Are We Fat Because We Overeat? Or Do We Overeat Because We re Getting Fat?

Are We Fat Because We Overeat? Or Do We Overeat Because We re Getting Fat? David S. Ludwig, MD, PhD Director, Optimal Weight for Life (OWL) Program Director, New Balance Foundation Obesity Prevention Center Boston Children s Hospital Professor of Pediatrics, Harvard Medical School Professor of Nutrition, Harvard School of Public Health

First Law of Thermodynamics Energy can neither be created or destroyed Calorie intake - Calorie expenditure = Calories stored (change in adiposity)

Conventional Interpretation of the First Law Obesity, a failure of voluntary control over energy balance Overeating (ubiquitous tasty foods) Energy intake Energy expenditure Circulating metabolic fuels (glucose, lipids) Fat storage Physical inactivity (TV, computer, etc)

Conventional Interpretation of the First Law Obesity, a failure of voluntary control over energy balance Overeating (ubiquitous tasty foods) eat less move more Energy intake Energy expenditure Circulating metabolic fuels (glucose, lipids) Fat storage Physical inactivity (TV, computer, etc)

Conventional View of Obesity Individual responsibility to control energy balance Reaching a healthier weight is a balancing act. The secret is learning how to balance your "energy in" and "energy out"... -- USDA advice on weight management online, accessed January 13, 2013 http://www.choosemyplate.gov/weight-managementcalories/weight-management/better-choices/amount-

Nutrients Fat Carbohydrate

Secular Trends in Dietary Fat Inverse relationship with obesity prevalence Percent Dietary Fat Year

Long-term RCT of a Low Fat Diet The Women s Health Initiative 48,835 women ages 50 to 79 years Intervention: counseling sessions to promote a low fat diet Control: written education materials Dietary fat decreased from 39% to < 30% in the intervention group Howard. JAMA 2006, 295:39-49

Meta-analyses of Low Fat Diets LESS effective than comparison diets Tobias DK et al. Randomized trials of low-fat vs. other diet interventions on weight loss: a meta-analysis. Circulation 2014; 129: AMP63 (abstract) Bueno NB et al. Very-low-carbohydrate ketogenic diet v. low-fat diet for long-term weight loss: a meta-analysis of randomised controlled trials. Br J Nutr 2013;110:1178-87. Nordmann AJ et al. Meta-analysis comparing Mediterranean to lowfat diets for modification of cardiovascular risk factors. Am J Med 2011;124:841-51.

Conventional Obesity Treatment in Adults National Health & Nutrition Examination Survey 1999-2006 Only 1 in 6 overweight and obese adults in the US report ever having maintained weight loss of at least 10% for 1 year Kraschnewski et al. Int J Obes. 2010, 34:1644-54

Conventional Obesity Treatment in Children Systematic reviews and meta-analyses Most pediatric obesity interventions are marked by small changes in relative weight or adiposity and substantial relapse... Epstein. Pediatrics 1998, 101:554-70 McGovern. JCEM 2008, 93:4600-5 Kamath. JCEM 2008, 93:4606-15 Waters. Cochrane Rev 2011,12:CD001871

eat less move more Conventional View of Obesity Failure of voluntary control over energy balance Overeating (ubiquitous tasty foods) Energy intake Energy expenditure Circulating metabolic fuels (glucose, lipids) Why hasn t this paradigm worked in practice? Fat storage Physical inactivity (TV, computer, etc)

Body Weight is Under Biological Control Complex interconnected feedback mechanisms Ahima, Gastroenterology 2007

Body Weight is Under Biological Control Physiological adaptations antagonize weight change Hunger Baseline body weight Energy Expenditure Body Weight Leibel, NEJM 1995, 332:621-8; Kissileff, AJCN 2012, 95:309 17

Body Weight is Under Biological Control Physiological adaptations antagonize weight change Hunger Reduced body weight Energy Expenditure Body Weight Leibel, NEJM 1995, 332:621-8; Kissileff, AJCN 2012, 95:309 17

Body Weight is Under Biological Control Physiological adaptations antagonize weight change Hunger Reduced body weight Baseline body weight Energy Expenditure Body Weight Leibel, NEJM 1995, 332:621-8; Kissileff, AJCN 2012, 95:309 17

Body Weight is Under Biological Control Physiological adaptations antagonize weight change Hunger Increased body weight Energy Expenditure Body Weight Leibel, NEJM 1995, 332:621-8; Kissileff, AJCN 2012, 95:309 17

Body Weight is Under Biological Control Physiological adaptations antagonize weight change Hunger Baseline body weight Increased body weight Energy Expenditure Body Weight Leibel, NEJM 1995, 332:621-8; Kissileff, AJCN 2012, 95:309 17

Body Weight is Under Biological Control Complex interplay of biological & environmental factors Hunger Body Weight Set Point Energy Expenditure Body Weight

The Obesity Epidemic Rising BMI among genetically stable populations Key Questions: Why has the level of defended body weight the observed Set Point increased in recent years? What can we do about it?

Conventional View of Obesity Failure of voluntary control over energy balance Overeating (ubiquitous tasty foods) eat less move more Energy intake Energy expenditure Circulating metabolic fuels (glucose, lipids) Fat storage Physical inactivity (TV, computer, etc)

Conventional View of Obesity Failure of voluntary control over energy balance Overeating (ubiquitous tasty foods) eat less move more Energy intake Energy expenditure?? Circulating metabolic fuels (glucose, lipids)? Fat storage Physical inactivity (TV, computer, etc)

Alternative View of Obesity Excessive anabolic drive in adipose tissue Hunger Energy intake Energy expenditure Circulating metabolic fuels (glucose, lipids) Fat storage Fatigue, physical inactivity

Alternative View of Obesity Excessive anabolic drive in adipose tissue Hunger Energy intake Energy expenditure Circulating metabolic fuels (glucose, lipids) Fat storage Resting energy expenditure Muscular efficiency Fatigue, physical inactivity

Alternative View of Obesity Excessive anabolic drive in adipose tissue Hunger eat less move more Energy intake Energy expenditure Circulating metabolic fuels (glucose, lipids) Fat storage Resting energy Muscular expenditure efficiency Fatigue, physical inactivity Symptomatic treatment, destined to fail in an environment with excess calories

Alternative View of Obesity Excessive anabolic drive in adipose tissue Hunger Energy intake Energy expenditure Circulating metabolic fuels (glucose, lipids) Insulin secretion Fat storage Resting energy Muscular expenditure efficiency Fatigue, physical inactivity

Insulin & Body Weight A dominant anabolic hormone Regulates availability of all key metabolic fuels - Stimulates fat synthesis and deposition - Inhibits fat release and oxidation Increased action causes weight gain - Excessive insulin treatment in diabetes Decreased action causes weight loss - Under-treatment of type 1 diabetes UKPDS Lancet 1998, 352:837; Carlson & Campbell. Diabetes 1993, 42:1700; Le Stunff, Nat Gen 2000, 26:444-6; Lustig, IJO 2006, 30:331-41

Alternative View of Obesity Excessive anabolic drive in adipose tissue Hunger Dietary carbohydrate Energy intake Energy expenditure Circulating metabolic fuels (glucose, lipids) Insulin secretion Fat storage Resting energy Muscular expenditure efficiency Fatigue, physical inactivity

Carbohydrate Amount & Type Most potent effects of all macronutrients on insulin secretion Amount total carbohydrate (grams) Type glycemic index

The Glycemic Index A measure of carbohydrate digestion rate Blood Glucose 0 - White bread Soy beans 0 1 2 3 4 5 Time (hr) Area under the glycemic curve after consumption of 50 g CHO from test food divided by area under curve after 50 g CHO from control food

Glycemic Index and Hunger Low GL Medium GI High GI 55 g whole egg 63.9 g steel-cut oats 60.9 g instant oatmeal 45 g egg white 160 g 2% milk 160 g 2% milk 40 g lowfat cheese 15 g H & H cream 15 g H & H cream 200 g spinach 16.0 g fructose 19.0 g dextrose 30 g tomato 0.0 g saccharine 0.2 g saccharine 185 g grapefruit 397 g water 397 g water 115 g apple slices Macronutrients (% carbohydrate/protein/fat): 40/30/30 64/16/20 64/16/20 Energy density (KJ/g): 2.46 2.52 2.52

Glycemic Index and Hunger Metabolic fuels Glucose (mmol/l) 4 3 2 1 0-1 High GI Med GI Low GL 0 1 2 3 4 5 Time (hr) Ludwig. Pediatrics 1999, 103:e26

Glycemic Index and Hunger Plasma epinephrine 60 Epinephrine (ng/l) 50 40 30 20 10 0-10 High GI Med GI Low GL 0 1 2 3 4 5 Time (hr) Ludwig. Pediatrics 1999, 103:e26

Glycemic Index and Hunger Cumulative food intake Kilocalories Consumed 1500 1000 500 0 1 2 3 4 5 Time (hr) High GI Med GI Low GL Ludwig. Pediatrics 1999, 103:e26

Glycemic Index & Brain Function Methods Subjects: 12 overweight/obese young men Design: Double-blind, cross-over feeding study Intervention: high vs. low GI liquid meals, controlled for: - macronutrients - calorie content - sweetness Neuroimaging: Arterial spin labeling 4 hr after the meal Lennerz. AJCN 2013, 98:641-7

Glycemic Index & Brain Function Effects of test meals on plasma glucose and hunger Plasma Glucose (mmol/l) Hunger rating (10-pt scale) Time (hr) Time (hr) Lennerz. AJCN 2013, 98:641-7

Glycemic Index & Brain Function Activation of nucleus accumbens after high GI meal p<0.001, adjusted for multiple comparisons Lennerz. AJCN 2013, 98:641-7

Chronic effects in an animal model

Effects of Glycemic Index in Rodents Study Design Sprague-Dawley rats given diets with identical macronutrients high GI (amylopectin starch), n = 11 low GI ( high amylose starch), n = 10 Energy intake controlled to maintain identical mean body weight between groups Body composition measured at 18 weeks with tritiated water

Effects of Glycemic Index in Rodents Food intake and body weight Energy restriction required, suggesting metabolic changes Body weight (g) 600 500 400 300 200 100 0 Low GI High GI 0 2 4 6 8 10 12 14 16 18 Cumulative food intake (g) 4000 3000 2000 1000 0 0 2 4 6 8 10 12 14 16 18 Time (weeks) Time (weeks) Pawlak, Ludwig. Lancet 2004, 364:778-85

Effects of Glycemic Index in Rodents Differences in body composition Adiposity (%) p <.01 High GI Low GI Pawlak, Ludwig. Lancet 2004, 364:778-85

Effects of Glycemic Index in Rodents Differences in body composition Low GI High GI Pawlak, Ludwig. Lancet 2004, 364:778-85

Energy Expenditure & Weight Loss Maintenance Methods 21 obese young adults, studied for 7 months 10 to 15% weight loss on a standard low calorie diet Then studied during weight maintenance on each of three test diets with the same calories: - Low fat (60% carbohydrate, 20% fat, 20% protein) - Low glycemic index (40% carbohydrate, 40% fat, 20% protein) - Atkins very low carb (10% carbohydrate, 60% fat, 30% protein) - 1 Endpoint: Resting and total energy expenditure

Energy Expenditure & Weight Loss Maintenance Effects on total energy expenditure (doubly labeled water) Kcal per day 3400 3200 3000 2800 325 kcal/d P=0.003 (LF=LGI=VLC) Mean ± SE 2600 2400 BL LF LGI VLC Ebbeling, JAMA 2012;307:2627-34

Long-term effects of macronutrients on body weight

Behavioral Diet Studies Characteristically little weight difference between diets Major Limitations: Unequal treatment intensity between groups Limited long-term behavior change Little difference in actual diets among all participants

Feeding Studies Characteristically substantial effect of dietary composition DIRECT Study Methods 322 obese adults, studied for 2 years Assigned to 3 diets designed to differ in macronutrients - Low fat, calorie-restricted - Mediterranean, calorie-restricted - Low carbohydrate, not calorie-restricted Intervention based at a work site, with partial food provision Completion rates approaching 90% Shai. NEJM 2008, 359:229-41

Feeding Studies Characteristically substantial effect of dietary composition Shai. NEJM 2008, 359:229-41

Effects of Glycemic Load on Body Weight Diogenes Study, NEJM 2010, 363:2102-13 773 adults from 8 European countries who initially lost >8% body weight Diet: Low vs high protein; low vs high GI for 26 weeks ad libitum Intervention: family counseling, food provision in some sites High GL (low protein, high GI) Medium GL (high protein, high GI) Medium GL (low protein, low GI) Low GL (high protein, low GI)

Alternative View of Obesity Excessive anabolic drive in adipose tissue Hunger Dietary carbohydrate Energy intake Energy expenditure Resting energy Muscular expenditure efficiency Fatigue, physical inactivity Circulating metabolic fuels (glucose, lipids) Fatty acid profile Pro- prebiotics (gut microbiome) Insulin secretion Fat storage Protein (type/amount) Micronutrients phytochemicals

Dietary Fat Quality & Body Composition Saturated vs. polyunsaturated fatty acids Methods Double-blind RCT with 39 normal weight young adults Receive muffins high in sunflower oil (PUFA) vs. palm oil (SFA) Overfed 750 kcal/d for 7 weeks, to achieve 1.5 kg weight gain Results (Change: SFA PUFA) Total fat (MRI): +0.57 L (p=0.01) Lean tissue (BodPod): -0.93% (p=0.02) Liver fat (MRI): +0.52% (p=0.03) Rosqvist. Diabetes, online Feb 18, 2014

Alternative View of Obesity Excessive anabolic drive in adipose tissue Hunger Energy intake Energy expenditure Resting energy Muscular expenditure efficiency Fatigue, physical inactivity Sleep, stress, physical activity Circulating metabolic fuels (glucose, lipids) Fatty acid profile Pro- prebiotics (gut microbiome) Dietary carbohydrate Insulin secretion Fat storage Protein (type/amount) Micronutrients phytochemicals

Summary & Conclusions 1. The conventional approach to weight loss, the calorie-restricted diet, has poor efficacy in an environment with unlimited calorie availability 2. An alternative approach aims to reduce anabolic drive, leading to reduced adiposity with ad libitum conditions 3. Reduced anabolic drive may be achieved by lowering carbohydrate amount and/or glycemic index, and other qualitative changes in diet 4. Findings from behavioral RCTs must be interpreted cautiously, as they often fail to achieve significant changes in dietary intakes 5. Future research is needed to compare strategies to improve dietary composition vs. reduce calorie intake in the treatment of obesity

Closing Thought These ideas may be provocative, but they aren t new The editors of a leading medical journal wrote: When we read that the fat woman has the remedy in her own hands or rather between her own teeth... there is an implication that obesity is usually merely the result of unsatisfactory dietary bookkeeping... [Although logic suggests that body fat] may be decreased by altering the balance sheet through diminished intake, or increased output, or both... [t]he problem is not really so simple and uncomplicated as it is pictured. JAMA 1924, 83(13):1003 See also: Taubes. BMJ 2013, 346:f1050 Ludwig & Friedman, JAMA online