Presentation on theme: "The Aetiology of Obesity"— Presentation transcript:
1The Aetiology of Obesity A New Hope – Part 1 of 6
2William BantingIncreased exercise and decrease caloric intake but no weight lossAte 3 meals a day of meat, fish or game with an ounce or 2 of stale toast or cooked fruit on the sideScrupulously avoided any other food that might contain either sugar or starch – in particular – bread, milk, beer, sweets, and potatoesAvoid ‘fattening’ carbohydratesPublished 16 page pamphlet “Letter on Corpulence” in 1863Age 62 weighed 202lbs and stood 5’5”
3William Osler “Father of Modern Medicine” Author of seminal textbook “The Principles and Practice of Medicine” 1907Discussed treatment of obesityThese diets featured lean beef, veal, mutton and eggs1882 monograph “Obesity and Its Treatment” – insisted that fatty foods were crucial because they increased satiety and so decreased fat accumulation“Father of Modern Medicine”
4The Fattening Carbohydrate - Common Knowledge Baby and Child Care“Rich desserts, the amount of plain, starchy foods (cereals, breads, potatoes) taken is what determines, in the case of most people, how much (weight) they gain or lose”1963 –British Journal of Nutrition“Every woman knows that carbohydrate is fattening: this is a piece of common knowledge, which few nutritionists would dispute”FatteningCarbohydratesObesity
5The Great Epidemic of Coronary Disease 1950s - Dietary fat increasingly vilified for heart disease due to its effects on LDL cholesterol “Diet-Heart hypothesis”1960s - the American Medical Association were insisting that low carbohydrate diets were dangerous fads (a 200 year old fad)Jean Mayer claimed advocating carbohydrate-restricted diets to the public were “the equivalent of mass murder”Low fat, high carbohydrate diets previously unknown in human historyBUT… the fattening carbohydrate could not be healthy (low fat) and unhealthy (causes obesity) at the same timeFattening carbohydrate suddenly transformed into the healthy whole grainFat, with dense calories assumed to cause obesityCalories in/ calories out model displaces traditional ‘fattening carbohydrate’ modelCreated in 1948
6Dietary Goals For the United States 1977 First time any government institution had told Americans they could improve their health by eating less fatDietary fat controversy was now a political issue and not a scientific oneDietary Goals1. Raise consumption of carbohydrates until they constituted 55-60% of calories2. Decrease fat consumption from approximately 40% to 30% of which no more than 1/3 from saturated fatUSDA Dietary Guidelines for Americans
8An Eating Plan for Healthy Americans: The American Heart Association Diet 1995 “To control the amount and kind of fat, saturated fatty acids and dietary cholesterol you eat, choose snacks from other food groups such as…low fat cookies, low-fat crackers…unsalted pretzels, hard candy, gum drops, sugar*, syrup, honey, jam, jelly, marmalade (as spreads)”*WTF??AHA endorsed ‘healthy snacks’
9How did we do?Conscious effort to eat less fat, less red meat, fewer eggsAverage fat intake of Americans (USDA) decreased from 45% of calories to less than 35% of calories1976 – % decline in hypertension28% decline in hypercholesterolemiaSmoking drops 33% to 25%Clear evidence that the general public listened to the leading authorities of the day and tried to complyRise in obesity was not simply a case of the general public not listening to conventional medical advice
14Caloric Reduction As Primary Eat too muchPersonal ChoiceBehaviourObesityExercise too littleImplicit Assumptions1. “A calorie is a calorie”2. Fat stores are essentially unregulatedA ‘dump’ for excess calories3. Intake and Expenditure of calories are under conscious controlIgnores effects Hunger and basal metabolic rates4. Intake and Expenditure of calories are independent of each other
15Energy Balance Paradigm Accumulation of fat due to caloric imbalance “First Law of Thermodynamics” True but completely useless Example – crowded airport at March Break Too many people entering, too few people leaving is the cause of the crowding Key question is WHY? Cause of overeating/ underactivity is BEHAVIOURALCalories in/ Calories out model
16Caloric Reduction – Popularity of Theory Easy to understandAppeals to American sense of self-determinism – it is your ‘choice’, ‘captain of your own ship’Obesity is not a medical condition, but a psychological, character defect ‘low willpower’
17Experts say… Eat Less and Exercise More Joslin’s Diabetes Mellitus (2005)“reduction of caloric intake” is “the cornerstone of any therapy for obesity”However, from low calorie to very low calorie diets “none of these approaches has any proven merit”Handbook of Obesity (1998) –“Dietary therapy remains the cornerstone of treatment and the reduction of energy intake continues to be the basis of successful weight reduction programs”Results of such diets are “known to be poor and not long-lasting”2005 USDA Dietary Guidelines for Americans “eating fewer calories while increasing physical activity are the keys to controlling body weight”
18Caloric Reduction as Primary… An easily tested hypothesis Eat too muchPersonal ChoiceBehaviourObesityExercise too littleKey Assumption – Caloric intake and expenditure are independent of each other
19Elusive Benefits of Under-eating 12 young men put on semi-starvation diets of calories/daySubjects lost weight, but constantly complained of hunger“almost impossible to keep warm, even with an excessive amount of clothing”30% decrease in metabolismreduced energy expenditure so much that if they ate more than 2100 calories/day – would start to regain weightDecreases in BP, HR, inability to concentrate and marked weakness during physical activityExcess eating immediately after experimentCarnegie Institution of Washington’s Nutrition Laboratory 1917
20The Biology of Human Starvation 36 men put on a 24 weeks semi-starvation diet1570 calories per dayThe men’s resting metabolic rates declined by 40 percentHeart volume shrank by 20 percentHeart rate slowedBody temperatures droppedObsessive thoughts about food, binge eating1944 Ancel Keys University of Minnesota
21Changes in Energy Expenditure Resulting from Altered Body Weight Rudolph L. Leibel NEJM 1995 march 9, 332 (10);18 obese and 23 non obese subjects with a stable weightFed a liquid diet of 40% fat, 45% carbohydrates and 15% proteinCaloric intake adjusted until weight stableSubjects then measured for energy expenditure
22Mean (±SD) Observed-minus-Predicted Total Energy Expenditure (Shaded Bars) Based on the Regression of Total Energy Expenditure in a Model with a Variable Combining Fat-free Mass and Fat Mass in the Same Subjects at Their Initial Weight.Figure 2. Mean (±SD) Observed-minus-Predicted Total Energy Expenditure (Shaded Bars) Based on the Regression of Total Energy Expenditure in a Model with a Variable Combining Fat-free Mass and Fat Mass in the Same Subjects at Their Initial Weight. The components of total energy expenditure are given in Table 2.Leibel RL et al. N Engl J Med 1995;332:
23Long-term persistence of adaptive thermogenesis in subjects who have maintained a reduced body weight21 Subjects fed liquid diet of 45% carbohydrates Maintained weight loss of 10% over 1 year Measured total, resting and non resting energy expenditureDecreased energy expenditureEven 1 year after weight loss
24Long-Term Persistence of Hormonal Adaptations to Weight Loss Mean (±SE) Changes in Weight from Baseline to Week 62.N Engl J Med 2011; 365: October 27, 2011Figure 1 Mean (±SE) Changes in Weight from Baseline to Week 62. The weight-loss program was started at week 0 and completed at week 10. ITT denotes intention to treat.50 patients given 10 weeks of 500 calorie liquid shakes (51% carbohydrates)Hormonal analysis after 1 year of weight lossSumithran P et al. N Engl J Med 2011;365:
25Long-Term Persistence of Hormonal Adaptations to Weight Loss Mean (±SE) Fasting and Postprandial Levels of Ghrelin, Peptide YY, Amylin, and Cholecystokinin (CCK) at Baseline, 10 Weeks, and 62 Weeks.“Hunger hormone”Figure 2 Mean (±SE) Fasting and Postprandial Levels of Ghrelin, Peptide YY, Amylin, and Cholecystokinin (CCK) at Baseline, 10 Weeks, and 62 Weeks.Persistent increase in hunger signalling 1 year after weight lossSumithran P et al. N Engl J Med 2011;365:
26Mean (±SE) Fasting and Postprandial Ratings of Hunger and Desire to Eat at Baseline, 10 Weeks, and 62 Weeks.Figure 3 Mean (±SE) Fasting and Postprandial Ratings of Hunger and Desire to Eat at Baseline, 10 Weeks, and 62 Weeks. Ratings were based on a visual-analogue scale ranging from 0 to 100 mm. Higher numbers indicate greater hunger or desire.Circulating mediators of appetite that encourage weight regain after diet- induced weight loss do not revert to the levels recorded before weight lossWeight is regained as body increases hunger and decreases energy expenditureSumithran P et al. N Engl J Med 2011;365:
27Body Weight “Thermostat” 10% increaseweight16% increaseEnergy expended10% decreaseweight15% decreaseEnergy expendedAdaptions to weight loss:Reduction in energy expenditureIncreased hungerPhysiological changes aimed at increasing the ‘metabolic efficiency’ and fuel supply of the tissues at a time of energy deficitThe body is smart!!Body fat is finely regulated
28Caloric Reduction as Primary CoalPower plantStorage
29Low-fat dietary pattern and weight change over 7 years: the Women's Health Initiative Dietary Modification TrialRandomized controlled trial started in ,000 women age enrolled 19,541 randomized to low-fat diet rich in fruits, vegetables and fibre 29,294 usual diet Dietary counselling – goal to lower fat calories from 38% to less than 20%Howard BV et al. Journal of the American Medical Association 2006; 295:39-49
32What happened?Women should have lost 36 pounds of fat in the first year alone!
33The Cruel HoaxVirtually all studies of ‘semi-starvation’ diets are remarkably similar and unsuccessfulA perfect 35 year record unblemished by successCaloric deprivation triggers 2 adaptive mechanisms1. Reduced energy output2. Increased hungerThe Cruel Hoax of the low fat, calorie-restricted dietTHEY DON’T WORK!
34Vicious Cycle of Under-eating Eat Less CaloriesRegain WeightLose WeightDecreased Energy ExpenditureIncreased HungerContinues until it is intolerable – then we blame the victim
35The Overeating Paradox Studied convicts at Vermont State PrisonInitially raised food consumption to 4000 calories/ daygained some weight but then weight stabilizedAte up to 10,000 calories a day, while carefully controlling exerciseTook 4-6 months to increase weight by 20-25%One man less than 10 pound weight gainMetabolism increased by 50%Most famous of overeating studies done in late 1960’s by endocrinologist Ethan Sims Most returned to normal weight with surprising rapidity
36Metabolic response to experimental overfeeding in lean and overweight healthy volunteers Am J Clin Nutr Oct 1992;56(4): Diaz EOOverfed volunteers by 50% over 42 days followed by 6 weeks of monitoring46% carbohydrate diet
37Caloric Reduction As Primary Eating less does not result in weight lossInduces hunger and a compensatory decrease in energy expenditureEating more does not result in weight gainIn response to caloric surplus we increase energy expenditureBody weight acts as if it has an ‘set point’Body acts as a thermostat NOT a scaleCaloric deprivation is difficult because it is a fight against mechanisms which have evolved to precisely minimize its effects
39Exercise More…1966 US Public Health Service advocated increased physical activity and diet as the best ways to lose weight1980’s “new fitness revolution” led by running and aerobics“Experts” routinely claim that exercise is the key to weight loss
41Physical Activity and Weight Gain Prevention Women’s Health Study JAMA 2010;303(12): Buring et alProspective cohort study womenCompleted health questionnaires every 6 months
42Women’s Health Study - Results Average increase in weight loss over 3 years0.12 kgJust over ¼ pounds weight loss in 3 years!!3 years of 60 minutes per day, every day!!
43Changes in Weight, Waist Circumference and Compensatory Responses with Different Doses of Exercise among Sedentary, Overweight Postmenopausal Women464 womenRandomized to 0, 72, 136, 194 min/wk exerciseChurch et al PLoS One (Public Library of Science) Feb 2009 Vol 4 #2 e4515No change in dietary habits24 week study durationNo difference in any of the group in weight lost!
44Exercise Effect on Weight and Body Fat in Men and Women McTiernan et al, Obesity (2007) 15,12 month randomised, controlled trial102 men and 100 women – sedentary6 days per week of 1 hour moderate – vigorous exerciseAt baseline average weightWomen 78 kgMen 96 kgResults – at 12 months1.4 kg! (3 pounds) – women1.8 kg! (4 pounds) - men
45Marathons must work….Food intake and body composition in novice athletes during a training period to run a marathon.International Journal of Sports Medicine, May 1989; 10(1 suppl.):S17-21 Janssen GMTrained sedentary subjects to run marathon over 18 monthsMen – average weight loss 5 pounds9 women – no weight lost“no change in body composition was observed”
46CompensationMultiple studies lasting more than 25 weeks that average weight loss was only 30% of predicted*Difference between actual weight loss and predicted weight loss called “compensation”Possible mechanisms1. Increased caloric intake2. Decreased activity outside of prescribed exercise*Ross R et al Physical activity, total and regional obesity: dose-response considerations. Med Sci Sports Exerc 33: SChurch et al 2009 PLos
47European Congress on Obesity 2009 Alissa FremeauxMeasured physical activity of 206 children aged 7-8 by accelerometerAveraged 9.2 hours per week of physical education in schoolNo difference in total weekly activity“children who got a lot of PE time at school were compensating by doing less at home, while those who got very little PE time compensated by cranking up their activity at home, so that over the week, they all accumulated the same amount"
49Exercise More…Baseline Energy Expenditure estimated to calories per poundIn bed bound state caloric needs is (BEE) * 1.2For 140 pound person, approximately calories per dayCaloric expenditure of 45 minute walk (150 pound person) at 2 miles per hour is 102 calories – 4% of daily caloric intakeMajority of calories expended is NOT exercise but basal metabolic rate – mostly used in heating the bodyWhy do we get so hungry after swimming?Why do patients on semi-starvation dietsget cold?
50Exercise More… WE SHOULD ALL GET EXERCISE Despite 40 years of constant and utter failure ‘experts’ still insist exercise is the key to weight loss1. Burn surprising few calories with exercise – we focus on the 4% of daily caloric intake and ignore the 96% (Basal Metabolic Rate)2. Compensation effectsIncrease in appetiteDecreased other activityWE SHOULD ALL GET EXERCISEBut simply not that effective for weight lossIncrease muscle toneIncrease insulin sensitivity of musclesDecrease vascular diseaseIncreased bone density
51Eat Less… An easily tested hypothesis Eat too muchBehaviourGluttony/SlothObesityExercise too littleNot True!
53Hormonal Obesity Theory– An Easily tested hypothesis HighInsulin(cortisol)LevelsEat too muchObesityExercise too littleImplicit AssumptionsFat, like all body systems, are regulated under hormonal controlIntake and Expenditure of calories are under hormonal controlHunger/ Basal metabolic RateIntake and Expenditure of calories are linked to each other
54Insulin – fattening agent 1923 clinicians successfully used insulin to fatten chronically underweight children 1930’s clinicians using it regularly in Europe and USA for pathologically underweight patients Often gained as much as 6 pound per week using insulin and meals “rich in carbohydrates”Insulin discovered in 1921
56Correlation of insulin and weight gain Intensive control of type 1 DM in DCCT trial resulted in average 4.75 kg more weight gainDiabetes Control and Complications (DCCT) Trial Research Group. Influence of intensive diabetes treatment on body weight and composition of adults with type 1 diabetes in the Diabetes Control and Complications Trial. Diabetes Care 2001;24:
57Weight gain during insulin therapy in patients with type 2 diabetes mellitus Fig. 1. Weight gain over time in type 2 diabetes patients undergoing intensive or conventional treatment with insulin or sulfonylureas. (The Lancet, vol. 352, 1998, pp. 837–853)
58Intensive Conventional Insulin Therapy for Type II Diabetes Diabetes Care 16:21-31 Henry RR 14 DM2 patients treated with intensive insulin therapyAt 6 months100 units insulin/dayDecrease of 300 calories/dayWeight gain of 8.7 kg (19lbs)!
59Addition of Biphasic, Prandial, or Basal Insulin to Oral Therapy in Type 2 Diabetes 708 patients on oral hypo-glycemics who added insulinIncreasing insulin dose leads to increased weightMean Wt Gain4.7 kg5.7 kg1.9 kgMean Insulin Dose485642N Engl J Med 2007;357: Holman RR
60Insulin Lipohypertrophy Insulin acts through LPL (Lipoprotein Lipase) – and HSL (Hormone Sensitive Lipase) ‘Lipogenic’ effect of insulin – self injections of insulin can lead to masses of fat at site of injection
61Combining insulin and oral agents The American Journal of Medicine Volume 108, Issue 6, Supplement 1, 17 April 2000, Pages 23–32 John Buse et al
62Change in Weight Change in daily dose of insulin From: Long-Term Efficacy of Dapagliflozin in Patients With Type 2 Diabetes Mellitus Receiving High Doses of Insulin: A Randomized TrialAnn Intern Med. 2012;156(6): doi: /Change in WeightChange in daily dose of insulin
63Is weight reduction related to its effect on blood glucose? Metformin does not increase insulin levelsIncreases insulin sensitivity
64Is Weight Gain related to change in blood glucose? Postgraduate Medicine:Volume 124 No. 4Pencek et alPooled data from 7 randomized trials
66J Clin Endocrinol Metab 97: 1020–1031, 2012 Effects of Dapagliflozin on Body Weight, Total Fat Mass, and Regional Adipose Tissue Distribution in Patients with Type 2 Diabetes Mellitus with Inadequate Glycemic Control on MetforminJ Clin Endocrinol Metab 97: 1020–1031, 201224-wk multicenter, randomized, parallel-group, double-blind, placebo-controlled study182 diabetic patients with T2DMSGLT2I vs placebo
67Effects of Dapagliflozin on Body Weight, Total Fat Mass, and Regional Adipose Tissue Distribution in Patients with Type 2 Diabetes Mellitus with Inadequate Glycemic Control on Metformin
68Drugs that increase basal insulin No IncreaseInsulinSulfonylureasGlyburideGlicizideMetforminDPP IV inhibitorsJanuviaOnglyzaTrajentaSGLT – 2With exception of TZD class
69Drugs that cause weight gain IncreaseNo IncreaseInsulinSulfonylureasGlyburideGlicizideMetforminDPP IV inhibitorsJanuviaOnglyzaTrajentaSGLT – 2
70I can make you thin… Untreated and treated Type 1 Diabetes Mellitus Type 1 diabetes Aretaeus’ classic description “Diabetes is …a melting down of the flesh and limbs into urine...” Lack of insulin leads to rapid loss of weight and fat Lose all fat! No matter how many calories are ingestedUntreated and treated Type 1 Diabetes Mellitus
71DiabulimiaDiabulimia (diabetes and bulimia) refers to an eating disorder in which people with Type 1 diabetes deliberately give themselves less insulin than they need, for the purpose of weight lossWell known in Type 1 DM community that a lack of insulin causes immediate and substantial weight loss
72I can make you fat… Excess cortisol result in weight gain Exogenous – steroids, prednisoneEndogenous – Cushings syndromeExcess fat deposition due to hormonal dys-regulation – not character defect (lack of willpower) ”the hallmark sign of Cushing's syndrome is accelerated weight gain”
73I can make you thin….Lack of cortisol results called Addison’s disease “Most patients with Addison's disease experience fatigue, generalized weakness, loss of appetite and weight loss”
74Hormones are the Key! Eat too much Exercise too little Insulin = Weight Cortisol = WeightWhat makes us fat?Eat too muchExercise too littleHormones! Obesity is a hormonal dis-regulation of fat!Insulin (cortisol)
75Caloric Reduction As Primary Eat too muchBehaviourGluttony/SlothObesityExercise too littleBelief in CRAP theory led to singular research focus on behavioural/ psychological issue (lack of willpower, overeating, lack of exercise)Entire generation of health professionals endorsing low fat caloric restriction as treatmentUninterrupted 35 year string of failure in treatment of obesity “a perfect record - unblemished by success”
76Hormonal Theory of Obesity HighInsulin(cortisol)LevelsEat too muchObesityExercise too littleOvereating and under-activity are the result not the cause of obesityCalories are primarily pushed into storage leaving inadequate amounts for energy expenditure – thus either increase caloric intake or decrease energy expenditureWe do not get fat because we overeatWe overeat because we get fat!
77The Aetiology of Obesity The absolutely crucial question in obesity is not how many calories am I eatingCalories are largely irrelevant – increased caloric intake will be matched by increased caloric expenditureMore calories in, more calories outWhat is driving my insulin (cortisol) levels up?Answer – The fattening carbohydratesFatteningCarbohydratesOver-eatingUnder-activityHigh InsulinLevelsObesity
79Obesity Set Point Body acts as a thermostat not a scale Insulin adjusts the “body weight setpoint”Insulin tells the body to get fat – calories and energy expenditure are adjusted to meet that goalBody acts as a thermostat not a scale
80The Practice of Endocrinology 1951 Food to be avoided:1. Bread, and everything else made with flour2. Cereals, including breakfast cereals and milk puddings3. Potatoes and all other white root vegetables4. Foods containing much sugar5. All sweetsYou can eat as much as you like of the following foods:1. Meat, fish, birds2. All green vegetables3. Eggs, dried or fresh4. Cheese5. Fruit, if unsweetened, except bananas, and grapes