# The Biology of Obesity

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
5’6” 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
5’6” and weighed
145 lb
• At age 60 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 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
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.
How did this happen?
• EI age 20=2,586
kcal/d
• EI age 60=2,430
kcal/d
• EI age 60 =2,104
kcal/d
Energy In
Energy Out
Stored Fuel
Brain
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
Body Weight is Regulated
Obesity
Prone
Obesity
Resistant
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
Body Weight is Regulated
Time
W
e
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g
h
t

College
Marriage
Pregnancy
Wt Watchers
Stressful
Job
Alli
Humans
Rats
The development of weight
related illnesses
Diabetes
Coronary Artery
Disease
Hypertension
Diet/Physical
Activity
Overweight Lean
Time
Obese
Arthritis
Cancer
Genes
Environment
Db Mouse
Ob Mouse
Parabiosis Experiments of Douglas Coleman
Boy with Leptin Deficiency
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?
Rare, but Profound
Monogenic Forms
Of Human Obesity
-Leptin Receptor Deficient
-Leptin Deficient
-MC4 receptor deficient
Farooqi, IS, NEJM 2007; 356:237-47
Example of a Genome
Wide Association Study
(GWAS)
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

Energy In
Energy Out
Stored Fuel
Brain
Fat
Glucose
Protein
Fat
Glucose
Protein
Fat
Glucose
Protein
Maintaining Energy “Homoestasis”
Positive energy state:
Assimilate exogenous
nutrients

Negative energy state:
Mobilizing/utilizing
stored nutrients
Time
Regulated Parameter
Breakfast
Lunch
Dinner
Night
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 when
in energy balance
Relationship Between Weight
and Energy Expenditure
Weyer C, IJO 23:715-722
Obesity is associated with increased food intake
Esparza, Int J Obes Relat Metab Disord 24:55; 2000
TEE in Pima People Living In Mexico or USA
Diet Physical Activity and Weight Gain
NEJM, 2011 Jun 23;364(25):2392-404
TS Church, PLoS One.
2011;6(5):e19657.
Why are we gaining weight?
Occupations and Obesity
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?
Gross AJCN 79:774 2004
Are we Gaining Weight Because our Diet?
Interactions
Among
Hormonal and
Neural
Pathways
That Regulate
Food Intake
and Body-Fat
Mass
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
Food intake and Reward
►Much has been learned from drug addition
research about reward and control/inhibition of
►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
►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 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
Lean vs Obese Performance on
Weller RE, Appetite
51(3) 563-569; 2008
The Role of Social Networks in the
Christakis NA, NEJM 2007, 357: 370-9
• Densely connected social network of
12,067 individuals followed longitudinally
from 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 person’s chance of becoming obese
increased by 57% if they had a friend who
became obese over a given interval.
Christakis NA, NEJM 2007, 357: 370-9
Body Weight in a Social
Network
Christakis NA, NEJM 2007, 357: 370-9
Evolution of weight
change in a social
network over time
Regulation of Body Weight
by the Brain
Homeostatic Factors
Leptin
Glucose
NPY
Non Homeostatic
Factors
Hedonics
Dopamine
Social/Cognitive
Factors
Social meaning of food
Ideas of Diet
and Health

Unconscious
Self Control
Decision making
Emotions
Gut Microbiome and Weight
►Studies in germ free mice demonstrated
that gut microbiome has effects on weight.
►Work has focused on characterizing the
differences in the microbiome between lean,
obese and reduced obese.
►More recently work has focused on the
acquisition of the gut microbiome and
potential therapeutic effects.
Antibiotic Use and Weight
Nature 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 and
examined body fat, the gut microbiome
and metabolic genes.
Antibiotic use and weight
Nature 2012; 488: 621-626
• 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:
The Nurses Health Study
Am J Epidemiol. Nov 15, 2006; 164(10): 947–954.
68,000 women followed
for 16 years
Sleep Duration and Weight Gain:
Adipocyte Specific KO of Clock Gene
Results in Obesity Paschos GK,Nature Med, 2012
►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
►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/m
2
). 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.
Paradigm of Obesity Development, Treatment, and Relapse
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Weeks of Study
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(
g
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Treated
Untreated
Weight
Maintenance
Weight
Regain
Weight
loss
Treatment
Phase
g
Relapse
Phase
Development
Phase
Pre-Obese
Obese
Relapsed-Obese
Weight-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 Weight
Gain 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 Loss
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500
1000
1500
2000
2500
3000
Before Weight
Loss
After Weight
Loss
k
c
a
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s
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d
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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.
Effects of Weight Loss on
Appetite and Hunger Hormones
Sumithran, NEJM 2011; 365:1597-604
If you keep your weight down long enough do

Control
Rats
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16 wks
Time in
weight
maintenance
Period of Relapse
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a
a a
b
c
d
a,b
b,c
c
a,b
b
D
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.

Control
Rats
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Time in Weeks
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Obese
Never-Obese
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Weight-Reduced
Rats
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Time in Weeks
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(
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Initial gain
0 wks
8 wks
16 wks
Time in
weight
maintenance
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Relapsed-Obese
Rats
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900
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Time in Weeks
W
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(
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Initial gain
0 wks
8 wks
16 wks
Time in
weight
maintenance
C
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20
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week 1 week 2 Final 4 weeks
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Control
0 wks
8 wks
16 wks
Time in
weight
maintenance
Period of Relapse
a
a
a a
b
c
d
a,b
b,c
c
a,b
b
D
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.

Control
Rats
200
300
400
500
600
700
800
900
0 4 8 12 16 20 24 28 32 36 40
Time in Weeks
W
e
i
g
h
t

(
g
)
Obese
Never-Obese
A
Weight-Reduced
Rats
200
300
400
500
600
700
800
900
0 4 8 12 16 20 24 28 32 36 40
Time in Weeks
W
e
i
g
h
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(
g
)
Initial gain
0 wks
8 wks
16 wks
Time in
weight
maintenance
B
Relapsed-Obese
Rats
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300
400
500
600
700
800
900
0 4 8 12 16 20 24 28 32 36 40
Time in Weeks
W
e
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(
g
)
Initial gain
0 wks
8 wks
16 wks
Time in
weight
maintenance
C
0
10
20
30
40
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60
70
80
90
week 1 week 2 Final 4 weeks
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(
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Control
0 wks
8 wks
16 wks
Time in
weight
maintenance
Period of Relapse
a
a
a a
b
c
d
a,b
b,c
c
a,b
b
D
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.
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