OBESITY AND THE REGULATION OF BODY WEIGHT

OBESITY: A Huge Public Health Problem

Definition of obesity: BMI>30

BMI = weight (kg)/ height2 (m)

•30% of the US population are obese•Another 35% are overweight•The incidence of obesity and overweight is increasing•Obesity is becoming more common in children•Obesity is also increasing in other parts of the world

What’s my BMI?

What’s my BMI?

About 30.5 (based on height of 1.87 m and weight of 107 kg)

Obesity Trends* Among U.S. AdultsBRFSS, 1985

(*BMI ≥30, or ~ 30 lbs overweight for 5’ 4” person)

No Data <10% 10%–14%

www.cdc.gov

Obesity Trends* Among U.S. AdultsBRFSS, 1986

(*BMI ≥30, or ~ 30 lbs overweight for 5’ 4” person)

No Data <10% 10%–14%

Obesity Trends* Among U.S. AdultsBRFSS, 1987

(*BMI ≥30, or ~ 30 lbs overweight for 5’ 4” person)

No Data <10% 10%–14%

Obesity Trends* Among U.S. AdultsBRFSS, 1988

(*BMI ≥30, or ~ 30 lbs overweight for 5’ 4” person)

No Data <10% 10%–14%

Obesity Trends* Among U.S. AdultsBRFSS, 1989

(*BMI ≥30, or ~ 30 lbs overweight for 5’ 4” person)

No Data <10% 10%–14%

Obesity Trends* Among U.S. AdultsBRFSS, 1990

(*BMI ≥30, or ~ 30 lbs overweight for 5’ 4” person)

No Data <10% 10%–14%

Obesity Trends* Among U.S. AdultsBRFSS, 1991

(*BMI ≥30, or ~ 30 lbs overweight for 5’ 4” person)

No Data <10% 10%–14% 15%–19%

Obesity Trends* Among U.S. AdultsBRFSS, 1992

(*BMI ≥30, or ~ 30 lbs overweight for 5’ 4” person)

No Data <10% 10%–14% 15%–19%

Obesity Trends* Among U.S. AdultsBRFSS, 1993

(*BMI ≥30, or ~ 30 lbs overweight for 5’ 4” person)

No Data <10% 10%–14% 15%–19%

Obesity Trends* Among U.S. AdultsBRFSS, 1994

(*BMI ≥30, or ~ 30 lbs overweight for 5’ 4” person)

No Data <10% 10%–14% 15%–19%

Obesity Trends* Among U.S. AdultsBRFSS, 1995

(*BMI ≥30, or ~ 30 lbs overweight for 5’ 4” person)

No Data <10% 10%–14% 15%–19%

Obesity Trends* Among U.S. AdultsBRFSS, 1996

(*BMI ≥30, or ~ 30 lbs overweight for 5’ 4” person)

No Data <10% 10%–14% 15%–19%

Obesity Trends* Among U.S. AdultsBRFSS, 1997

(*BMI ≥30, or ~ 30 lbs overweight for 5’ 4” person)

No Data <10% 10%–14% 15%–19% ≥20%

Obesity Trends* Among U.S. AdultsBRFSS, 1998

(*BMI ≥30, or ~ 30 lbs overweight for 5’ 4” person)

No Data <10% 10%–14% 15%–19% ≥20%

Obesity Trends* Among U.S. AdultsBRFSS, 1999

(*BMI ≥30, or ~ 30 lbs overweight for 5’ 4” person)

No Data <10% 10%–14% 15%–19% ≥20%

Obesity Trends* Among U.S. AdultsBRFSS, 2000

(*BMI ≥30, or ~ 30 lbs overweight for 5’ 4” person)

No Data <10% 10%–14% 15%–19% ≥20%

Obesity Trends* Among U.S. AdultsBRFSS, 2001

(*BMI ≥30, or ~ 30 lbs overweight for 5’ 4” person)

No Data <10% 10%–14% 15%–19% 20%–24% ≥25%

(*BMI ≥30, or ~ 30 lbs overweight for 5’ 4” person)

Obesity Trends* Among U.S. AdultsBRFSS, 2002

No Data <10% 10%–14% 15%–19% 20%–24% ≥25%

Obesity Trends* Among U.S. AdultsBRFSS, 2003

(*BMI ≥30, or ~ 30 lbs overweight for 5’ 4” person)

No Data <10% 10%–14% 15%–19% 20%–24% ≥25%

Obesity Trends* Among U.S. AdultsBRFSS, 2004

(*BMI ≥30, or ~ 30 lbs overweight for 5’ 4” person)

No Data <10% 10%–14% 15%–19% 20%–24% ≥25%

Obesity Trends* Among U.S. AdultsBRFSS, 2005

(*BMI ≥30, or ~ 30 lbs overweight for 5’ 4” person)

No Data <10% 10%–14% 15%–19% 20%–24% 25%–29% ≥30%

Obesity Trends* Among U.S. AdultsBRFSS, 2006

(*BMI ≥30, or ~ 30 lbs. overweight for 5’ 4” person)

No Data <10% 10%–14% 15%–19% 20%–24% 25%–29% ≥30%

Obesity Trends* Among U.S. AdultsBRFSS, 2007

(*BMI ≥30, or ~ 30 lbs. overweight for 5’ 4” person)

No Data <10% 10%–14% 15%–19% 20%–24% 25%–29% ≥30%

www.cdc.gov/nccdphp/dnpa/obesity/trend/index.htm

From: Handbook of Obesity: Etiology and Pathophysiology, 2nd edition, G.A. Bray and C. Bouchard, editors, Marcel Dekker, NY,2004

%

Obesity is a risk factor for:

1) Type II diabetes2) Hypertension3) Atheroschlerosis4) Some types of cancer5) Asthma6) Gall bladder problems7) Gastroesophageal reflux8) Sleep apnea9) Fertility problems10) Osteoarthritis

Prevalence of type II diabetes by BMI

From: Handbook of obesity, Marcel Dekker Inc, 2004

Source: Mokdad et al., Diabetes Care 2000;23:1278-83; J Am Med Assoc 2001;286:10.

Diabetes Trends* Among Adults in the U.S.,

(Includes Gestational Diabetes) BRFSS, 1990,1995 and 2001

1990 1995

2001

From: Handbook of Obesity: Etiology and Pathophysiology, 2nd edition, G.A. Bray and C. Bouchard, editors, Marcel Dekker, NY,2004

Ris

k of

pre

mat

ure

deat

h

BMI

20 25 30 3515

From: Ludwig, D.S. New England JournalOf Medicine 357:2325-27, 2007.

Risk factors for the development of obesity

Genetics•twin concordance rates are very high (80%)•obesity is higher in certain ethnic groups (Pacific Islanders, native American’s, African Americans)•animals can be bred for fatness•there are inbred strains of mice and rats that are spontaneously obese• whole genome wide studies have replicated in a large number of studies, an association of a SNP in the FTO gene with obesity

Environment•Animals on a high fat diet gain weight•Human who live in other cultures gain weight when they move to the US or other places with a Western diet•Sleep duration affects BMI

Ob/ObWildtype

(C57BL/6J)

Risk factors for the development of obesity

Genetics•twin concordance rates are very high (80%)•obesity is higher in certain ethnic groups (Pacific Islanders, native American’s, African Americans)•animals can be bred for fatness•there are inbred strains of mice and rats that are spontaneously obese• whole genome wide studies have replicated in a large number of studies, an association of a SNP in the FTO gene with obesity

Environment•Animals on a high fat diet gain weight•Human who live in other cultures gain weight when they move to the US or other places with a Western diet•Sleep duration affects BMI

From: Frayling, TM et al Science 316:889, 2007

Association of a SNP in the FTO gene with obesity

Short sleep duration increases BMI

From: Taheri et al, PLoS Med 3:e62, 2004

-Elevations of BMI are observed in subjects who sleep fewer than6 h per night

-Experimental acute sleep curtailment increases hunger and appetiteespecially for energy rich foods

-Mice in which circadian rhythms are disrupted become obese

-More than 33% of adolescents get less sleep than recommended

Sleep and Obesity

WHY IS OBESITY INCREASING?

1) Genetics? Unlikely. It takes thousands of years to change the gene pool that drastically.

2) Changes in environment?• Diet: more carbohydrates and less fat, also

different types of fat• Exercise: more sedentary lifestyles

3) Gene environment interactions? Susceptibility genesthat are only expressed in conjunction with certain diets

Not all fats are created equal:

•Amount of trans fat in diet is significantly relatedto waist circumference gain

•Total amount of fat in diet is not

Koh-Banerjee et al, Am J Clin Nutr, 2003

•Also called “partially hydrogenated” oil

•Performed to increase shelf life and increase flavor stability

•Present in most processed foods

•Makes fat solid at room temperature

Okie, S. New York to Trans Fats: You're Out! NEJM: 356:2017-2021, 2007

Consumption of trans fats increases the risk of heart disease

Mozaffarian et al NEJM 354:1601-1613, 2007

HOW IS BODY WEIGHT REGULATED?

Body weight represents a balance between calorie inputand calorie expenditure.

Inputs Expenditures

food eaten basal metabolic ratecost of food digestion (liver)exercise

(ex: PYY)

GHRELIN (meal initiation)

•Peptide hormone produced by the stomach•Levels rise just before a meal and fall afterwards•Levels are low in obesity and rise after weight loss•Acts in the hypothalamus to stimulate appetite•Inhibits leptin-induced appetite suppression•Also stimulates glucose production in liver and inhibitsglucose uptake in muscle and fat

Ghrelin isproduced inthe stomach

Normal

GastricResection

PYY (involved in meal termination)

•Peptide hormone produced by the small intestines and colon•Secreted postprandially in proportion to calories ingested•Causes satiety and meal termination

-effects on gut motility-effects on sensory neurons signaling satiety

•Fasting levels are reduced in obesity and levels don’t increaseto the same extent as in lean subjects even after a large meal

Endogenous PYY after a meal in lean and obese subjects

Batterham et al.New Engl.J. Med. 349:941-948, 2003

Batterham et al. N Engl J Med. 2003 349:941-8.

Calorie intake afterPYY infusion

What is actually regulated?

Data suggest that input is matched to expenditures overlong periods of time (weeks to months) but not over shorterperiods (days).

Suggests something that doesn’t change much acutely,for example, body energy stores are what is regulated.

Body fat!

Daily food intake Weekly food intakeDa

ily e

ne

rgy

ex

pen

dit

ure

We

ekly

en

erg

y e

xp

en

dit

ure

What is actually regulated?

Data suggest that input is matched to expenditures overlong periods of time (weeks to months) but not over shorterperiods (days).

Suggests that something that doesn’t change much acutely,for example, body energy stores, is what is regulated.

Body fat!

An extra 10 calories a day results in an approximate 12 poundweight gain over 10 years.

How is body fat regulated?

Leptin:

•Hormone produced in adipocytes in proportion to fat mass

•Acts in hypothalamus to signal satiety (prevent eating)

•Also acts in hypothalamus to increase metabolism

•Acts in muscle to prevent lipid storage and to promoteutilization of fatty acids to produce ATP

Ob/ObWildtype

(C57BL/6J)

•Genetic defects in leptin are not very common in humans

•Genetic variations in the leptin receptor also very uncommon

•Obese humans have increased serum leptin (because theyhave more fat and fat makes leptin)

•How come the leptin doesn’t prevent them from eating?- leptin resistance just like insulin resistance in type IIdiabetes?- leptin doesn’t get across the blood brain barrier

Leptin and human obesity

From: Taheri et al, PLoS Med 3:e62, 2004

Short sleep duration isassociated with increasedgrelin and decreased leptin

lept

ingh

reli

n

ADIPOSE TISSUE

CYTOKINESTNFIL-6IL-1

PBEFTGFIL-10

CHEMOKINESIL-8

EotaxinMCP-1MIP-1

ENERGY REGULATING HORMONES

LeptinAdiponectin

Resistin

ACUTE PHASE REACTANTSSerum amyloid AC-reactive protein

PAI-11-acid glycoprotein

OTHER FACTORSAngiotensinogen

Complement B, C3, DAcylation-stimulating protein

VEGFIL-1RA

Retinol-binding protein-4

Macrophage specific antigen F4/80 in adipose tisse

Lean female

Lean male

Agouti female

DIO male

Ob/ob

Ob/ob male

Weisberg et al, JCI 112:1796-1808,2003

Weisberg et al, JCI 112:1796-1808,2003

Macrophage specific antigen F4/80 in skeletal muscle

Ob/ob

Ob/ob

Lean

Lean

muscle

liver

Wang et al, Am. J. Clin. Nutr. 81:555-63, 2005

Abdominal fat is more important than subcutaneous fat for type 2 diabetes

ADIPONECTIN

•Produced by adipocytes•Most abundant gene product in adipocytes•Decreases in obesity and increases during weight loss•No effect on body weight•Effects on are energy metabolism

- causes glucose uptake- promotes fatty acid oxidation- inhibits gluconeogenesis

•Improves glucose tolerance and increases insulin sensitivity•Reduces hyperglycemia in animal models of type II diabetes•Animals with no adiponectin are susceptible to atherosclerosis

Bobbert et al, Diabetes 54:7212-9, 2005

HMW Adiponectin

Mice overexpressingAdiponectin using a Liver specific promoter

Yamauchi et al, J. Biol. Chem.278:2461, 2003

Yamauchi et al, J. Biol. Chem.278:2461, 2003

From: Kubota et al, J. Biol. Chem. 277:25863, 2002.

Adiponectin knockout mice are susceptible to atheroschlerosis

Pajvani et al, J Biol Chem 279:12152-62, 2004

Rosiglitazone induced changes in insulin sensitivitycorrelate with changes in adiponectin

TREATMENT OF OBESITY

1) Liposuction2) Gastric reduction surgery (side effects)3) Wiring of the jaw4) Drugs (side effects)5) Diet and exercise 6) Behavior modification