obesity and the regulation of body weight

OBESITY AND THE REGULATION OF BODY WEIGHT

OBESITY: A Huge Public Health Problem

Definition of obesity: BMI>30

Definition of overweight: BMI >25

BMI = weight (kg)/ height2 (m)

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%

Obesity Trends* Among U.S. AdultsBRFSS, 2008

(*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 2 diabetes2) Hypertension3) Atherosclerosis4) Some types of cancer5) Asthma6) Gall bladder problems7) Fertility problems8) Osteoarthritis9) Sleep disordered breathing10) Gastroesophageal reflux

Prevalence of type 2 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

What’s my BMI?

What’s my BMI?

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

Normal BMI doesn’t necessarily mean normal body fat

A. Romero-Corral et al, Eur. Heart J. 31:737-746, 2010

A. Romero-Corral et al, Eur. Heart J. 31:737-746, 2010

Body fat increases disease risk in normal weight subjects

A. Romero-Corral et al, Eur. Heart J. 31:737-746, 2010

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BMI

20 25 30 3515

Risk factors for the development of obesity

Genetics• animals can be bred for fatness• there are inbred strains of mice and rats that are spontaneously obese• whole genome wide genetic studies have identified several genes

associated 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• Animals born to obese mothers tend to also become obese• Amount of sleep affects weight gain

Ob/ObWildtype

(C57BL/6J)

Risk factors for the development of obesity

Genetics• animals can be bred for fatness• there are inbred strains of mice and rats that are spontaneously obese• whole genome wide genetic studies have identified several genes

associated 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• Animals born to obese mothers tend to also become obese• Amount of sleep affects weight gain

Risk factors for the development of obesity

Genetics• animals can be bred for fatness• there are inbred strains of mice and rats that are spontaneously obese• whole genome wide genetic studies have identified several genes

associated 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• Animals born to obese mothers tend to also become obese• Amount of sleep affects weight gain

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

- Childhood sleeping problems predict adult BMI

- 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 (but could beepigenetic effects).

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

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 rate- cost 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

• Acts in the hypothalamus to stimulate appetite

Ghrelin isproduced inthe stomach

Normal

GastricResection

PYY (involved in meal termination)

• Peptide hormone produced by the small intestines and colon

• Secreted after a meal in proportion to calories ingested

• Causes satiety and meal termination • 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

Daily food intake Weekly food intakeDa

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Longterm energy regulation

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!

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

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

Ob/ObWildtype

(C57BL/6J)

Day

Administering leptin to leptin deficient (ob/ob)mice reduces food intakeand decreases body weight

Farooqi et al, New Engl. J. Med 341:879-884, 1999

• 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

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ADIPOSE TISSUE

CYTOKINESTNFaIL-6IL-1

PBEFTGFbIL-10

CHEMOKINESIL-8

EotaxinMCP-1MIP-1a

ENERGY REGULATING HORMONES

LeptinAdiponectin

Resistin

ACUTE PHASE REACTANTSSerum amyloid AC-reactive protein

PAI-1a1-acid glycoprotein

OTHER FACTORSAngiotensinogen

Complement B, C3, DAcylation-stimulating protein

VEGFIL-1RA

Retinol-binding protein-4

Macrophage specific antigen F4/80 in adipose tissue

Lean female

Lean male

Agouti female

DIO male

Ob/ob

Ob/ob male

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

Obese adipose tissue is laden with inflammatory cells

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

Macrophage specific antigen F4/80 in skeletal muscle

Ob/ob

Ob/ob

Lean

Lean

muscle

liver

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

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

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

Spread of obesity in social networks

Gut microbiome from obese mice has increased capacity for energy harvest