Obesity Surgery, 15, 3-10

Review Article

Contribution of Bariatric Surgery to the Comprehension of Morbid Obesity Picard Marceau, MD, PhD, FRCSC Laval Hospital, Quebec, Canada Convinced that morbid obesity was not due to food excess but rather to a metabolic disorder, we searched in the literature for data in favor of a metabolic disorder. We have found evidence in support of the thesis that the cause of morbid obesity is the inability to burn excessive caloric intake normally. It would involve the difficulty to increase heat with the amount of calories taken, which would be faulty and force fat deposition. This mechanism called dietinduced thermogenesis (DIT) allows the dispersion by heat of excessive calories to obtain energy balance. Results from bariatric surgery and particularly biliopancreatic diversion (BPD) give further support to this thesis. BPD would improve heat production to a meal (DIT) by one of these mechanisms: increased insulin sensitivity, change in intestinal hormone secretion, or chronic lipid malabsorption. Available results show that surgery, to be efficient, must change the physiology and not solely decrease food intake. Key words: Morbid obesity, thermogenesis, bariatric surgery, biliopancreatic diversion

treatment, and more recently the high failure rate with mechanical food restriction. Permanent cure of this disease requires more than food restriction; it requires changing the physiology. In searching for another explanation than food excess to explain severe obesity, we looked for basic and clinical research data that would better fit our clinical experience. We were able to obtain from the literature a more appealing general view which contradicts the prejudice that morbid obesity is due to abnormal eating habits. As others have said,1 obese patients need more than to “eat less and exercise more” to ameliorate their condition. We will present from the literature the evidence for the existence of a self-regulated mechanism for energy balance and weight maintenance. We will then convey evidence that in morbidly obese patients this mechanism is faulty and probably the source of their disease. Finally, we will attempt to show how, in our view, bariatric surgery contributes to the comprehension of the obesity-energy balance disease.

Introduction Mechanism for Weight Maintenance Most individuals who care for morbidly obese patients become convinced that the disease, contrary to the commonly held belief, is not due to excessive eating but to a metabolic disorder. Their conviction is based on their personal contact with morbidly obese patients, the persistent failure of medical Reprint requests to: P. Marceau, MD, PhD, Laval Hospital, 2725, chemin Ste-Foy, Quebec G1V 4G5, Canada. Fax: 418-656-4825; e-mail: [email protected]

© FD-Communications Inc.

How can we explain the fact that the great majority of people not only do not become obese but also show a gradual predictable yearly progression of their weight? Statistically, a healthy adult gains on average, 0.3 kg a year. This slow steady progression despite a 25% variation between meals and between days undoubtedly requires an automatism. The mean yearly caloric intake is over a million and a gain of only 0.3 kg represents about 400 calories in Obesity Surgery, 15, 2005 3

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excess. This is a one-tenth of one percent precision. It defies any human calculation and cannot be the result of any good behavior. Nothing else can match such precision except a continuous automatic daily control mechanism. This evidence have been repeatedly emphasized in the literature.1-3 On the one hand, it is evident that weight gain implies an excess in energy intake over energy output. However, on the other hand, the imbalance between the two may very well be due to a deficiency in expenditure rather than an excess in the intake. There is strong evidence that this balance is achieved by adjusting expenditure following intake, and this is inherently logical. Ravussin et al4 found that weight gain depended on the capacity of the organism to lose energy. Observing a 100 persons for about 4 years, they found that the risk of weight gain over the years, independent of eating habits, correlated by >80% with the initial 24-hour energy expenditure. For each 200 kcal/day below the mean for the group, the risk of weight gain was four times greater. It could be interpreted as meaning: the less that the initial capacity was to lose, the greater that the risk was to gain weight, disregarding the intake. Increased energy output following increased intake has always characterized experiments with overfeeding. Weight change does not usually follow increased caloric intake. Neumann5 over 100 years ago, was the first to show on himself that he was able to increase his food intake by 800 kcal without weight gain. Sims6 found that food intake could be doubled in a group of thin persons, without weight gain. Angel et al7 experimenting on students, increased their caloric intake by 1,400 kcal and found that only 20% of these excess calories were converted to weight gain. In infants, Morgan et al8 showed that there was no correlation between the amount of milk taken and weight change. All these experiments demonstrate a variable capacity of the organism to dispose of excess calories and maintain weight. Bouchard and co-workers9 in a study on overfeeding identical twins, reported an individual variation between 0 to 60% in the capacity to dispose of extra calories without fat deposition. Appetite and satiety are not considered in these experiments, but we find it difficult to give these signals a preponderant role in weight maintenance. It is evident that they play a role,10,11 but they are too weak and too slow to fit the precision required for 4 Obesity Surgery, 15, 2005

weight maintenance. Furthermore, there are many distracting factors, particularly gustative quality of food, which affect these signals in both directions independent of body weight.12 It is difficult to believe that appetite and satiety are the mechanisms required for weight maintenance.

Thermogenesis There is scientific evidence for a mechanism by which the organism succeeds in disposing of excess calories and maintaining energy balance. There is also evidence that this role is played by thermogenesis, which is the capacity of the organism to burn excess calories by producing heat. Neumann5 was the first to propose the theory that increased food intake was accompanied by increased heat production, and this was able to maintain energy balance without having to use fat deposition. This has never found general agreement, but over the years this theory has reemerged repeatedly. Miller et al13 were able to demonstrate this increased temperature with increased caloric intake; they called it “Diet-Induced Thermogenesis (DIT)”. It was evident that diet like a cold environment, was able to induce thermogenesis. Furthermore, they showed that heat was boosted by activity, giving the rise a greater importance than what is usually estimated because measures were done with subjects at rest. Over the years, thermogenesis has been given increasing importance,2,3,6,14-19 and progressively researchers see in thermogenesis a role in energy balance and a mechanism that prevents obesity.1,20-22 It has been argued that the number of calories involved in thermogenesis is insufficient to play a major role in energy balance. This is contradicted by Miller’s experiments showing a possible ten-fold increase in energy expenditure, depending on diet.13,23 It is also contradictory to the findings of Levine et al21 that 1) a ten-fold difference in fat storage from overeating was due to increased expenditure and 2) two-thirds of this spontaneous increase in expenditure was due to non-exercise activity thermogenesis (NEAT). What mechanism makes temperature rise after a meal? There is evidence that insulin would be an important trigger factor, although not the only one.24

Comprehension of Morbid Obesity

In humans, the higher the level of insulin, the greater the thermogenesis.25 Insulin would stimulate adrenaline, neuro-hormones and the autonomous nervous system.17,26 Recently, Dulloo and Jacquet22 have presented evidence for an additional pathway by which thermogenesis would be triggered for regulating weight. Thermogenesis would be directly influenced by body fat content. When body fat decreases, thermogenesis decreases, and when body fat increases, thermogenesis increases. After a period of starvation when alimentation is resumed, thermogenesis related to insulin will rapidly increase, while the adipose-specific thermogenesis will continue to lower the basic metabolism until the return of body fat volume. There is some evidence that individual capacity to reach energy balance is principally genetic. From his study on identical twins reared apart, Stunkard and colleagues27 had enough data to estimate that this capacity was >70% genetic. According to Friedman,1 heritability of obesity is estimated between 70 to 80%.

Disorder in Heat Production in Morbid Obesity What is the problem in morbidly obese patients that could explain their obesity? There is evidence that something is wrong in their thermogenesis, and this can be the cause of their obesity. Instead of burning excess calories, obese patients tend to transform them into fat.3,6 Their “furnace” to burn calories on demand is defective. Many experiments have shown the difficulty for the obese to produce heat. It has been shown that obesity is accompanied by an impaired calorigenic response to meals or glucose which is still present after weight loss.28,29 Jéquier and Schutz17 found that diet-induced thermogenesis in the obese was 50% of that in the non-obese, and this characteristic persisted after weight loss. Geissler30 showed that for all levels of activity, an ex-obese required 15% less energy than a non-obese person. Andrews and Jackson31 also showed that for an obese person, the energy needed to face cold was less than a non-obese person. Pittet et al32 showed that heat metabolism of obese persons differed from non-obese persons. While a non-obese person loses

heat during fasting, an obese person retains heat. After eating, a non-obese person produces twice as much heat as an obese person. This is consistent with Miller’s finding that obese patients were inefficient in burning off excess calories. This difference between obese and non-obese individuals in regard to heat production and energy expenditure is also consistent with Leibel’s 33 findings that for weight maintenance an ex-obese person requires 25% fewer calories than a person of the same age and weight who has never been obese. It is also consistent with the findings of Roberts34 that infants who became obese at 1 year had an energy expenditure 20% lower than normal at 3 months. All these experiments show that obese persons behave differently than normal people in terms of heat production. If heat production competes with fat deposition in the clearance of excess calories, it is possible that this difficulty in producing heat is the mechanism of abnormal fat deposition.A normal person would be equipped to maintain weight and absorb a 25% variation in daily calorie intake. For example, for a normal 2,000 kcal daily need, dietinduced thermogenesis will assure balance between 1,500 and 2,500 kcal. If this is reduced by half in the obese, for the same need, the margin of weight stability will be reduced between 1,050 and 1,750 kcal, above which there will be fat deposition. The situation would be greatly worsened with any attempt to lose weight when basal metabolism can decrease 25% more than normally33,35 and when thermogenesis decreases due to the decrease in fat.22,36 Basic need being further decreased, the margin of weight stability would decrease between 800 and 1,300 kcal/day. This is half of what a normal person needs, and this is consistent with Sims’s data6 who evaluated required calories for weight maintenance to be 1,300 kcal/m2 for the spontaneous obese and 2,700 kcal/m2 for normal weight subjects rendered obese by over-alimentation. The greater the deficiency in thermogenesis, the greater the tendency to become obese, and the greater the difficulty to lose weight. Considering the possible role of insulin in thermogenesis, the increased insulin resistance with increased obesity37 may increase the tendency to weight gain, although this is still controversial.38,39 Obesity Surgery, 15, 2005 5

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Contribution of Bariatric Surgery The first contribution of bariatric surgery has been to confirm that excessive food and lack of exercise were not the prime determinants of morbid obesity. This is not new; for years, attempts to document excessive food intake in these patients have failed, and this is frequently acknowledged.4,6,19 This does not deny the possible under-estimation of food intake40,41 by these patients nor that excessive eating does exist in some patients, but it negates overeating as the prime determinant in the majority of these patients. Failure to maintain weight loss after gastric restrictive operations adds to our historic failures by other approaches. From our own unpublished study, using a standard 3 days alimentary journal, there was no difference in caloric intake between 58 consecutive morbidly obese women before surgery, a group of 17 moderately obese women (BMI 30-35 kg/m2), and 110 women of normal weight (BMI 2025 kg/m2). Respective mean caloric intake were 2,283 ± 672, 2,250 ± 550 and 2,200 ± 500 kcal/day. In fact, half of these morbidly obese patients were eating less than half of the control group. This raises a fundamental issue. It is established that basal metabolism increases with weight. Therefore, if obese subjects consume a comparable amount of calories as normal subjects, it means that morbidly obese patients were taking a mean of only 20 Cal per kg of body weight per day compared to 36 Cal per kg of body weight for normal weight persons. It follows that the percentage of calories reserved for activities and the satisfaction of appetite will be reduced by as much as a half in obese subjects compared with normal weight subjects. The experience with bariatric surgery has confirmed the extreme restriction necessary for maintaining weight loss. The figures were the same as when weight loss was obtained by dieting.6,35,42 For major weight loss, intake needed to be <800 kcal and for maintaining weight loss it had to remain around 1,300 kcal/day. All measurements of caloric intake after different types of surgery have been within the same range, i.e. <800 kcal during the first 6 months and <1,300 kcal at 1 year.43-45 It is believed that above 1,500 6 Obesity Surgery, 15, 2005

kcal, morbid obesity recurs.45 It means that a morbidly obese individual will gain weight with a normal diet and would need to limit intake permanently at a level that is unsustainable by most subjects. A normal healthy diet for one is an excessive diet for another. More than 30 years’ experience with different attempts using only food restriction, have failed to produce favorable results at 5 years. If one can define cure as not being morbidly obese (BMI <40) 5 years after surgery, there are no reported series with “5 year cures”. All operations for which a cure rate is available involve an attempt to change the physiology and the greater the change in physiology, the greater the cure rate. The 5-year cure rate after gastric bypass varies between 2546 and 50%47 while it is over 90% after biliopancreatic diversion (BPD).48,49 The other major contribution of bariatric surgery has been the opportunity to study long-term effects of major weight loss. This was not readily available previously. Also, different physiological changes depending on the surgical approach that was used, made it possible to study the role of various factors on obesity and its morbidity. BPD is the only operation aimed at modifying intestinal physiology rather than food restriction. It is the most informative operation in the study of obesity. BPD, a procedure first described by Scopinaro,50 consists in diverting bile to limit its role in the digestive process. Depending on the length of intestine used for conveying bile, more or less intestine is left for food contact. By a simple technique, both the length of intestine for food contact and the participation of the bile in the digestive process can be varied as desired. Natural entrance of bile in the intestine is at the outlet of the stomach where it normally neutralizes gastric acid. The removal of bile from this location increases the risk of ulcer formation. For this reason, gastric acid needs to be decreased, which is usually done by partial gastrectomy. The primary goal of BPD is to decrease caloric absorption by decreasing particularly fat absorption. Initially, Scopinaro proposed to allow food to be in contact with half the intestinal length and introduced bile in the last 50 cm of intestine. For decreasing gastric acidity, he proposed the classic subtotal gastrectomy. This construction is still in use by Scopinaro, but most surgeons have modified this

Comprehension of Morbid Obesity

procedure, principally by replacing distal gastrectomy by a sleeve gastrectomy to decrease sideeffects – the so-called duodenal switch.51-53 Most studies with this procedure were performed by Scopinaro's group. BPD revealed the beneficial effects of creating a physiological change. In our opinion, it helped better understand the mechanism underlying obesity and gave support to the theory of deficient thermogenesis in these patients.

Beneficial Effects of Biliopancreatic Diversion There is evidence to support the following actions of BPD: 1) BPD decreases intestinal absorption while allowing normal eating habits; 2) BPD improves insulin sensitivity; 3) BPD improves energy expenditure; 4) BPD changes the secretion of intestinal hormones, and 5) BPD decreases fat absorption. All these factors contribute to making these patients healthier, and able to live a normal life while eating normally.

1. BPD Decreases Intestinal Absorption Scopinaro studied absorption in 15 men >2 years after BPD when weight was rendered stable; absorption was 60% of ingested calories including 70% absorption of protein (measured by radioactive albumin) and 30% of fat (based on the amount of fat recovered in the stool). Greco et al54 reported (in 8 women), an absorption of 70% at 4 years after BPD. Because of the gastrectomy, food intake is decreased during the early months after BPD and contributes to a rapid early weight loss in addition to the decreased absorption. We have documented (unpublished data) a mean 1,600 kcal intake in 15 women at 6 months after BPD compared to 2,200 kcal found before BPD in 58 morbidly obese women. Scopinaro and co-workers55 reported mean caloric intake of 3,070 kcal in 15 men 2 years after BPD. Four years after BPD, Greco reported mean caloric intake of 2,700 kcal in 8 women. These figures are within the range of normal eating habits. Effective absorption being decreased by one-third, effective caloric intake averaged 960 kcal at 6

months (in women), 1,741 kcal at 2 years (in women) and 1,900 kcal at 4 years (in men).

2. BPD Improves Insulin Sensitivity Sarson56 measured the level of insulin in 16 patients before BPD, in 38 patients from 6-12 months after BPD and in 13 non-obese controls of the same age and sex. Before BPD, fasting serum insulin was three times higher in obese than in controls (89.4 ± 10.9 vs 29.7 ± 5.0 pmol/l). After BPD, insulin level dropped to 17.8 ± 4.0 pmol/l. Before BPD, postprandial insulin secretion was not different between obese and non-obese (26.3 ± 3.1 nmol/l/180 min) but after surgery it dropped to 13.2 ± 1.9 (P<0.005). This lowered insulin production was still present 4 years after surgery.57 Improved insulin sensitivity has been demonstrated,58 and the postoperative clinical evolution also clearly demonstrated improved sensitivity. There was less insulin with better efficiency. In our own series, all diabetic patients were cured or improved. Not only was hyperglycemia normalized, but also glycemia within the “normal range” before BPD decreased while remaining within the normal range after BPD in 272 patients from a mean of 5.2 ± 0.5 to 4.8 ± 0.7 mmol/l (P<0.003).59 Improved insulin sensitivity after bariatric surgery has also been reported after gastric bypass60,61 and after jejuno-ileal bypass62 but to a lesser extent after pure gastric restrictive procedures.61

3. BPD Improves Energy Expenditure Resting energy expenditure (REE) was studied by Scopinaro et al63 at different times after BPD. After weight loss, resting energy expenditure (REE) remained significantly higher than that of non-obese controls while it was expected to decrease. In 68 patients, mean REE was 1,715 kcal before BPD and 1,580 kcal 1 year after BPD which was higher than the 1,271 kcal for controls. REE was also found to remain higher if weight loss was obtained by BPD rather than by food restriction alone. Once weight had stabilized, mean REE for 14 patients was 1,979 kcal compared to 1,497 kcal (P<0.05) for 5 patients who had lost their weight by dieting.64 The fact that energy expenditure remained higher than expected after BPD may be explained by the concomitant Obesity Surgery, 15, 2005 7

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improved insulin sensitivity. Better energy expenditure and weight maintenance despite greater caloric intake speaks in favor of a greater role for energy expenditure in the etiology of obesity.

4. BPD Changes Intestinal Hormones Two intestinal hormones have gained interest recently as being involved in the etiology of obesity and diabetes.65 One called “entero-gastrone (GIP) (E-gastrone)” is secreted by the first part of the intestine and may induce obesity and insulin resistance.66-68 The other “entero-glucagon (GLP-1) (Eglucagon)” is secreted by the distal intestine, and may increase insulin sensitivity.66-69 In BPD, the first part of the intestine is not stimulated by food so that there is a decrease in “E-Gastrone”, and the early stimulation of the distal intestine causes an increase in “E-glucagon”. Sarson56 studied these hormones in 16 obese patients before BPD, in 38 others after BPD, and in 13 non-obese controls. Before BPD, fasting “E-gastrone” was found to be higher in obese than in normal (13.7 ± 1.8 vs 6.1 ± 1.2 pmol/l (P<0.005)), and after BPD it decreased to 11.4 ± 2.1 pmol/l (P<0.05)). Postprandial “E-gastrone” secretion was found normal before BPD and dropped after BPD from 5.2 ± 0.7 to 1.1 ± 0.2 nmol/l/180 min (P<0.001). It was the reverse for “Eglucagon”. Before BPD, mean fasting levels were also found to be higher in obese than in controls (28.9 ± 2.5 vs 21.9 ± 1.9 pmol/l (P<0.05)), but these levels tripled after BPD to 91.0 ± 14.0 pmol/l (P<0.001). Postprandial secretion increased from 0.8 ± 0.4 to 9.3 ± .3 nmol/l/180 min (P<0.005). The reader is referred to a recent review by Patriti70 discussing the mechanism of action of these hormonal changes after bariatric surgery. More recently, this increase in postprandial E-glucagon was also reported after gastric bypass.71,72

5. BPD Decreases Fat Absorption The selective decrease of fat absorption, by limiting the role of bile, is another major benefit of BPD. Not only is it the most efficient way to decrease the total caloric content from food, but at the same time it prevents the detrimental effect of excessive fat intake.73,74 Furthermore, not only did it normalize blood lipid levels, but also it unexpectedly increased 8 Obesity Surgery, 15, 2005

high density cholesterol (HDL). This effect has been still present 20 years after surgery.59

Summary BPD has been found to have much greater beneficial effect than what was initially expected. It creates positive physiological changes probably all linked to each other. The advantage of BPD is that it appears to affect both sides of the energy balance. It decreases energy intake, and it appears to increase energy expenditure, for better energy balance and weight maintenance. Whether this is the result of chronic lipid malabsorption or the improved insulin sensitivity, needs to be clarified.

Conclusion That good results have been obtained when the physiology was changed in contrast to poor results when only food restriction was employed, is another demonstration against the prejudice that obesity is due to gluttony. In reviewing the literature for data that fits our clinical evidence, we have been able to make a strong case in favor of deficient thermogenesis rather than over-alimentation as the prime mechanism of morbid obesity. We believe that the fundamental characteristic of morbidly obese patients is their inability to disperse extra calories to maintain energy balance, resulting in fat deposition. Permanent cure of this disease requires physiological change.

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26. Landsberg L. Saville ME, Young JB. Sympathoadrenal system and regulation of thermogenesis. Am J Physiol 1984; 247: E181-189. 27. Stunkard AJ, Harris JR, Pedersen NL et al. The bodymass index of twins who have been reared apart. N Engl J Med 1990; 322: 1483-7. 28. Kaplan ML, Leveille GA. Calorigenic response in obese and nonobese women. Am J Clin Nutr 1976; 29: 110813. 29. Astrup A, Andersen T, Christenses NJ et al. Impaired glucose-induced thermogenesis and arterial norepinephrine response persist after weight reduction in obese humans. Am J Clin Nutr 1990; 51: 331-7. 30. Geissler CA, Miller DS, Shah M. The daily metabolic rate of the post-obese and the lean. Am J Clin Nutr 1987; 45: 914-20. 31. Andrews F, Jackson F. Increasing fatness inversely related to increase in metabolic rate but directly related to decrease in deep body temperature in young men and women during cold exposure. Ir J Med Sci 1978; 147: 329-30. 32. Pittet P, Chappuis P, Acheson K et al. Thermic effect of glucose in obese subjects studied by direct and indirect calorimetry. Br J Nutr 1976; 35: 281-92. 33. Leibel RL, Rosenbaum M, Hirsch J. Changes in energy expenditure resulting from altered body weight. N Engl J Med 1995; 332: 621-8. 34. Roberts SB, Savage J, Coward WA et al. Energy expenditure and intake in infants born to lean and overweight mothers. N Engl J Med 1988; 318: 461-6. 35. Leibel RL, Hirsch J. Diminished energy requirements in reduced-obese patients. Metabolism 1984; 33: 164-70. 36. Doucet E, St Pierre S, Alméras N et al. Evidence for the existence of adaptive thermogenesis during weight loss. Br J Nutr 2001; 85: 715-23. 37. Sims EAH, Danforth E Jr, Horton ES et al. Endocrine and metabolic effects of experimental obesity in man. Recent Progress in Hormone Research 1973; 29: 457-96. 38. Swinburn BA, Nyomba BL, Saad MF et al. Insulin resistance associated with lower rates of weight gain in Pima Indians. J Clin Invest 1991; 88: 168-73. 39. Eckel RH. Insulin resistance: An adaptation for weight maintenance. Lancet 1992; 340: 1452-3. 40. Goris AHC, Westerterp-Plantenga MS, Wesberterp KR. Undereating and undercording of habitual food intake in obese men: selective under-reporting of fat intake. Am J Clin Nutr 2000; 71: 130-4. 41. Hill RJ, Davies PSW. The validity of self reported energy intake as determined using the doubly labeled water technique. Br J Nutr 2001; 85: 415-30. 42. Jeffery RW, Epstein LH, Wilson GT et al. Long-term maintenance of weight loss: current status. Health Psychology 2000; 19 (1 S): 5-16. 43. Coughlin K, Bell RM, Bivins BA et al. Preoperative and postoperative assessment of nutrient intakes in patients Obesity Surgery, 15, 2005 9

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(Received August 28, 2004; accepted September 15, 2004)