Dr. Daniel H. Bessesen: The Biology of Obesity

8/12/2019 Dr. Daniel H. Bessesen: The Biology of Obesity

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The Biology of Obesity

Dan Bessesen, MDProfessor of Medicine

University of Colorado, School of MedicineChief of Endocrinology

Denver Health Medical [email protected]


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Two old friends come to clinic

At age 20 AJ was

56 and weighed

145 lb At age 60 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 60 he weighs

150 lb (BMI=24)

His health is

currently good.


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Two old friends come to clinic

AJ works a desk

job, eats out

frequently, gets noregular exercise,

gets 5-6 hrs

sleep/night

GB works a

construction job,

wife cooks healthyand he hikes and

skis on weekends.


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How did this happen?

AJ had a change in

fat mass over 40

years of 60 lbs This represents a

net caloric balance

of +160,650 kcal

EI age 20=2,586

kcal/d

EI age 60=2,430

kcal/d

GB had a change in

fat mass over 40

years of 5 lbs This represents a

net caloric balance

of +22,950 kcal

EI age 60 =2,104

kcal/d


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And over this same time they

ate 40 yrs x 365 days/yr x 2300 kcal/d =

33,580,000 kcal

Or 15,389 lbs of food

Suggests that the system governing

energy balance and body weight must

be relatively well regulated.


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Energy In Energy Out

Stored Fuel

Brain


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Figure 1. Animals tend to adjust their food intake to achieve anormal body weight. The graph shows a schematized growthcurve for 3 groups of rats that were either force-fed (a), allowedfree access to food (b), or food restricted (c) for the period betwee

the arrows. Note that the animals slowly returned to normal weightwhen allowed free access to food. (From Keesey et al, 1976)

Body Weight is Regulated

ObesityProne

Obesity

Resistant

Over-feeding

Under-Feeding


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Figure 1. Animals tend to adjust their food intake to achieve anormal body weight. The graph shows a schematized growthcurve for 3 groups of rats that were either force-fed (a), allowedfree access to food (b), or food restricted (c) for the period betweethe arrows. Note that t he animals slowly returned to normal weightwhen allowed free access to food. (F rom Keesey et al, 1976)

Body Weight is Regulated

Time

Weig

ht

College

Marriage

Pregnancy

Wt Watchers

StressfulJob Alli

Humans

Rats


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The development of weight

related illnesses

Diabetes

Coronary Artery

Disease

Hypertension

Diet/Physical

Activity OverweightLean

Time

Obese

Arthritis

Cancer

Genes

Environment


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Db Mouse

Ob Mouse


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Parabiosis Experiments of Douglas Coleman


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Boy with Leptin Deficiency


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Genetics

Candidate genes

Leptin, MC4R

Leptin Receptor

Whole Genome Scans

Many genes with small effects

FTO is the most common

Interacts with the environment

What do we do with this?


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Rare, but Profound

Monogenic FormsOf Human Obesity

-Leptin Receptor Deficient

-Leptin Deficient

-MC4 receptor deficient

Farooqi, IS, NEJM 2007; 356:237-47


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Example of a GenomeWide Association Study

(GWAS)


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Genetics: Interaction of Diet and Genes

N Engl J Med 2012;367:1387-96.

Those with 10 high risk genetic alleles who consumed >1 SSB/d had

a mean BMI 2.4 kg/m2 greater than those who consumed SSB but

were at low genetic risk


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Energy In Energy Out

Stored Fuel

Brain

Fat

Glucose

Protein

Fat

Glucose

Protein

Fat

Glucose

Protein

Maintaining Energy Homoestasis


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Positive energy state:

Assimilate exogenous

nutrients

Negative energy state:

Mobilizing/utilizing

stored nutrients

Time

Regulated Parameter

Breakfast

Lunch

Dinner

Night


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How much do I get to eat every day?

Basal Metabolic Rate

Thermic Effectof Food

Physical Activity Energy Expenditure

Total Energy Expenditure

= Energy Intake whenin energy balance


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How About Genetics? Pima Indians


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

TEE in Pima People Living In Mexico or USA


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Diet Physical Activity and Weight Gain

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


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TS Church, PLoS One.

2011;6(5):e19657.

Why are we gaining weight?

Occupations and Obesity


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Lichtman, NEJM 327:1893; 1992

Are we gaining weight because of low metabolism


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Gross AJCN 79:774 2004

Are we Gaining Weight Because our Diet?


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Gross AJCN 79:774 2004

Are we Gaining Weight Because our Diet?


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InteractionsAmong

Hormonal and

NeuralPathwaysThat Regulate

Food Intake

and Body-FatMass

SOLID LINE = Hormonal

stimulatory effects

DASHED LINE =

Hormonal

inhibitory effects

Batterham RL, et al. Inhibition of food intake in obese subjects by peptide YY 3-36. N Engl J Med 2003;349:941-948.7


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Food intake and Reward

Much has been learned from drug additionresearch about reward and control/inhibition ofaddictive 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 toaddiction and obesity.

Liking versus wanting.


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

Cocaine Distribution FollowingIntravenous Injection


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

Food Stimuli Increase Dopamine in

the Striatum

Remember Marcs fMRI Data?


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Brain areas responsible for decision making and controlForstmann BU PLoS One 3 4 e1899, 2008


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Frontal Regulatory Regions:Impulsivity/Self Control

Activity is reduced in drug addicts.

Activity is increased in drug addicts usingstrategies to resist drug cues.

Activity is increased in reduced obesewomen.

Increased activity seen in indivduals with

anorexia nervosa.Reduced activity correlates with

performance on delayed discounting task.


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Lean vs Obese Performance onDelayed Discounting Task.

Weller RE, Appetite

51(3) 563-569; 2008

The Role of Social Networks in the


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The Role of Social Networks in the

Spread of ObesityChristakis NA, NEJM 2007, 357: 370-9

Densely connected social network of12,067 individuals followed longitudinallyfrom 1971-2003 as part of the

Framingham Heart Study Examined weight change over time in

individuals as a function of the weight of

their social contacts (ego..alter) A persons chance of becoming obese

increased by 57% if they had a friend whobecame obese over a given interval.

Body Weight in a Social


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Christakis NA, NEJM 2007, 357: 370-9

Body Weight in a Social

Network


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Christakis NA, NEJM 2007, 357: 37

Evolution of weighchange in a social

network over time

Regulation of Body Weight


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Regulation of Body Weight

by the Brain

Homeostatic Factors

Leptin

Glucose

NPY

Non HomeostaticFactors

Hedonics

Dopamine

Social/Cognitive

Factors

Social meaning of foodIdeas of Diet

and Health

Unconscious

Self Control

Decision making

Emotions


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Antibiotic Use and WeightNature 2012; 488: 621-626

In agriculture use of antibiotics is found to

increase animal body weight and growth

rate.

The average American child receives 1

course of antibiotics per year.

Blaser group exposed mice to sub-

therapeutic doses of antibiotics andexamined body fat, the gut microbiome

and metabolic genes.


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Antibiotic use and weightNature 2012; 488: 621-626


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Circadian Rhythms and Weight

Epidemiological data shows that shortened

sleep time is associated with obesity

Shortened sleep time is associated with

increased food intake associated with ghrelin Unclear if increasing sleep in those with short

sleep time increases effectiveness of weight loss

treatment.

Recent data suggests peripheral clock genes

are involved as well.

Sleep Duration and Weight Gain:


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Sleep Duration and Weight Gain:The Nurses Health Study

Am J Epidemiol. Nov 15, 2006; 164(10): 947954.

68,000 women followed

for 16 years


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Adipocyte Specific KO of Clock Gene


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Adipocyte Specific KO of Clock Gene

Results in Obesity Paschos GK,Nature Med, 2012

AJ d id t t k bik idi d ti


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AJ decides to take up bike riding and eatinga healthy diet. He cuts out fast food, eats

breakfast, weighs himself, and writes downwhat he eats every day.

He loses 42 lbs and his blood glucose andblood pressure return to normal.

Over the next 5 years his companyrestructures, his job is eliminated, he movesto a new firm and works 60 hours per weekin a high stress position

His weight rises to 307 lbs (BMI= 49kg/m2). A1C=8.5%

Wh i it h d f l


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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.


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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

BodyWe

ight(g)

Treated

Untreated

Weight

Maintenance

Weight

Regain

Weight

loss

Treatment

Phase

Relapse

Phase

Development

Phase

Pre-Obese

Obese

Relapsed-ObeseWeight-Reduced

Never-Obese

Changes in Energy Expenditure Resulting


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Changes in Energy Expenditure ResultingFrom Altered Body Weight

Leibel RL, NEJM 332:621-628, 1995


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Leibel RL, NEJM332:621-628, 1995

Effects of WeightGain or Loss onTEE and RMR


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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.


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Effects of Weight Loss on


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Effects of Weight Loss onAppetite and Hunger Hormones

Sumithran, NEJM 2011; 365:1597-604

If you keep your weight down long enough do


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y p y g g g

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

Weight(g)

Obese

Never-Obese

ARelapsed-Obese

Rats

200

300

400

500

600

700

800

900

0 4 8 12 16 20 24 28 32 36 40Time in Weeks

Weight(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

Weight(g)

Initial gain

0 wks

8 wks

16 wks

Time in

weight

maintenance

B


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Summary

Body weight is regulated by a complex

system with many inter-related parts.

Weight tends to increase as we getolder

The body responds to weight loss with

adaptations that promote weight regain.

Despite this some weight loss and

weight loss maintenance is possible.

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Dr. Daniel H. Bessesen: The Biology of Obesity