and treatment 01 intection caused by Candida (Monilia) species in the intestinal tract and tor protection against candidal overgrowth during antimicrobial or corticosteroid therapy. Dosage: Usual prophylactic and therapeutic dose is 1 tablet (500,000 units) 3 times daily. Administration should be continued br at least 48 hours alter clinical cure to prevent relapse. Supply: Bottles 01100 tablets 01500,000 units per tablet.
ALL DOSAGE FORMS Contraindication: Hypersensitivity to nystatin. Precaution: Use 01 the vaginal applicator may not be considered desirable during pregnancy. Adverse Reactions: Mycostatin is virtually nonsensitizing and nontoxic and is well tolerated, even on prolonged administration. Large oral doses may produce diarrhea and GI. distress. It irritation or hypersensitivity should occur tollowing intravaginal or topical use, discontinue medication.
Product Monograph available to physicians and pharmacists on request.
phia, 1966
S. STUART RB: Behavioural control of overeating. Behav Res Ther 5: 357, 1967 6. KEYS A, ARAvANIS C, BLACKBURN H, et al: Coronary heart disease: overweight and obesity as risk factors. Ann
Intern Med 77: 15, 1972
1384 CMA JOURNAL/DECEMBER 23, 1978/VOL. 119
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the increase in the concentration of plasma insulin that is a consequence of the ingestion of food. Mobilization of fat from adipose tissue results from activation of a tissue lipase, which breaks down stored triglyceride, releasing free fatty acid from fat tissue. This reaction is regulated by the concentration of insulin in plasma; it is activated by the reduction in the plasma insulin concentration that occurs with fasting and is inhibited by the increase in the plasma insulin concentration that occurs with feeding. Thus, prolonged positive caloric balance results in enhanced incorporation of plasma triglyceride in fat cells, enhanced de novo synthesis of lipid within adipocytes, and inhibition of fat mobilization from the adipose tissue. These events culminate in an increase in adipocyte fat content and size.2 There is less complete knowledge as to the mechanisms responsible for the control of the cellularity of adipose tissue. It is evident that a minority of obese subjects display an increased number of fat cells. Usually these patients have been obese for many years, often from early childhood.1 Animal experimentation suggests that the pattern of infant nutrition can affect fat cell number, and it is possible that the presence of fat cell hyperplasia in adult humans reflects this kind of early control. There is also evidence that the fat cell is among the more long-lived of the cellular elements in mammals. In the rat, marked depletion of total body fat by starvation does not lead to the destruction of fat cells; these cells remain intact and capable of reaccumulating lipid when feeding is resumed.3
The remarkable advances that have been made in understanding the metabolism of adipose tissue have not been accompanied by similar changes in the therapy of obesity. Obesity remains one of the most intractable disorders known to man, and the infrequency with which long-standing obesity can be reversed is well known to all physicians and to most patients. Fundamental to this lack of progress in the therapy of obesity is the fact that there is no clear understanding of why obese patients enter into the prolonged period of positive caloric balance that results in obesity. In some patients, positive caloric balance is due to overt gluttony; these individuals often have profound psychiatric abnormalities and should be treated appropriately. However, in most, obesity develops with a diet that is not greatly different from the North American norm, and in these instances positive caloric balance may result as much from an alteration in energy expenditure as from an alteration in food intake. While a number of investigators have postulated the presence of an inherited disorder of energy metabolism in patients with obesity, to date no such disorder has been found. However, there is evidence that obese subjects have a different pattern of kinetic behaviour than do normal-weight individuals. Time-motion photography has been used to demonstrate that overweight subjects display fewer spontaneous movements and move less frequently during exercise than do individuals who are of normal weight.4 Further, the infant offspring of obese patients have been described as displaying less movement than infants of normal-weight parents. Thus, it is conceivable that movement pat-
CMA JOURNAL/DECEMBER 23, 1978/VOL. 119 1383
terns are abnormal in the obese and that this abnormality is an inherited characteristic. The extent of genetic influences in the development of obesity has been explored in some detail. Despite this attention, all that is known is that genetic factors are important in the causation of the obese state; the genetic determinants that are involved have not been elucidated. All attempts to uncover an inherited metabolic abnormality fundamental to the development of obesity have been unsuccessful. The existing information suggests that the many metabolic derangements that occur with obesity are the result and not the cause of the obese state. For example, the most common metabolic derangement seen in obesity, hyperinsulinism, can be induced in normal volunteers by the simple expedient of having them overeat. Further, when obese subjects who are hyperinsulinemic are fasted, serum insulin values rapidly fall to within the normal range. Also, there is no clear evidence that genetic factors impose an inbred abnormality of eating behaviour; once again the available data suggest that these patterns are learned rather than inherited. However, it is just conceivable that there is a genetic basis for the abnormalities in kinetic behaviour previously mentioned. The data are too preliminary to allow a definitive conclusion, but this possibility is worth serious consideration. The absence of a primary, reversible, metabolic or psychiatric basis for the development of human obesity has made the treatment of the vast majority of patients unsatisfactory in the extreme. There is probably no other disease, including cancer, in which patients are more prone to the acceptance of fad or quack remedies. Compounding attempts at therapy is the fact that only a few physicians have much knowledge of human nutrition or much time and compassion for the fat patient. An alternative approach would be to direct most obese adults into treatment programs staffed by nutritionists and public health personnel. As behaviour therapy has been shown to be successful, at least in the short term, in the management of small groups of patients,5 behaviour therapists may be useful additions to this team. Physicians might concentrate
their attention on those patients in whom significant cardiovascular or metabolic complications of obesity have developed. The importance of proper control of these complications is emphasized by the recent demonstration that they, and not the degree of fatness itself, are responsible for much of the excess mortality associated with obesity. Ultimately, the public health problem posed by the fact that 10% to 15% of the North American populaion is significantly overweight can only be approached by the development of proper preventive techniques. Because of the many studies that have indicated that unless obese children are treated in an early, energetic and appropriate fashion they will mature into obese adults refractory to treatment, these preventive measures should be directed at children and their parents. At the very least, steps should be taken to improve nutrition education in the schools, including school-parent organizations, and to provide nutrition counselling services to those families with a distinct genetic predisposition to the development of the disease. These programs will require resources and, in view of our very limited success in treating adult obesity, serious consideration should be given to diverting money and manpower from adult to pediatric initiatives. C.H. HOLLENBERG, MD, FRcP[c], FACP Professor and chairman Department of medicine University of Toronto Toronto, Ont.
References 1. SALANS LB, CUSHMAN SW, WETSMANN RE: Studies of human adipose tissue. Adipose cell size and number in nonobese and obese patients. J Clin Invest 52: 929, 1973 2. HOLLENBERG CH: The fat cell and
the fat patient. Ann R Coil Physicians Surg Can 8: 119, 1975
3. HOLLENBERG CH, VosT A: Regulation of DNA synthesis in fat cells and stromal elements from rat adipose tissue. I Clin Invest 47: 2485, 1968 4. MAYER J: Obesity: Progress and remaining ignorance, chap 16, in Con-
troversies in internal Medicine, INGELFINGER FJ (ed), Saunders, Philadel-
Myeostatin Vaginal Cream plus Oral Tablets
Amost effective way to treat recurrent vaguud candidiasis. MYCOSTATIN VAGINAL CREAM MYCOSTATIN VAGINAL TABLETS Indications: Vaginal infections caused by Candida (Monilia) species. Dosage: Cream: Usual dosage is 4 g (100,000 units) once or twice daily. Tablets: Usual dosage is 1 tablet (100,000 units) once or twice daily. In most cases 2 weeks ot therapy will be sufficient but in some cases more prolonged treatment may be necessary. Administration should be continued tor at least 48 hours after clinical cure to prevent relapse. Instructions tor the patient are enclosed in each package. Supply: Cream: Tubes ot 120 g with applicator designed to deliver a 4 g dose. Each gram contains 25,000 units ot nystatin in a cream base. Tablets: Packages 0115 and 30 tablets with applicator. Each tablet contains 100,000 units 01 nystatin and 0.95 g ot lactose.
MYCOSTATIN ORAL TABLETS indications: Prevention and treatment 01 intection caused by Candida (Monilia) species in the intestinal tract and tor protection against candidal overgrowth during antimicrobial or corticosteroid therapy. Dosage: Usual prophylactic and therapeutic dose is 1 tablet (500,000 units) 3 times daily. Administration should be continued br at least 48 hours alter clinical cure to prevent relapse. Supply: Bottles 01100 tablets 01500,000 units per tablet.
ALL DOSAGE FORMS Contraindication: Hypersensitivity to nystatin. Precaution: Use 01 the vaginal applicator may not be considered desirable during pregnancy. Adverse Reactions: Mycostatin is virtually nonsensitizing and nontoxic and is well tolerated, even on prolonged administration. Large oral doses may produce diarrhea and GI. distress. It irritation or hypersensitivity should occur tollowing intravaginal or topical use, discontinue medication.
Product Monograph available to physicians and pharmacists on request.
phia, 1966
S. STUART RB: Behavioural control of overeating. Behav Res Ther 5: 357, 1967 6. KEYS A, ARAvANIS C, BLACKBURN H, et al: Coronary heart disease: overweight and obesity as risk factors. Ann
Intern Med 77: 15, 1972
1384 CMA JOURNAL/DECEMBER 23, 1978/VOL. 119
(go
SQUiBB Squibb Quality-the Priceless Ingredient R SQUIBB & SONS LTD 2365 COTE DE LIESSE. L..........J MONTREAL. DUE
