The conventional approach to weight loss, based on the calorie balance model, offers the simple advice, “eat less and move more.” Unfortunately, few people can maintain weight loss over the long term through calorie restriction because the body fights back, with rising hunger and slowing metabolism. An alternative approach to treatment aims to target the underlying driver of weight gain – fat cells overstimulated to hoard too many calories – leading to weight loss with less struggle.

1. 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
Which Comes First: Overeating or Obesity?

2. First Law of Thermodynamics
Energy can neither be created or destroyed
Calorie intake Calorie expenditure- Calories stored
(adipose tissue)
=

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

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

5. 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-management-
calories/weight-management/better-choices/amount-

6. Fat
Carbohydrate
Nutrients

7. Year
PercentDietaryFat
Secular Trends in Dietary Fat
Inverse relationship with obesity prevalence

8. Long-term RCT of a Low Fat Diet
The Women’s Health Initiative
-5
-4
-3
-2
-1
0
1
2
0 1 2 3 4 5 6 7 8 9
ChangeinWeight(kg)
Years
Control Intervention
• 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

9. Meta-analyses of Low Fat Diets
LESS effective than comparison diets
Mansoor N. Effects of low-carbohydrate diets v. low-fat diets on body
weight and cardiovascular risk factors: a meta-analysis of randomised
controlled trials. Br J Nutr 2016, 115:466-79
Tobias DK. Effect of low-fat vs. other diet interventions on long-term weight
change in adults: a systematic review and meta-analysis. Lancet Diabetes
Endocrinology 2015, 3:968-79
Bueno NB. 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. Meta-analysis comparing Mediterranean to low-fat diets for
modification of cardiovascular risk factors. Am J Med 2011, 124:841-51.

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

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

12. Energy
intake
Energy
expenditure
Fat storage
(anabolic adipose)
eat
less
move
more
Why hasn’t this paradigm
worked in practice?
Circulating
metabolic fuels
(glucose, lipids)
Physical inactivity
(TV, computer, etc)
Conventional View of Obesity
Failure of voluntary control over energy balance
Overeating
(ubiquitous tasty
foods)

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

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

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

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

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

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

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

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

21. Body Weight is Under Biological Control
Complex interplay of biological & environmental factors
Body Weight
Energy
ExpenditureHunger
“Body Weight Set Point”

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

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

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

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

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

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

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

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

30. Metabolic Effects of Processed Carbohydrate
Methods
• Subjects: 12 obese adolescents
• Design: cross-over feeding study on 3 separate days
• Intervention: breakfasts with identical calories:
- Instant oatmeal (highly processed grain) – high glycemic index
- Steel-cut oatmeal (less processed) – moderate glycemic index
- Vegetable omelet with fruit (no grains) – low glycemic index
• Blood tests and hunger followed through the day

31. -1
0
1
2
3
4
∆Glucose(mmol/L)
0 1 2 3 4 5
Time (hr)
Low GL
Med GI
High GI
Glycemic Index and Hunger
Metabolic fuels
-400
-300
-200
-100
0
100
200
∆FreeFattyAcids(uEg/L
)
0 1 2 3 4 5
Time (hr)
Low GL
Med GI
High GI
Ludwig. Pediatrics 1999, 103:e26

32. -10
0
10
20
30
40
50
60
∆Epinephrine(ng/L)
0 1 2 3 4 5
Time (hr)
Low GL
Med GI
High GI
Acute Effects of Glycemic Load
Plasma epinephrine
Ludwig. Pediatrics 1999, 103:e26

33. 0
500
1000
1500
KilocaloriesConsumed
1 2 3 4 5
Time (hr)
High GI
Med GI
Low GL
Acute Effects of Glycemic Load
Cumulative food intake
Ludwig. Pediatrics 1999, 103:e26

34. Glycemic Index & Brain Function
Methods
Lennerz. AJCN 2013, 98:641-7
• Subjects: 12 overweight/obese young men
• Design: Double-blind, cross-over feeding study
• Intervention: high GI vs. low GI liquid meals, with the same:
- macronutrients
- calorie content
- sweetness
• Brain imaging 4 hour after the meal

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

36. 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

37. • 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)
Energy Expenditure & Weight Loss Maintenance
Methods

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

39. Long-term effects of macronutrients
on body weight

40. Methods
• 811 overweight/obese adults, studied for 2 years
• Assigned to 4 diets designed to differ in macronutrients
- Carbohydrate: 35 – 65%
- Fat: 20 – 40%
- Protein: 15 – 25%
• Intervention: individual and group behavioral counseling
Results
• No difference in body weight according to diet group
POUNDS LOST Study
Sacks. NEJM 2009, 360:859-73
Behavioral Diet Studies
Characteristically little weight difference between diets

41. Behavioral Diet Studies
Characteristically little weight difference between diets
Sacks. NEJM 2009, 360:859-73
POUNDS LOST Study
Major Limitation: Did not achieve targeted dietary goals
• Reported maximum differences in intakes less than half intended:
• Even these relatively small differences may be overestimated, due to
“social-desirability bias” inherent to self reporting
• Biomarkers demonstrated poor compliance at 2 years:
- No difference in triglycerides (marker of carbohydrate intake)

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

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

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

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

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

47. Methods
• 7447 Spanish adults at risk for cardiovascular disease
• Assigned to 3 diets:
- Standard Low Fat
- Mediterranean High Fat, with 1 liter olive oil per week
- Mediterranean High Fat, with 1 oz nuts per day
Results
• Trial stopped early because effects were unexpected large
• Higher fat groups showed 30% reductions in cardiovascular disease
• Subsequent analyses showed benefits for diabetes, breast cancer,
age-related cognitive decline, other outcomes
PREDIMED STUDY
Estruch. NEJM 2013, 368:1279-90
High Fat Diets and Cardiovascular Disease
Good for your waist, great for your heart!

48. 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 storage of calories in fat cells
directly, leading to reduced body fat with ad libitum conditions
3. Reduced fat storage may be achieved by lowering total amount or
processing of carbohydrate, and other qualitative changes in diet
4. Findings from behavioral trials 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

49. 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

50. Grand Central Publishing
January 2016