1

Obesity:Causes and

ConsequencesJack A. Yanovski, M.D.. Ph.D.

Chief, Section on Growth and Obesity

Program in Developmental Endocrinology and Genetics

National Institute of Child Health and Human Development

Objectives

• WHAT is obesity?

• WHAT are the medical consequences of obesity?

• WHY do some people become obese?

What is Obesity?

Obesity is an excess of body fat

from L. obesitas "fatness, corpulence"

Body Mass Index (BMI)

• BMI = weight (kg)/height (m)2

• Measure of weight adjusted for height

• Highly correlated with body fat– Relationship varies with age, gender, ethnicity, and

body build

• Easy to obtain

• Does not distinguish between body fat and muscle

OVERFAT: 220 LBS

One can be overweight but not overfat

OVERWEIGHT: 220 LBS

0

10

20

30

40

50

60

70

Relationship Between BMI and Percent Body Fat in Men and Women

Adapted from: Gallagher et al. Am J Clin Nutr 2000;72:694.

Bo

dy

Fa

t (%

)

Body Mass Index (kg/m2)

0 10 30 40 6020 50

Women

Men

2

By BMI, >65% of US Adults Are Overweight, >30% are Obese

Prevalence of obesity (BMI ≥ 95th percentile) in children has

tripled, but stable in girls over past 10 years

0

5

10

15

20

25

Boys Girls Boys Girls

1971-74 1976-80 1988-94 1999-2002

2003-2006 2006-2008 2009-2010

6-11 years 12-19 years

Ogden et al JAMA 307:483-490, 2012

BM

I ≥

95th

Per

cent

ile

BMI-Associated Disease Risk

Clinical Guidelines on the Identification, Evaluation, and Treatment of Overweight and Obesity in Adults—The Evidence Report. Obes Res 1998;6(suppl 2).

Additional risks: Poor aerobic fitnessLarge waist circumference (men > 40 in; women > 35 in)

Classification BMI (kg/m2) Risk

Underweight < 18.5 Increased

Normal 18.5 – 24.9 Normal

Overweight 25.0 – 29.9 Increased

Obese I 30.0 – 34.9 High

II 35.0 – 39.9 Very high

III ≥ 40 Extremely high

Rel

ativ

e R

isk

of C

VD

Mor

talit

y

1

2

3

4

5

6

7

8

Lean Normal Obese

Body Fat Category (% Weight as Fat)

< 16.7% 16.7% – 24.9% 25%

Fatness, Fitness, and Cardiovascular Disease Mortality

Lee et al. Am J Clin Nutr 1999;69:373.

Aerobically fit

Unfit

Subcutaneous Fat

Abdominal Muscle Layer

Intra-abdominal Fat

Visceral Adiposity:

Amount of intra-abdominal (visceral) fat is well correlated to the complications of obesity

Medical Complications of Obesity

Phlebitisvenous stasis

Coronary heart disease

Pulmonary diseaseabnormal functionobstructive sleep apneahypoventilation syndrome

Gall bladder disease

Gout

Diabetes

Osteoarthritis

Nonalcoholic fatty liver diseasesteatosissteatohepatitiscirrhosis

HypertensionDyslipidemia

Cataracts

Skin

Pancreatitis

Idiopathic intracranial hypertension

Cancerbreast, uterus, cervix, prostate,kidney, colon, esophagus, pancreas, liver

Gynecologic abnormalitiesabnormal mensesinfertilitypolycystic ovarian syndrome

Stroke

3

Why do people become obese?

Obesity Is Caused by Long-Term Positive Energy Balance

FatStores

America’s Weapons of Mass Destruction

• 50 - 80% of the variance in human body weight is accounted for by genetic variation

• The remainder is explained by common environmental factors

Genetic Epidemiology of Human Obesity: Twin studies

Indianfamily from

Mexico

Pima Indianfamily in the

US

Portion size and pediatric obesity

0

10

20

30

40

50

60

70

Nu

mb

er o

f L

arge

-Siz

e P

orti

ons

Intr

odu

ced

1970 - 74 1975 - 79 1980 - 84 1985 - 89 1990 - 94 1995 - 99

0

3

6

9

12

15

Per

cen

t O

verw

eigh

t (>

95t

h c

enti

le)

1970 - 74 1975 - 79 1980 - 84 1985 - 89 1990 - 94 1995 - 99

12-19 year olds

6-11 year olds

4

Portion sizes have increased over the years

100

200

300

400

500

600

700 19552001

Ca

lori

es

McDonald’sFries

Coca-Cola Snickers

2.3 oz 6.9 oz 6.5 oz 20 oz 1.1 oz 3.7 oz

Nutrition Action, 2001.

Environmental Changes in Physical Activity

• Decreased physical activity in schools/workplace/communities– Few schools offer daily P.E.– Fewer jobs require manual labor– Lack of sidewalks

• Increased sedentary behavior– Office and home– Computer, video games, television

Relative Risk of Developing Obesity and TV Viewing in Adults

Nurses Health Study (1992-1998)

0

0.5

1

1.5

2

2.5

0 to 1 2 to 5 6 to 20 21 to 40 >40

Hu et al., JAMA; 2003:1785

P<0.001

Hours per Week

Season Matters: Weight change is

greatest during thewinter holiday season

Yanovski et al

NEJM 342

861-72000

Sept - Nov Holiday Jan - March March - Nov

0.00

0.25

0.50

0.75

p < .001

Wei

gh

t C

han

ge

(kg

)

5

Why Do People Become Obese?

• Changes in our environment explain why obesity has become more common over the last 40 years

• Our genes make us respond to our current environment by becoming obese

Identical Twins Fraternal Twins

Effects of Parental Obesity on Child Body Adiposity

0

5

10

15

20

25

Per

cen

t of

Cas

es

-3 -2 -1 0 1 2 3

Triceps fatfold SDS

two lean parents

0

5

10

15

20

25

Per

cen

t of

Cas

es

-3 -2 -1 0 1 2 3

2 obese parents

Garn and Clark, Pediatr. 57: 443, 1976

<15% >75%

Age 14y Height 172 cm, weight 166 kg, BMI 56.3 kg/m2

• Endocrinologic abnormalities• Medication-related• Hypothalamic damage related• Genetic

– Established syndromes– Leptin signaling pathway defects

Differential Diagnosis of Obesity Classical Endocrinologic causes of obesity

• Hypothyroidism– weight gain

– fatigue

• Hypercortisolism– 1 in 1,000,000 prevalence

– weight gain, striae, depression…

• Hyperinsulinemia (insulinoma)– Hypoglycemic episodes with

weight gain

Before After

6

Medications associatedwith pediatric obesity

• Glucocorticoids

• Psychotropic Agents– Antipsychotics: phenothiazines, clozapine,

resperidone

– Mood stabilizers: lithium, gabapentin

– Antidepressants: amitryptiline, mirtazapine

• Anticonvulsants: valproate, carbamazepine

• Serotonin Receptor Antagonist: cyproheptadine

• Antihypertensives: propranolol, nifedipine, clonidine

Genetic Syndromes Associated with Obesity

– Down Syndrome (trisomy 21)

– Prader Willi - (15 q 11.2-12)

– Bardet Biedl Syndromes

– Pseudohypoparathyroidism - inactivation of the stimulatory G protein subunit (20-q13.3)

– Achondroplasia - FGF-R3 (4p16.3)

– Turner Syndrome (45 XO)

Brushfield spot

Epicanthal fold

Palmar Crease

Cupped pinnae

Down Syndrome

Prader Willi Syndrome• Hypotonia, poor feeding neonatal period,

• After age 2y, obesity, “insatiable appetite, small hands/feet, hypogonadism,

• Abnormalities of 15q11-q12– Paternal deletions

– Uniparental (maternal)disomy

– Abnormal methylation

Bardet Biedel Syndromes

• Obesity

• Retinal degeneration

• Extra digits hands/toes

• Genital hypoplasia or hypogonadism (most males, 50% females)

• Mental retardation 75%

New Genetic Syndromes Associated with Obesity

• Leptin deficiency

• Leptin Receptor Deficiency

• Prohormone Convertase 1 deficiency

• POMC processing mutation

• Melanocortin 4 Receptor mutation

• Melanocortin 3 Receptor mutation

7

Wild-Type Mice ob/ob (leptin deficient)

Discovery of Leptin, Dec. 1994Transforming Event in Obesity Research

Zhang et al, Nature 372:425 (1994)

Leptin

Hypothalamic Leptin

receptors

PC-1POMC

Neuropeptide Y

α - MSH

Melanocortin Receptors

NPY Receptors

Autonomic Nervous System

Beta-3 Adrenergic receptors

Appetite

CRH,GnRH,TRH

Leptin Signaling and Obesity

Leptin Gene Deletion

Montague et al, Nature 387:903-908, 1997

• 2 cousins from a highly consanguineous Pakistani family

• Normal at birth, rapid weight gain

• Very low leptin despite high % fat

• Single base deletion introducing a premature stop codon

Plasma Leptin

0

15

30

45

60P

lasm

a L

epti

n (n

g/m

L)

10 20 30 40 50 60

DXA Percent Fat

Leptin Mutation

Healthy Children

Leptin-Deficiency

Farooqi et al, NEJM 341:879-884, 1999

0

10

20

30

40

50

60

70

80

90

100

Wei

ght

(kg)

0 1 2 3 4 5 6 7 8 9 10

Age (years)

98thPercentile

50thPercentile

2ndPercentile

Leptin treatment

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Leptin treatment

Farooqi et al J Clin Invest; 106: 1093-1103, 2002

Effects of leptin

injections in a child

with leptin

deficiency

Little efficacy of leptin in obese humans who are not leptin deficient

Hypothalamic Leptin

receptors

PC-1

Leptin

POMC

Neuropeptide Y

α - MSH

Melanocortin Receptors

NPY Receptors

Autonomic Nervous System

Beta-3 Adrenergic receptors

Appetite

CRH,GnRH,TRH

Leptin Signaling and Obesity

Human Leptin Receptor Mutations

• Early-onset obesity

• High leptin

• Failure to enter puberty normally

Clement et al. Nature 392, 398–401, 1998

z

500 kcal/d diet

Patients with leptin receptor deficiency (LEPR-/-) have significant hyperleptinemia

LEPR-/- Controls0

25

50

75

100

125 p=0.003

Ser

um

Lep

tin

(n

g/m

L)

Adapted from Farooqi et al. N Engl J Med 2007Adjusted for fat mass

9

Leptin Receptor Deficiency –NIH Family

• Two siblings with early-onset obesity

• High leptin, even forobese children

Gil et al, Obesity, In Press, 2014

Leptin Receptor Deficiency –NIH Family

• Two siblings with early-onset obesity

• High leptin, even forobese children

• Consanguinity

Gil et al, Obesity, In Press, 2014

Whole Exome Sequencing of affected siblings

• 36,100 shared single nucleotide variants– 1537 rare and non-synonymous

• 4,702 shared recessive indels– 1,213 both rare and functional (frameshift, amino acid

insertion or deletion, or splice site)

• Filtering by pathogenicity and conservation: – Homozygous for 15 potentially damaging variants (10

SNVs and 5 indels)

• 1 Homozygous leptin receptor change

Mutation in Leptin Receptor

Premature stop codon after insertion of 9 novel amino acids

Gil et al, Obesity, In Press, 2014

Some obese humans with normal leptin receptor sequence are as obese and hyperleptinemic as those with leptin receptor deficiency

Farooqi et al, NEJM 356: 237-247, 2007

10

100

1000

Normal leptinreceptor sequence

Leptin receptordeficiency

Se

rum

Le

pti

n (

ng

/mL

)

Bardet-Biedl syndrome (BBS):Obesity, leptin resistance & hyperleptinemia

• BBS: a pleiotropic, polygenic obesity syndrome

10

Bardet-Biedl syndrome (BBS):Obesity, leptin resistance & hyperleptinemia

• BBS: a pleiotropic, polygenic obesity syndrome

• BBS proteins essential for normal function of primary cilium

• Inactivation of BBS proteins in miceleads to aberrant leptin receptor trafficking in hypothal impaired

Bardet-Biedl syndrome (BBS):Obesity, leptin resistance & hyperleptinemia

• BBS: a pleiotropic, polygenic obesity syndrome

• BBS proteins essential for normal function of primary cilium

• Inactivation of BBS proteins in miceleads to aberrant leptin receptor trafficking in hypothalamic neurons, impaired leptin signaling, and hyperleptinemia

Hyperleptinemia consistent with leptin resistance in patients with

Bardet-Biedl syndrome

Obese Controls BBS0

10

20

30

40

50 p<0.001

(n=63) (n=37)

Lep

tin

(n

g/m

L)

J Clin Endocrinol Metab; 96:E528-35, 2011

Adjusted for age, sex, race, & body fat %

Leptin

Hypothalamic Leptin

receptors

PC-1POMC

Neuropeptie Y

α - MSH

Melanocortin Receptors

NPY Receptors

Autonomic Nervous System

Beta-3 Adrenergic receptors

Appetite

CRH,GnRH,TRH

Leptin Signaling and Obesity

NH3 COOH

ß-lipotropin

BetaMSH

BetaEndorphin

GammaMSH

ACTH

Alpha MSH

16 K Fragment

Mutations disrupting ACTH / alpha MSH synthesis

= normal processing cleavage sites

Krude et al, Nature Genetics 19: 155-157, 1998

Pro-opio-melanocortin (POMC)

POMC Processing Human POMC Mutations

Krude et al, Nature Genetics 19: 155-157, 1998

• Can interfere with Processing of POMC into ACTH, alpha MSH, and beta-endorphin

• Red Hair (MC-1R)

• Congenitaladrenal hypoplasia(MC-2R)

• Obesity(MC-4R)

11

Leptin

Hypothalamic Leptin

receptors

PC-1POMC α - MSH

Melanocortin Receptors

NPY Receptors

Autonomic Nervous System

Beta-3 Adrenergic receptors

Appetite

CRH,GnRH,TRH

Leptin Signaling and Obesity

Neuropeptide Y

NH3 COOH

ß-lipotropinACTH

Alpha MSH

GammaMSH

BetaMSH

BetaEndorphin

16 K Fragment

Mutations disrupting prohormone convertase 1

= normal processing cleavage sites

Krude et al, Nature Genetics 19: 155-157, 1998

Pro-opio-melanocortin (POMC)

POMC Processing

x x x x

Human Prohormone Convertase 1 Mutations

Jackson et al. Nature Med 16, 303-306, 1997

• Early-onset Obesity

• Abnormal post-translational hormone processing:– Hypogonadotropic hypogonadism

– Low cortisol

– Low insulin

– High pro-insulin

– High POMC

Leptin

Hypothalamic Leptin

receptors

PPAR--2 receptors

PC-1POMC α - MSH

Melanocortin Receptors

NPY Receptors

Autonomic Nervous System

Beta-3 Adrenergic receptors

Appetite

CRH,GnRH,TRH

Leptin Signaling and Obesity

Neuropeptide Y

MC4R -/-

Wild Type

Photograph courtesy of Daniel Marks, M.D., Ph.D.

Melanocortin 4 Receptor Knock-Out

Mouse

9y old with homozygous MC4-R mutation and 16y old normal brother

Farooqi et al NEJM 348:1085-1095,2003

12

Melanocortin 4 receptor heterozygous inactivating

mutations are common• 1.4% of 140 obese adults Gu et al Diabetes 48:635-9, 1999

• 0.7% of 306 children with BMI 34 ± 7 kg/m2

Hinney et al, J Clin Endocrinol Metab 84:1483-6;1999

• 4.0% of 209 French adults with BMI > 40 kg/m2

Vaisse et al, J Clin Invest 106:253-62, 2000

• 3.3% of 243 UK adults with history of onset of obesity before age 10y Farooqi et al, J Clin Invest 106:271-9, 2000

2.4% of severely obese may have heterozygous mutations of MC4 receptor

Melanocortin 3 ReceptorMC3R Knock-out

mice:• Increased fat mass• Reduced lean mass• Higher feeding

efficiency

– Chen AS, et al. Nature Genetics, 2000; 26:97-102

BMI-SD and DXA Fat Mass by Genotype of Function-Altering

MC3R Polymorphisms in African American and Caucasian Children

BMI-SD Score

African American Caucasian0

2

4

6

8Wt/WtWt/PP/P

BM

I-S

D S

core

DXA Fat Mass

African American Caucasian0

10

20

30

40

50

60Wt/WtWt/PP/P

DX

A f

at m

ass

(kg

)

P = 0.024 P = 0.041

P = 0.017P = 0.021

Double Mutant hMC3R knockin mice are more adipose than Wild Type hMC3R knockin mice

MC3RhWT/hWTMC3RhDM/hDM MC3RhWT/hWTMC3RhDM/hDM

…Back to our patient

Plasma Leptin

OurPatient

0

15

30

45

60

Pla

sma

Lep

tin

(ng/

mL

)

10 20 30 40 50 60

DXA Percent Fat

Leptin Mutation

Healthy Children

13

Our Patient

• He has a function-altering variant of the melanocortin 3 receptor, (Thr6Lys+Val81Ile)

• He has hyperinsulinemia and hypercholesterolemia

How should he be treated?

AAP Recommended Weight Goals for Overweight Children and

Adolescents

Weight Maintenance

BMI95th Percentile

Mild complication=hypertension, dyslipidemia, increased liver enzymes, and insulin resistance

Barlow and Dietz. Pediatrics 1998;102:e29.

Age 2–7 y: Weight Maintenance

Age >7 y: Weight Loss

Mild Complication

Yes

Mild Complication

No

BMI85th–94th Percentile

Mild Complication

No

Mild Complication

Yes

Age 2–7 y: Weight Maintenance

Age >7 y: Weight Loss

Weight Loss

Our Patient

• Enrolled in a 6 month randomized placebo-controlled trial of orlistat

• Lost 7 kg over first 3 months

• Lost 2 kg over months 3-6

• Regained all of his lost weight over the next 24 months