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

daniel.bessesen@ucdenver.edudaniel.bessesen@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

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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

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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

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ake (h

ou

rs/d

ay)

Pro

portio

n H

isp

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ic a

nd

/or a

ged

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een

35

an

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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.