OBESITY AND THE REGULATION OF BODY WEIGHT
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Transcript of OBESITY AND THE REGULATION OF BODY WEIGHT
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OBESITY AND THE REGULATION OF BODY WEIGHT
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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
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What’s my BMI?
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What’s my BMI?
About 30.5 (based on height of 1.87 m and weight of 107 kg)
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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
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Obesity Trends* Among U.S. AdultsBRFSS, 1986
(*BMI ≥30, or ~ 30 lbs overweight for 5’ 4” person)
No Data <10% 10%–14%
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Obesity Trends* Among U.S. AdultsBRFSS, 1987
(*BMI ≥30, or ~ 30 lbs overweight for 5’ 4” person)
No Data <10% 10%–14%
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Obesity Trends* Among U.S. AdultsBRFSS, 1988
(*BMI ≥30, or ~ 30 lbs overweight for 5’ 4” person)
No Data <10% 10%–14%
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Obesity Trends* Among U.S. AdultsBRFSS, 1989
(*BMI ≥30, or ~ 30 lbs overweight for 5’ 4” person)
No Data <10% 10%–14%
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Obesity Trends* Among U.S. AdultsBRFSS, 1990
(*BMI ≥30, or ~ 30 lbs overweight for 5’ 4” person)
No Data <10% 10%–14%
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Obesity Trends* Among U.S. AdultsBRFSS, 1991
(*BMI ≥30, or ~ 30 lbs overweight for 5’ 4” person)
No Data <10% 10%–14% 15%–19%
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Obesity Trends* Among U.S. AdultsBRFSS, 1992
(*BMI ≥30, or ~ 30 lbs overweight for 5’ 4” person)
No Data <10% 10%–14% 15%–19%
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Obesity Trends* Among U.S. AdultsBRFSS, 1993
(*BMI ≥30, or ~ 30 lbs overweight for 5’ 4” person)
No Data <10% 10%–14% 15%–19%
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Obesity Trends* Among U.S. AdultsBRFSS, 1994
(*BMI ≥30, or ~ 30 lbs overweight for 5’ 4” person)
No Data <10% 10%–14% 15%–19%
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Obesity Trends* Among U.S. AdultsBRFSS, 1995
(*BMI ≥30, or ~ 30 lbs overweight for 5’ 4” person)
No Data <10% 10%–14% 15%–19%
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Obesity Trends* Among U.S. AdultsBRFSS, 1996
(*BMI ≥30, or ~ 30 lbs overweight for 5’ 4” person)
No Data <10% 10%–14% 15%–19%
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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%
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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%
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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%
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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%
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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%
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(*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%
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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%
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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%
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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%
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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%
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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%
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www.cdc.gov/nccdphp/dnpa/obesity/trend/index.htm
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From: Handbook of Obesity: Etiology and Pathophysiology, 2nd edition, G.A. Bray and C. Bouchard, editors, Marcel Dekker, NY,2004
%
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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
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Prevalence of type II diabetes by BMI
From: Handbook of obesity, Marcel Dekker Inc, 2004
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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
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From: Handbook of Obesity: Etiology and Pathophysiology, 2nd edition, G.A. Bray and C. Bouchard, editors, Marcel Dekker, NY,2004
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Ris
k of
pre
mat
ure
deat
h
BMI
20 25 30 3515
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From: Ludwig, D.S. New England JournalOf Medicine 357:2325-27, 2007.
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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
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Ob/ObWildtype
(C57BL/6J)
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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
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From: Frayling, TM et al Science 316:889, 2007
Association of a SNP in the FTO gene with obesity
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Short sleep duration increases BMI
From: Taheri et al, PLoS Med 3:e62, 2004
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-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
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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
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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
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•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
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Okie, S. New York to Trans Fats: You're Out! NEJM: 356:2017-2021, 2007
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Consumption of trans fats increases the risk of heart disease
Mozaffarian et al NEJM 354:1601-1613, 2007
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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
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(ex: PYY)
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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
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Ghrelin isproduced inthe stomach
Normal
GastricResection
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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
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Endogenous PYY after a meal in lean and obese subjects
Batterham et al.New Engl.J. Med. 349:941-948, 2003
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Batterham et al. N Engl J Med. 2003 349:941-8.
Calorie intake afterPYY infusion
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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!
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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!
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An extra 10 calories a day results in an approximate 12 poundweight gain over 10 years.
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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
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Ob/ObWildtype
(C57BL/6J)
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•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
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From: Taheri et al, PLoS Med 3:e62, 2004
Short sleep duration isassociated with increasedgrelin and decreased leptin
lept
ingh
reli
n
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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
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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
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Weisberg et al, JCI 112:1796-1808,2003
Macrophage specific antigen F4/80 in skeletal muscle
Ob/ob
Ob/ob
Lean
Lean
muscle
liver
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Wang et al, Am. J. Clin. Nutr. 81:555-63, 2005
Abdominal fat is more important than subcutaneous fat for type 2 diabetes
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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
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Bobbert et al, Diabetes 54:7212-9, 2005
HMW Adiponectin
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Mice overexpressingAdiponectin using a Liver specific promoter
Yamauchi et al, J. Biol. Chem.278:2461, 2003
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Yamauchi et al, J. Biol. Chem.278:2461, 2003
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From: Kubota et al, J. Biol. Chem. 277:25863, 2002.
Adiponectin knockout mice are susceptible to atheroschlerosis
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Pajvani et al, J Biol Chem 279:12152-62, 2004
Rosiglitazone induced changes in insulin sensitivitycorrelate with changes in adiponectin
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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