How Body Weight Works (or How Body Weight Works (or doesn’t work so well…)doesn’t work so well…)
Dan Bessesen, MDDan Bessesen, MDProfessor of MedicineProfessor of Medicine
University of Colorado, School of University of Colorado, School of Medicine Medicine
Chief of EndocrinologyChief of EndocrinologyDenver Health Medical CenterDenver Health Medical Center
[email protected]@ucdenver.edu
Two old friends come to clinic
• At age 20 AJ was 5’6” and weighed 145 lb
• At age 51 he weighs 205 lb (BMI=33)
• He now has diabetes, hypertension and arthritis.
• At age 20 GB was 5’6” and weighed 145 lb
• At age 51 he weighs 150 lb (BMI=24)
• His health is currently good.
Two old friends come to clinic
• AJ works a “desk job”, eats out frequently, gets no regular exercise, gets 5-6 hrs sleep/night
• GB works a construction job, wife cooks “healthy” and he hikes and skis on weekends.
How did this happen?
• AJ had a change in fat mass over 31 years of 60 lbs
• This represents a net caloric balance of +160,650 kcal
• GB had a change in fat mass over 31 years of 5 lbs
• This represents a net caloric balance of +22,950 kcal
And over this same time they ate
• 31 yrs x 365 days/yr x 2300 kcal/d =
• 29,382,500 kcal
• Or 2,323 lbs of food
• Suggests that the system governing energy balance and body weight must be relatively well regulated.
Energy In Energy Out
Stored Fuel
Brain
Energy In Energy Out
Stored Fuel
Brain
FatGlucoseProtein
FatGlucoseProtein
FatGlucoseProtein
Maintaining Energy “Homoestasis”
Positive energy state:Assimilate exogenousnutrients
Negative energy state:Mobilizing/utilizing stored nutrients
Time
Regulated Parameter
BreakfastLunch
Dinner
Night
Figure 1. Animals tend to adjust their food intake to achieve a normal body weight. The graph shows a schematized growth curve for 3 groups of rats that were either force-fed (a), allowed free access to food (b), or food restricted (c) for the period between the arrows. Note that the animals slowly returned to normal weight when allowed free access to food. (From Keesey et al, 1976)
Body Weight is Regulated
Obesity Prone
ObesityResistant
Over-feeding
Under-Feeding
Figure 1. Animals tend to adjust their food intake to achieve a normal body weight. The graph shows a schematized growth curve for 3 groups of rats that were either force-fed (a), allowed free access to food (b), or food restricted (c) for the period between the arrows. Note that the animals slowly returned to normal weight when allowed free access to food. (From Keesey et al, 1976)
Body Weight is Regulated
Time
Weig
ht
College
Marriage
Pregnancy
Wt Watchers
StressfulJob Alli
Humans
Rats
The development of weight related illnesses
Diabetes
Coronary Artery Disease
Hypertension
Diet/Physical Activity OverweightLean
Time
Obese
Arthritis
Cancer
Genes
Environment
How much do I get to eat every day?How much do I get to eat every day?
Basal Metabolic Rate
Thermic Effect of Food
Physical Activity Energy Expenditure
Total Energy Expenditure
= Energy Intake whenin energy balance
Relationship Between Weightand Energy Expenditure
Weyer C, IJO 23:715-722Obesity is associated with increased food intake
Lichtman, NEJM 327:1893; 1992
Are we gaining weight because of ‘low metabolism’
Gross AJCN 79:774 2004
Are we Gaining Weight Because our Diet?Are we Gaining Weight Because our Diet?
Gross AJCN 79:774 2004
Are we Gaining Weight Because our Diet?Are we Gaining Weight Because our Diet?
Things that Correlate with the Things that Correlate with the Increase inIncrease in ObesityObesity
Keith SW et al. Int J Obes. 2006;30:1585-1594.
121314151617181920212223242526272829303132
789
10111213141516171819202122232425
636465666768697071727374757677787980
5556575859606162636465666768697071727374757677787980
54.55555.55656.55757.5
58.5
59.559
6060.56161.56262.56363.56464.56565.56666.5
67.5
58
67
2121.2521.521.752222.2522.522.752323.2523.523.752424.2524.524.752525.2525.525.7526
0
250
500
750
1000
1225
1500
1750
2000
2250
2500
2750
3000
3250
3500
3750
4000
.34
.35
.36
.37
.38
.39
.40
.41
.42
.43
.44
.45
.46
.47
.48
.49
.50
15.515.615.715.815.91616.116.216.316.416.516.616.716.816.91717.117.217.3
Pre
vale
nce o
f A
C (
%)
Non
sm
oker
pre
vale
nce (
%)
An
tid
ep
ressan
t p
rescri
pti
on
s (
million
s)
Ad
ult
ob
esit
y p
revale
nce (
%) T
ime s
pen
t aw
ake (h
ou
rs/d
ay)
Pro
portio
n H
isp
an
ic a
nd
/or a
ged
betw
een
35
an
d 5
5 y
ears
PB
DE c
on
cen
tratio
n (p
g/g
)
Mean
ag
e o
f moth
ers
at fi
rst b
irth (y
ears
)
Avera
ge h
om
e te
mp
era
ture
(F)
196019651970197519801985199019952000
YearAdult obesity prevalence (%)
Antidepressant prescriptions(millions)
Average home temperature (F)
Mean age of mothers at firstbirth (years)
Nonsmoker prevalence (%)
PBDE concentration (pg/g)
Prevalence of AC (%)Proportion of Hispanicand/or aged between35 and 55 yearsTime spent awake(hours/day)
How About Genetics? Pima Indians
Esparza, Int J Obes Relat Metab Disord 24:55; 2000
TEE in Pima People Living In Mexico or USATEE in Pima People Living In Mexico or USA
TS Church, PLoS One. 2011;6(5):e19657.
Why are we gaining weight?Occupations and Obesity
Diet Physical Activity and Weight Gain
NEJM, 2011 Jun 23;364(25):2392-404
►AJ decides to take up bike riding and eating a AJ decides to take up bike riding and eating a healthy diet. He cuts out fast food, eats healthy diet. He cuts out fast food, eats breakfast, weighs himself, and writes down what breakfast, weighs himself, and writes down what he eats every day.he eats every day.
►He loses 42 lbs and his blood glucose and blood He loses 42 lbs and his blood glucose and blood pressure return to normal.pressure return to normal.
►Over the next 5 years his company restructures, Over the next 5 years his company restructures, his job is eliminated, he moves to a new firm and his job is eliminated, he moves to a new firm and works 60 hours per week in a high stress positionworks 60 hours per week in a high stress position
►His weight rises to 307 lbs (BMI= 49 kg/mHis weight rises to 307 lbs (BMI= 49 kg/m22). ). A1C=8.5%A1C=8.5%
Why is it so hard for people Why is it so hard for people maintain a reduced state?maintain a reduced state?
►Body weight is regulated in a manner that…►With weight reduction energy expenditure
declines.►metabolism changes in a manner that
promotes weight regain.►appetite increases.►These forces can be counteracted with
exercise, diet and environmental changes.
Paradigm of Obesity Development, Treatment, and Relapse
200
300
400
500
600
700
800
900
0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36 38 40 42
Weeks of Study
Bo
dy
We
igh
t (g
)
Treated
Untreated
Weight Maintenance
Weight Regain
Weight loss
TreatmentPhase
gRelapsePhase
DevelopmentPhase
Pre-Obese
Obese
Relapsed-ObeseWeight-Reduced
Never-Obese
Changes in Energy Expenditure Resulting From Altered Body Weight
Leibel RL, NEJM 332:621-628, 1995
Leibel RL, NEJM 332:621-628, 1995
Effects of WeightGain or Loss on
TEE and RMR
Why does EE go down?
• Lean body mass declines.• Thyroid hormone goes down.• Sympathetic nervous system activity
declines.• Absolute amount of physical activity probably
does not decline, but energy cost declines.• Energy efficiency of physical activity may
increase.• Leptin may counteract these effects.
EE Before and After Weight EE Before and After Weight LossLoss
0
500
1000
1500
2000
2500
3000
Before WeightLoss
After WeightLoss
kcals
/day
TDAT
TEF
RMR
2600 kcal/day 2250 kcal/day
Example: 200 lb woman losing 20-30 lbs experiences a 350 kcal/day reduction in TEE as a result of weight loss.
Energy Balance with Weight loss and Relapse
0
20
40
60
80
100
120
140
Obese Weight-Reduced
Day 1 Day 3 Day 7 Day 14
kc
al/d
ay
EI TEE
Time of Relapse
a
b b,cc,d
d d
a
b
c cc c
Maclean PS, Am J Physiol. 2004 Dec;287(6):R1306-15
Visual Stimuli
Basic or “Utilitarian” Food Highly Palatable or “Hedonic” Food
“Control” Object
Neuronal Responses of fasted Thin Neuronal Responses of fasted Thin Subjects to Food Images of High Subjects to Food Images of High
Hedonic ValueHedonic Value
Cornier et al, Cornier et al, Am J Clin NutrAm J Clin Nutr, 86:965-971, 2007, 86:965-971, 2007..
Neuronal Responses of Thin Neuronal Responses of Thin Individuals Individuals
Following OverfeedingFollowing Overfeeding
Cornier et al, Am J Clin Nutr, 86:965-971, 2007.
Reduced Obese Subjects Following Overfeeding:
Hedonic Foods > Basic Foods
Reduced obese subjects fail to suppress neuronal activation following overfeeding like normal thin subjects do.
Cooke D; Nature Reviews Drug Discovery 5, 919-931
Homeostatic Control of Feeding
Ghrelin and Leptin with Energy DeficitIn Obese Subjects
Cummings DE; N Engl J Med. 2002 May 23;346(21):1623-30
Wisse B; Am J Clin Nutr. 1999 Sep;70(3):321-30
Effects of Weight Loss on Effects of Weight Loss on Appetite and Hunger Appetite and Hunger
HormonesHormones
Sumithran, NEJM 2011; 365:1597-604
Food intake and Reward
► Much has been learned from drug addition research about reward and control/inhibition of addictive behavior.
► Same pathways are likely involved in food intake.
► Dopamine action in the ventral striatum correlates with rewarding stimuli.
► Variations in dopamine receptor density relate to addiction and obesity.
► Liking versus wanting.
Fowler JS, Synapse. 1989;4(4):371-7
Cocaine Distribution Following Intravenous Injection
Valkow ND, Synapse. 2002 Jun 1;44(3):175-80.
Food Stimuli Increase Dopamine in the Striatum
Remember Marc’s fMRI Data?
Brain areas responsible for decision making and control Forstmann BU PLoS One 3(4) e1899, 2008
Frontal Regulatory Regions: Impulsivity/Self Control
►Activity is reduced in drug addicts.Activity is reduced in drug addicts.►Activity is increased in drug addicts using Activity is increased in drug addicts using
strategies to resist drug cues.strategies to resist drug cues.►Activity is increased in reduced obese Activity is increased in reduced obese
women. women. ► Increased activity seen in indivduals with Increased activity seen in indivduals with
anorexia nervosa. anorexia nervosa. ►Reduced activity correlates with Reduced activity correlates with
performance on delayed discounting performance on delayed discounting task.task.
Lean vs Obese Performance on Lean vs Obese Performance on Delayed Discounting Task.Delayed Discounting Task.
Weller RE, Appetite 51(3) 563-569; 2008
Regulation of Body Weight by the Brain
Homeostatic Factors
LeptinGlucoseNPY
Non Homeostatic Factors
HedonicsDopamine
Social/Cognitive Factors
Social meaning of foodIdeas of Diet and Health
Unconscious
Self ControlDecision makingEmotions
So what should AJ do?
• Accept weight where it is
• Diet/Exercise, 3-5% weight loss
• Drugs, 5-8% weight loss
• Surgery 30% weight loss
Low
High
Effectiveness
Currently Available Options
• Accept weight where it is
• Diet/Exercise, 3-5% weight loss
• Drugs, 5-8% weight loss
• Surgery 30% weight loss
Low
High
Risk
If you keep your weight down long enough do you “reset your setpoint”?
Control
Rats
200
300
400
500
600
700
800
900
0 4 8 12 16 20 24 28 32 36 40Time in Weeks
We
igh
t (g
)
Obese
Never-Obese
A Relapsed-Obese
Rats
200
300
400
500
600
700
800
900
0 4 8 12 16 20 24 28 32 36 40Time in Weeks
We
igh
t (g
)
Initial gain
0 wks
8 wks
16 wks
Time in weight
maintenance
C
Weight-Reduced Rats
200
300
400
500
600
700
800
900
0 4 8 12 16 20 24 28 32 36 40Time in Weeks
We
igh
t (g
)
Initial gain
0 wks
8 wks
16 wks
Time in weight
maintenance
B
Figure 5. Body weights and the rate of weight regain. (A) Obesity-prone rats became obese with 16 wks of high fat feeding. These Obese rats were examined metabolically prior to or after 26 subsequent weeks on the low fat diet. Obesity-resistant rats, designated Never-Obese, were examined metabolically after 16 wks on a low fat diet. (B) Weight-Reduced rats were obesity-prone rats that had developed obesity with 16 wks of high fat feeding, but then underwent weight loss on a intake-regulated low fat diet and were maintained at this reduced weight for 0, 8, or 16 wks prior to metabolic monitoring. (C) Relapsed-Obese rats were obesity-prone rats that had developed obesity, underwent weight loss, maintained at this reduced weight for 0, 8, or 16 wks, and then allowed free access to the low fat diet for 8 subsequent wks prior to metabolic monitoring. (D) The rate of weight regain for Relapsed-Obese rats is represented as the average for the first week, the second week, and the final 4 weeks of the relapse period. Data are expressed as mean SEM, with Duncan’s post-hoc analysis to examine homogeneous groups. With each time period, groups that are not significantly different are represented by having the same letter designation.
► 75% weigh more than 75% weigh more than once a weekonce a week
► 44% weigh once a day44% weigh once a day► 50% still count calories 50% still count calories
or fat gramsor fat grams► On average, NWCR On average, NWCR
entrants report a high entrants report a high level of activitylevel of activity: 2621 : 2621 kcal/wk. (60-90 min/d)kcal/wk. (60-90 min/d)
Klem ML et al. Am J Clin Nutr. 66:239-46, 1997.
►3600 people who have maintained a 71 lb weight loss for 5.7 years
But some people succeed in losing weight… the NWCR
Fear of death isnot sustainable..
Joy of life issustainable..
Lancet. 2011 Apr 16;377(9774):1341-52
Topiramate/Phentermine (Qsymia) Effects on Weight
Sjostrom L NEJM 2007: 357-741-752
Weight Loss in the SOS Study
Summary
• Body weight is regulated by a complex system with many inter-related parts.
• Weight tends to increase as we get older• The body responds to weight loss with
adaptations that promote weight regain.• Despite this some weight loss and
weight loss maintenance is possible.