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Why Is It So Difficult to Lose Weight (or easy to gain it)?

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Why Is It So Difficult to Lose Weight (or easy to gain it)? Elizabeth J. Murphy, MD, DPhil April 19, 2008 Diabetes in the United States 7% of population (20.8 million ... – PowerPoint PPT presentation

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Title: Why Is It So Difficult to Lose Weight (or easy to gain it)?


1
Why Is It So Difficult to Lose Weight (or easy to
gain it)?
  • Elizabeth J. Murphy, MD, DPhil
  • April 19, 2008

2
Diabetes in the United States
  • 7 of population (20.8 million)
  • 1 in 3 Americans born in 2000 will develop
    diabetes
  • 4 increase in DM2 risk for every pound
    overweight

3
Diabetes Trends Among Adults in the
U.S. Behavioral Risk Factor Surveillance Survey,
1990,1995 and 2001
No Data lt4 4-6 6-8
8-10 gt10
Mokdad et al., Diabetes Care 2000231278-83 J
Am Med Assoc 200128610.
4
Wednesday, January 23, 2008
Study Obesity surgery can cure diabetes
5
Gastric Banding for DM2
  • Subjects with mild DM2
  • Dx lt 2 yrs
  • HbA1C 7.7
  • BMI 30-40 (BMI 37.1)
  • Randomized to gastric banding or conventional
    treatment (including VLC diet or weight loss
    medication as appropriate/desired)
  • Lifestyle intervention for all patients included
    visit every 6 weeks with nutrition/activity plans
  • Followed for 2 years

Dixon et al., JAMA 2008, 299316.
6
Gastric Banding for DM2
Gastric Banding
Lifestyle Intervention
Dixon et al, JAMA 2008, 299316.
7
Gastric Banding for DM2
Lifestyle Intervention
Gastric Banding
Percentage weight loss and baseline HbA1c were
independently associated with DM remission.
Weight loss of approximately 10 was required for
diabetes remission.
Dixon et al, JAMA 2008, 299316.
8
First Law of Thermodynamics
Energy is neither created or destroyed.
ENERGY IN ENERGY OUT
9
ENERGY IN
10
ENERGY OUT
11
Energy Balance
ENERGY IN ENERGY OUT Protein CHO
Fat EtOH RMR TEF EEactivity

12
ENERGY IN gt ENERGY OUT
WEIGHT GAIN
CHO
TEF
RMR
EtOH
EEACTIVITY
FAT
PROTEIN
13
ENERGY IN lt ENERGY OUT
WEIGHT LOSS
CHO
EtOH
TEF
RMR
FAT
PROTEIN
EEACTIVITY
14
Average Non-obese American consumes 900,000
kcalories/year
Average day to day caloric variation 200 kcal/d
Eat one cup of ice cream a night 500 kcal/night,
3500 kcal/wk
1 lb/week 52 lbs in a year 500 lbs in 10 years
15
Middle Age Spread
Age 25 to 55
Weight gain 20 lbs
Energy Imbalance 0.3 of ingested calories
16
Cumulative Effect of Small Daily Imbalances in
Energy Intake on Body Fat Mass
Change in body fat (lb/y)
1 million
Energy intake (kcal/y)
Energy expenditure (kcal/y)
1 million
Excess intake ( total) Excess intake (kcal/d)
0 0.5 1 5
12 25 125
Rosenbaum M et al. N Engl J Med. 1997337396-408.
www.obesityonline.org
17
Weight Maintenance
  • 59 yom Graves Dz
  • 2/26/08 219.3
  • 11/7/06 219.4
  • 8/06 217
  • 6/05 217
  • 76 yom Thyroid Ca
  • 2/26/08 153.6
  • 11/20/07 153.3
  • 4/17/07 153
  • 1/9/07 150
  • 11/06 149.7
  • 7/02 147

18
Discrepancy Between Reported and Actual Energy
Intake and Expenditure
Activity Energy Expenditure
Energy Intake
3000
2500
2000
Kcal/d
1500
1000
500
0
Reported
Actual
Reported
Actual
Plt0.05 vs reported.
Lichtman et al. N Engl J Med 19923271893.
19
Central Energy Balance Questions
  • How do we regulate weight so well?
  • How do we override the weight regulation system
    so well?
  • What do we do when faced with the realities of 1
    2 above?

20
Drivers of Energy Balance
  • Behavioral/Environmental
  • Biologically Driven Override Possible?
  • REE NO
  • TEF NO (slightly?)
  • NEAT Partially
  • EI (energy input) Yes!
  • Volitionally Driven
  • Exercise Activity Required!

21
Definitions
  • RMR (Resting Metabolic Rate) EE measured in the
    resting state after an overnight fast
  • BMR (Basic Metabolic Rate) Same as RMR
  • Sleeping MR Average EE during sleep
  • REE (Resting Energy Expenditure) EE at complete
    rest in the postabsorptive state at any time of
    the day (typically about 10 gt BMR)

22
REE REE throughout the day, TEE 2330 kcal/d
kcal/min
kcal/d
  • Sleeping MR 1.12 1612
  • BMR 1.25 1800
  • Daytime EE 1.44 2074

Ravussin et al JCI 781568, 1986.
23
TEE
BMR
Welle et al., Am J Clin Nutr, 1992 5514.
24
Relationship Between Resting Energy Expenditure
and Fat-Free Mass
3000
Lean females Obese females
Lean males Obese males
2000
REE (kcal/24 h)
1000
0
Fat-Free Mass (kg)
Owen. Mayo Clin Proc 198863503.
25
Determinants of RMR
  • Fat Free Mass (FFM) is the primary determinant
    (80 of variance)
  • Overweight/obese individuals have increased FFM
    and hence increased RMR
  • Decreased RMR in AA women compared to Caucasian
    women matched for FFM1
  • Decreased RMR with age2
  • Decreased FFM with age
  • Further decrease matched for FFM

1Albu et al., Am J Clin Nutr 66531,
1997. 2Fikagawa et al., AJP Endo 259E233, 1990.
26
Subjects who were obese (gt 28 BMI) or never obese
with forced weight gain or loss
Leibel et al, N Engl J Med 1995332621
27
Relationship Between Resting Energy Expenditure
and Fat-Free Mass
3000
Lean females Obese females
Lean males Obese males
2000
REE (kcal/24 h)
1000
0
Fat-Free Mass (kg)
Owen. Mayo Clin Proc 198863503.
28
Energy Expenditure per Fat-free Mass Before and
after Weight Gain or Loss
Leibel, R. L. et al. N Engl J Med 1995332621-628
29
Observed-minus-Predicted Total Energy Expenditure
Change
Leibel, R. L. et al. N Engl J Med 1995332621-628
30
Response to 1000 kcal/d Overfeeding on Weight and
BMR
8
7
6
5
Percent Increase
Over Baseline
4
Wt
3
2
1
0
0
1
2
3
4
5
6
7
8
9
Weeks
Harris et al Obesity, 14690, 2006.
31
Adaptive Response of REE
  • Obese Man
  • 104 kg, BMI 34.3
  • 700 kcal/d caloric restriction diet for 8 wks
  • Loses 7.3 kg (7 weight loss)

Modified from Doucet et al Br J Nutr 85715, 2001.
32
Adaptive Response of REE 7 Body Weight Loss
REE Decrease kcal/d kcal/d Baseline
1 1996 - Week 8 - Predicted 1851 144 Wee
k 8 - Actual 1690 306 Age - Baseline3 300 AA
woman - Baseline 167 AA woman weight loss2
61 TOTAL 834 kcal/d
1Doucet et al Br J Nutr 85715, 2001. 2Foster et
al, Am J Clin Nutr 6913 (1999). 3Fukagowa et al,
Am J P Endo 259 E233-E238, 1990.
33
Drivers of Energy Balance
  • Behavioral/Environmental
  • Biologically Driven Override Possible?
  • REE NO
  • TEF NO (slightly?)
  • NEAT Partially
  • EI (energy input) Yes!
  • Volitionally Driven
  • Exercise Activity Required!

34
NEAT NonExercise Activity Thermogenesis
  • Sitting
  • Transitioning of body position
  • Walking
  • Fidgeting

35
NEAT In Sedentary Individuals
  • Neat accounts for 100 of EEact
  • Average NEAT measured in a respiratory chamber
    was 348 kcal/d
  • NEAT varied greatly between individuals from
    100-800 kcal/d

Ravussin et al JCI 781568, 1986.
36
Energy of NEAT
kcal min
Over BMR
  • BMR 1.29 NA
  • Sitting Motionless 1.34 3.7
  • Sitting and Fidgeting 1.96 54
  • Standing Motionless 1.46 13
  • Standing and Fidgeting 2.46 94
  • Walking 1 mph 3.27 154
  • Walking 2 mph 3.92 202
  • Walking 3 mph 5.09 292
  • Chewing Gum 19

Levine et al Am J Clin Nutr 721451, 2000.
Levine NEJM, 3421531 (2000).
37
NEAT Biological Drives
  • Patients with cancer cachexia have reduced NEAT
  • Patients with hyperthyroidism have increased NEAT
  • Boys have greater NEAT than girls
  • In some countries men have greater NEAT than
    women
  • NEAT decreases with age
  • Large genetic role (29-62 heritability)

Levine, AJP Endo 286E675, 2004.
38
NEAT Response to Weight Gain
  • 16 non-obese volunteers overfed 1000 kcal/d for 8
    weeks.
  • On average 432 kcal stored, 531 kcal dissipated
  • 5 increase REE (79 kcal 8 of excess)
  • 14 increase TEF (137 kcal 14 of excess)
  • Increase in NEAT (328 kcal 33 of excess)
  • Fat gain varied 10 fold (0.36 - 4.23 kg) and was
    inversely related to increase in NEAT

Levine et al, Science, 283212, 1999.
39
NEAT Response to Weight Loss
  • 800 kcal/d energy restriction
  • In lean subjects, 10 weight loss
  • -432 kcal TEE
  • -221 kcal REE
  • -206 kcal NREE (daytime REE NEAT) (48)
  • In overweight/obese, 10 weight loss
  • -551 kcal TEE
  • -299 kcal REE
  • -262 kcal NREE (48)
  • In overweight/obese, 20 weight loss
  • -886 kcal TEE
  • -303 kcal REE
  • -500 kcal NREE (56)

Leibel, R. L. et al. N Engl J Med 1995332621-628
40
NEAT
  • NEAT represents a more random variable in
    response to energy imbalance
  • NEAT is a manipulable variable
  • NEAT is generally a greater component of TEE than
    exercise
  • Decreasing NEAT is more metabolically detrimental
    than not exercising
  • Every 2-10 h/d of TV watching in men is
    associated with 6 increased diabetes risk
    adjusting for all confounders

Hu FB. et al. JAMA 20032891785. Hu et al. Arch
Intern Med 2001 1611542.
41
Sedentary Activity Obesity and Diabetes Risk
  • Every 2 h/d of TV watching in women is associated
    with
  • 23 increase in obesity risk
  • 14 increase in diabetes
  • Every 2 h/d of sitting at work in women is
    associated with
  • 5 increase in obesity risk
  • 7 increase in diabetes risk
  • Every 2-10 h/d of TV watching in men is
    associated with
  • 11-17 increased diabetes risk
  • 6 increased diabetes risk adjusting for all
    confounders

Hu FB. et al. JAMA 20032891785. Hu et al. Arch
Intern Med 2001 1611542.
42
Drivers of Energy Balance
  • Behavioral/Environmental
  • Biologically Driven Override Possible?
  • REE NO
  • TEF NO (slightly?)
  • NEAT Partially
  • EI (energy input) Yes!
  • Volitionally Driven
  • Exercise Activity Required!

43
Energy Intake
Schwartz and Porte, Science 307375, 2005.
44
Human Leptin Deficiency
Age 3.5 years, 90 lbs, 36
Age 8 years, 72 lbs, 41
Farooqi, ORahilly et al, JCI 1101093, 2002.
45
Energy Input Adaptations to Changes in EB
  • Basal Fat Loss Fat Gain
  • - -
  • --

Anabolic ? EI ? EE NPY/AgRP
  • Catabolic
  • EI ?EE
  • POMC/CART

Schwartz et al, Diabetes 52232, 2003.
46
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47
Environmental Overrides
  • Eat More
  • Exert Less

48
Daily Caloric Intake in the US
3000
Recommended Intake
2500
2000
kcal/person/day
1500
1000
500
0
Female
Male
49
US Food Production
Recommended Intake
3000
1971 Intake
2500
2000 Intake
2000
kcal/person/day
1500
1000
500
0
Female
Male
50
US Food Production
Recommended Intake
3000
1971 Intake
2500
2000 Intake
2000
kcal/person/day
1500
1000
500
0
Female
Male
51
Food Economy
  • Food in the US is a supply driven economy
  • Agribusiness subsidies (25 billion a year) make
    food cheap
  • Corn fed cows produce fatter meat
  • High fructose corn syrup is now a near universal
    sweetner
  • In America more is always better

52
Larger Portion Sizes
8 oz 80 kcal
53
1931 100 cookies 1973 45 cookies (2) 1997
36 cookies (2.5)
54
High Caloric Density Foods
SMALL TALL
870 Calories Full RDA of Saturated Fat
55
High Caloric Density Foods
  • Super-sized meal (Big Mac, supersize fries and
    large coke)
  • 1500 calories

56
Food Advertising
  • 10,000 M/yr on direct advertising
  • 20,000 M/yr on indirect marketing
  • 2 M/yr on eat your fruits and vegetables
    campaign
  • 80 of commercials during kids T.V. are for food
    products
  • During the 4 hr Saturday morning cartoon time,
    there are an average of 202 junk food adds

57
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58
FULL SIZE USA TODAY ADD
59
The French Paradox Reliance on Internal versus
External Satiation Cues?
  • External Cues
  • I stop eating when the TV show Im watching is
    over.
  • I stop eating when I run out of a beverage.
  • I stop eating when Ive eaten what most think is
    normal.
  • Internal Cues
  • I stop eating when I start feeling full.
  • I stop eating when I want to leave room for
    dessert.
  • If it doesnt taste good, Ill still eat it if
    Im hungry.

Wansink et al, Obesity, 152920 (2007).
60
The French Paradox
  • French relied more heavily on internal cues for
    meal cessation than Americans
  • Normal-weight individuals were more likely to
    rely on internal cues than overweight individuals

Wansink et al, Obesity, 152920 (2007).
61
Increased Food Intake
  • Food is a supply driven economy
  • Increased portion size
  • Calorically dense foods
  • Food advertising
  • Increased food options
  • Reliance on external cues to stop eating

62
Exert Less
  • Kids
  • TV/Video games
  • Cuts in PE
  • Less time outdoors
  • Unsafe neighborhoods
  • Adults
  • TV/Video games
  • Labor saving devices leading to less energy for
    activities of daily living
  • Automobile supremacy

63
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64
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65
Central Energy Balance Questions
  • How do we regulate weight so well?
  • How do we override the weight regulation system
    so well?
  • What do we do when faced with the realities of 1
    2 above?

66
1) How do we regulate weight so well?
  • REE adjusts to energy inbalance and changes in
    FFM to re-establish balance
  • NEAT adjusts to energy inbalance to re-establish
    balance
  • EI adjusts to energy inbalance and sends cues to
    modify food intake (stronger cues for negative
    EB)
  • These changes lead to significant changes in TEE
    in the face of weight loss

67
Question 2 How do we override the weight
regulation system so well?
  • Override of EI is much easier than override of
    EE of activity
  • 60 minutes of moderately vigorous exercise versus
    3-4 minutes to eat a couple of jelly donuts
  • Inundated with environmental cues to override EI
  • Biological drive to protect from weight loss is
    greater than to protect from weight gain
  • Environmental changes force decreased NEAT and
    override of the environment is difficult
  • Cant buy a tv without a remote
  • Cant use a manual typewriter instead of a
    computer
  • Cant manually open automatic doors
  • Cant find the stairs

68
Question 3 What do we do when faced with the
realities of 1 2 above?
  • Encourage our patients to increase their NEAT
  • Get off the bus one stop earlier
  • Take the stairs
  • Save money by not buying labor saving devices
  • Park at the first spot you find and walk a little
    further
  • Encourage cues to decrease EI
  • Dont eat in front of the tv
  • Smaller plates
  • Demand smaller portions in restaurants
  • Support food manufacturers/providers who make
    smaller sizes
  • Community Planning
  • Sidewalks in ALL new housing developments
  • Encourage mixed use zoning
  • Provide bike paths/safe ways for kids to get to
    schools

69
IS THERE ANY HOPE????
70
National Weight Control Registry
  • Weight loss of 30 lb for gt 1 year to join
  • 3000 subjects, 80 women, 97 Caucasian, 45 yo
  • Lost 30 kg for 5.5 years
  • BMI from 35 to 25

Wing and Hill, Annu Rev Nutr 21323, 2001.
71
How did they do it?
  • 90 had tried and failed in the past
  • 89 modified diet and exercise
  • Significant variation on how they lost
  • Half lost on their
  • Half used a weight loss program
  • For weight maintenance little variation

Wing and Hill, Annu Rev Nutr 21323, 2001.
72
Weight Loss Maintenance Role of Diet
  • Low fat, high carbohydrate diet
  • 1381 kcal/d
  • 24 fat, 19 protein, 56 carbohydrates
  • Ave 4.87 meals or snacks a day
  • 3.25 meals a week at a restaurant

Wing and Hill, Annu Rev Nutr 21323, 2001.
73
Weight Loss Maintenance Role of Self Monitoring
and Physical Activity
  • Self Monitoring Weight
  • 44 weighed themselves once at least once a day
  • 31 weighed themselves at least once a week
  • Physical Activity
  • 1 hr of moderate physical activity (brisk
    walking) per day
  • 2545 kcal/wk women 3293 kcal/wk men
  • 72 exercised gt 2000 kcal/wk
  • No detailed information on NEAT but the majority
    reported increased lifestyle activity and
    exercise

74
Drivers of Energy Balance
Behavioral/Environmental Biologically Driven
Override Possible? REE NO TEF NO
(slightly?) Energy Efficiency NO
NEAT Partially EI (energy input) Yes! Voli
tionally Driven Exercise Activity Required!
Behavioral/Environmental Biologically Driven
Override Possible? REE NO TEF NO
(slightly?) Energy Efficiency NO
NEAT Partially EI (energy input) Yes! Voliti
onally Driven Exercise Activity Required!
75
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76
INSULINS
  • Long Acting
  • glargine (lantus)
  • detemir (Levemir)
  • Intermediate Acting
  • N(ph)
  • Short Acting
  • Regular
  • Rapid Acting
  • aspart (Novolog)
  • lyspro (Humolog)
  • glulisine (Apridra)

77
GLP-1 Glucagon-like peptide 1
  • Enhances insulin secretion (glucose dependent)
  • Decreases post-prandial glucoagon secretion
  • Slows gastric emptying
  • Weight loss (?appetite suppression)

78
New Agents
  • exenatide (Byetta) - long acing GLP-1 analog
  • sitagliptin (Januvia) - DPPIV Inhibitor
  • colesevelam (Welchol) - bile acid sequesterant

79
Update on Glitazones
  • Rosiglitazone has neutral to increased
    cardiovascular disease risk.
  • Pioglitazone has neutral to decreased
    cardiovascular disease risk.
  • Both drugs increase fractures.

80
Goal HbA1C
  • ADA goal lt 7
  • ACCORD trial
  • goal lt 6.0
  • Increased mortality
  • ADVANCE trial
  • goal lt 6.5
  • no increased risk of mortality

81
Goals of Oral DM Algorithm
  • Accelerate getting to goal
  • Cost effective
  • Uniformity of care
  • Guidelines for non-provider personnel to follow

82
Glucose Control Algorithm
TYPE 2 DIABETES
AT DM2 DIAGNOSIS
A1C gt 7?
yes
A1C gt 9?
Severe Symptoms or A1C gt10?
STEP I Start METFORMIN 500 mg (1 pill daily ?
1pill BID ? 2 pills BID) Increasing dose q 2
weeks until goal reached. See Biguanides for
Details/Troubleshooting
yes
yes
?Contraindications -LFTsgt3xULN
-Crgt1.4/1.5
-acute/unstable CHF See Biguanides for
Details
FBG gt 130 after 6 wks? Or A1Cgt7 after 12 wks?
Start METFORMIN GLIPIZIDE Escalate metformin
and glipizide in parallel.
Start METFORMIN INSULIN
yes
STEP II Add GLIPIZIDE 5 mg (1 pill daily? 1
pill BID ? 2 pills BID) Increasing dose q 2 weeks
until goal reached. See Sulfonyureas for
Details/Troubleshooting
TREATMENT TARGETS A1C lt 7 Fasting SMBG 90 -
130
Alternative Consider Tolbutamide 250mg w/ meals
for Pt w/ Irregular Meal Patterns. See
Sulfonyureas for Details/Troubleshooting
?Contraindications -Severe sulfa
allergy See
Sulfonyureas for Details
FBG gt 130 after 6 wks? Or A1Cgt7 after 12 wks?
Alternatives 1) Add Pioglitazone 15mg ?caution
CHF, osteoporosis See
Thiazolidinediones for Details/Troubleshooting 2
) Add Acarbose 25mg TID See Alpha-gulosidase
inhibitors for Details/Troubleshooting
yes
FBG gt 130 after 6 wks? Or A1Cgt7 after 12 wks?
STEP III Add NPH Insulin Start 10 units HS
yes
83
Whole Room Calorimeter
84
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