How Body Weight Works (or doesnt work so well)

Dan Bessesen, MD Professor of Medicine University of Colorado, School of Medicine Chief of Endocrinology Denver Health Medical Center daniel.bessesen@ucdenver.edu

Two old friends come to clinic

At age 20 AJ was 56 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 56 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.

Brain

Energy In

Energy Out

Stored Fuel

Maintaining Energy Homoestasis

Brain

Energy In Fat Glucose Protein

Stored Fuel

Energy Out Fat Glucose Protein Fat Glucose Protein

Positive energy state: Assimilate exogenous nutrients

Dinner
Lunch Breakfast

Regulated Parameter

Time Night Negative energy state: Mobilizing/utilizing stored nutrients

Body Weight is Regulated

Overfeeding
UnderFeeding Obesity Prone Obesity Resistant

Figure 1. Animals tend to adjust their food intake to achieve a normal body weight. The graph shows a schematized gro wth curve for 3 group s of rats that were eithe r force-fed (a), allowed free access to food (b), or food restricted (c) for the pe riod between the arrows. Note that the an imals slowly returned to normal weight when allowed free access to food. (From Keesey et al, 1976)

Body Weight is Regulated

Humans
Stressful Job Alli

Pregnancy

College
Marriage
Figure 1. Animals tend to adjust their food intake to achieve a normal body weight. The graph shows a schematized gro wth curve for 3 group s of rats that were eithe r force-fed (a), allowed free access to food (b), or food restricted (c) for the pe riod between the arrows. Note that the an imals slowly returned to normal weight when allowed free access to food. (From Keesey et al, 1976)

Wt Watchers

Weight
Time

Rats

The development of weight related illnesses

Arthritis Genes Diet/Physical Activity Lean Overweight Diabetes

Coronary Artery Disease Environment

Time

Obese Hypertension Cancer

How much do I get to eat every day?

Physical Activity Energy Expenditure Thermic Effect of Food

Total Energy Expenditure = Energy Intake when in energy balance

Basal Metabolic Rate

Relationship Between Weight and Energy Expenditure

Weyer C, IJO 23:715-722

Obesity is associated with increased food intake

Are we gaining weight because of low metabolism

Lichtman, NEJM 327:1893; 1992

Are we Gaining Weight Because our Diet?

Gross AJCN 79:774 2004

Are we Gaining Weight Because our Diet?

Gross AJCN 79:774 2004

Things that Correlate with the Increase in Obesity

80 79 78 77 76 75 74 73 72 71 70 69 68 67 66 65 64 63 62 61 60 59 58 57 56 55 80 79 78 77 76 75 74 73 72 71 70 69 68 67 66 65 64 63 25 24 23 22 21 20 19 18 17 16 15 14 13 12 11 10 9 8 7 32 31 30 29 28 27 26 25 24 23 22 21 20 19 18 17 16 15 14 13 12
1960 1965 1970 1975 1980 1985 1990 1995 2000 Adult obesity prevalence (%) Average home temperature (F)

67.5 67 66.5 66 65.5 65 64.5 64 63.5 63 62.5 62 61.5 61 60.5 60 59.5 59 58.5 58 57.5 57 56.5 56 55.5 55 54.5 Year
Mean age of mothers at first birth (years)

26 25.75 25.5 25.25 25 24.75 24.5 24.25 24 23.75 23.5 23.25 23 22.75 22.5 22.25 22 21.75 21.5 21.25 21

4000 3750 3500 3250 PBDE concentration (pg/g) Mean age of mothers at first birth (years)

.50 .49 .48 .47 .46 .45 .44 .43 .42 .41

Prevalence of AC (%)

3000 2750 2500

2250 2000 1750 1500 1225 1000 750 500 250 0

.40
.39 .38 .37 .36 .35 .34

17.3 17.2 17.1 17 16.9 16.8 16.7 16.6 16.5 16.4 16.3 16.2 16.1 16 15.9 15.8 15.7 15.6 15.5

Proportion Hispanic and/or aged between 35 and 55 years

Antidepressant prescriptions (millions)

Average home temperature (F)

Adult obesity prevalence (%)

Time spent awake (hours/day)

Nonsmoker prevalence (%)

Nonsmoker prevalence (%) PBDE concentration (pg/g)

Antidepressant prescriptions (millions)

Keith SW et al. Int J Obes. 2006;30:1585-1594.

Prevalence of AC (%) Proportion of Hispanic and/or aged between 35 and 55 years Time spent awake (hours/day)

How About Genetics? Pima Indians

TEE in Pima People Living In Mexico or USA

Esparza, Int J Obes Relat Metab Disord 24:55; 2000

Why are we gaining weight? Occupations and Obesity

TS Church, PLoS One. 2011;6(5):e19657.

Diet Physical Activity and Weight Gain

NEJM, 2011 Jun 23;364(25):2392-404

 AJ

decides to take up bike riding and eating a healthy diet. He cuts out fast food, eats breakfast, weighs himself, and writes down what he eats every day. He loses 42 lbs and his blood glucose and blood pressure return to normal. Over the next 5 years his company restructures, his job is eliminated, he moves to a new firm and works 60 hours per week in a high stress position His weight rises to 307 lbs (BMI= 49 kg/m2). A1C=8.5%

Why is it so hard for people 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.

900

Paradigm of Obesity Development, Treatment, and Relapse

Treated
Obese

800

Untreated

700

Weight-Reduced

Relapsed-Obese

Body Weight (g)

600

500

Never-Obese

400

Pre-Obese
300

Weight loss

Weight Maintenance

Weight Regain

Development Phase
200 0 2 4 6 8

Treatment Phase

Relapse Phase

10 12 14 16 18 20 22 24 26 28 30 32 34 36 38 40 42 Weeks of Study

Changes in Energy Expenditure Resulting From Altered Body Weight

Leibel RL, NEJM 332:621-628, 1995

Effects of Weight Gain or Loss on TEE and RMR

Leibel RL, NEJM 332:621-628, 1995

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 Loss

2600 kcal/day 2250 kcal/day

3000 2500

kcals/day

2000 1500 1000 500 0

TDAT TEF RMR

Before Weight After Weight Loss Loss 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

Maclean PS, Am J Physiol. 2004 Dec;287(6):R1306-15

140 120
a

EI

TEE
c c c c

a d d

100

kcal/day

80 60 40 20 0 Obese

b,c

c,d

WeightReduced

Day 1

Day 3

Day 7

Day 14

Time of Relapse

Visual Stimuli
Basic or Utilitarian Food Highly Palatable or Hedonic Food

Control Object

Neuronal Responses of fasted Thin Subjects to Food Images of High Hedonic Value

Cornier et al, Am J Clin Nutr, 86:965-971, 2007.

Neuronal Responses of Thin Individuals Following 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.

Homeostatic Control of Feeding

Cooke D; Nature Reviews Drug Discovery 5, 919-931

Ghrelin and Leptin with Energy Deficit

In 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 Appetite and Hunger Hormones

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.

Cocaine Distribution Following Intravenous Injection

Fowler JS, Synapse. 1989;4(4):371-7

Food Stimuli Increase Dopamine in the Striatum

Remember Marcs fMRI Data?

Valkow ND, Synapse. 2002 Jun 1;44(3):175-80.

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 increased in drug addicts using strategies to resist drug cues. Activity is increased in reduced obese women. Increased activity seen in indivduals with anorexia nervosa. Reduced activity correlates with performance on delayed discounting task.

Lean vs Obese Performance on Delayed Discounting Task.

Weller RE, Appetite 51(3) 563-569; 2008

Regulation of Body Weight by the Brain

Social meaning of food Ideas of Diet and Health Social/Cognitive Factors
Unconscious

Self Control Decision making Emotions Hedonics Dopamine

Non Homeostatic Factors

Leptin Glucose NPY Homeostatic Factors

So what should AJ do?

Accept weight where it is
Effectiveness
Low

Diet/Exercise, 3-5% weight loss Drugs, 5-8% weight loss Surgery 30% weight loss

High

Currently Available Options

Accept weight where it is
Diet/Exercise, 3-5% weight loss Drugs, 5-8% weight loss Surgery 30% weight loss Risk
Low

High

If you keep your weight down long enough do you reset your setpoint?
A
900 800 700
Weight (g)

Control Rats

900 800 700

Control Rats

900 800 700

Control Rats

900 800 700

900 Relapsed-Obese Relapsed-Obese 900 Relapsed-Obese Rats Rats Rats

800 700
Weight (g)

800 700

Weight (g)

Weight (g)

600 500 400 300 200 0 4 8

Weight (g)

600 500 400

600 500 400

600 500 400

Weight (g)

600 500 400

600 500

400 Initial gain Initial gain 0 wks Obese 0 wksTime in Time in 300 300 8 wks weight 300 8 wks weight Never-Obese 16 wks maintenance 16 maintenance wks 200 200 200 200 200 0 20 4 24 8 28 12 32 16 36 20 40 24 8 28 12 32 16 36 0 20 40 4 24 8 28 1232 1636 2040 24 28 12 16 020 424 828 12 32 16 36 40 0 20 4 24 8 2812 3216 36 0 4 40 Time in Weeks Time in Weeks Time in Weeks Time in Weeks Time in Weeks Time in Weeks

Obese 300 Never-Obese

ObeseTime in weight 300 Never-Obese maintenance

Initial gain 0 wks 8 wks 16 wks 32 36 40

900 800 700

900 Weight-Reduced Weight-Reduced 900 Weight-Reduced 90 Rats Rats Rats 80

800 700
Weight (g)

D 90
80
Weight regain in relapse (g/week)

D 90
Weight regain in relapse (g/week)
d in Time 80 weight maintenance 70

800 700

Weight regain in relapse (g/week)

70 60 50 40 30
b c

70 60 50 40 30
a,b
b

Control 0 wks 8 wks 16 wks

Time in weight maintenance

c

Control 0 wks Time in 8 wks weight 16 wks maintenance

Con 0 wk 8 wk 16 w

60 50 40 30 20 10
aa b

Weight (g)

600 500 400 300 200 0 4 8

Weight (g)

600 500 400

600 500

b,c

a 400 Initial gain 20 Initial gain 0 wks Time in 0 wks Time in 10 300 8 wks weight 8 wksweight 16 wks 0 maintenance 16maintenance wks 200 200 week 1 12 16 0 20 424 828 12 32 16 36 40 0 20 4 24 8 28 12 32 16 36 20 40 24 28 Time in Weeks Time in Weeks Time in Weeks

a Initial gain a 20

Time in weight 300 maintenance

10 8 wks
16 0 wks

0 wks

b,c a,b b a a,b

a,b
a

b,c
b

c b a a a,b

a a,b a

32

Period of Relapse

36

week week 2 1
40

0 Final 4 weeks week week 2 1

Period of Relapse

week 2 Final 4 weeks Period of Relapse

Final 4 weeks

Figure 5. Body weights the rate5. of and weight regain. (A) Obesity-prone rats became (A)rats Figure Body weights the rate of weight regain. Obesity-prone rats beca Figure 5. and Body weights the rate ofand weight regain. (A) Obesity-prone became

But some people succeed in losing weight the NWCR

3600 people who have maintained a 71 lb weight loss for 5.7 years

75%

weigh more than once a week 44% weigh once a day 50% still count calories or fat grams On average, NWCR entrants report a high level of activity: 2621 kcal/wk. (60-90 min/d)
Klem ML et al. Am J Clin Nutr. 66:239-46, 1997.

Fear of death is not sustainable..

Joy of life is sustainable..

Topiramate/Phentermine (Qsymia) Effects on Weight

Lancet. 2011 Apr 16;377(9774):1341-52

Weight Loss in the SOS Study

Sjostrom L NEJM 2007: 357-741-752

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.