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 BMIgt30
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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Whats my BMI?
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Whats 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 lt10 1014
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 lt10 1014
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Obesity Trends Among U.S. AdultsBRFSS, 1987
(BMI 30, or 30 lbs overweight for 5 4
person)
No Data lt10 1014
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Obesity Trends Among U.S. AdultsBRFSS, 1988
(BMI 30, or 30 lbs overweight for 5 4
person)
No Data lt10 1014
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Obesity Trends Among U.S. AdultsBRFSS, 1989
(BMI 30, or 30 lbs overweight for 5 4
person)
No Data lt10 1014
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Obesity Trends Among U.S. AdultsBRFSS, 1990
(BMI 30, or 30 lbs overweight for 5 4
person)
No Data lt10 1014
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Obesity Trends Among U.S. AdultsBRFSS, 1991
(BMI 30, or 30 lbs overweight for 5 4
person)
No Data lt10 1014
1519
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Obesity Trends Among U.S. AdultsBRFSS, 1992
(BMI 30, or 30 lbs overweight for 5 4
person)
No Data lt10 1014
1519
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Obesity Trends Among U.S. AdultsBRFSS, 1993
(BMI 30, or 30 lbs overweight for 5 4
person)
No Data lt10 1014
1519
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Obesity Trends Among U.S. AdultsBRFSS, 1994
(BMI 30, or 30 lbs overweight for 5 4
person)
No Data lt10 1014
1519
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Obesity Trends Among U.S. AdultsBRFSS, 1995
(BMI 30, or 30 lbs overweight for 5 4
person)
No Data lt10 1014
1519
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Obesity Trends Among U.S. AdultsBRFSS, 1996
(BMI 30, or 30 lbs overweight for 5 4
person)
No Data lt10 1014
1519
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Obesity Trends Among U.S. AdultsBRFSS, 1997
(BMI 30, or 30 lbs overweight for 5 4
person)
No Data lt10 1014
1519 20
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Obesity Trends Among U.S. AdultsBRFSS, 1998
(BMI 30, or 30 lbs overweight for 5 4
person)
No Data lt10 1014
1519 20
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Obesity Trends Among U.S. AdultsBRFSS, 1999
(BMI 30, or 30 lbs overweight for 5 4
person)
No Data lt10 1014
1519 20
20
Obesity Trends Among U.S. AdultsBRFSS, 2000
(BMI 30, or 30 lbs overweight for 5 4
person)
No Data lt10 1014
1519 20
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Obesity Trends Among U.S. AdultsBRFSS, 2001
(BMI 30, or 30 lbs overweight for 5 4
person)
No Data lt10 1014
1519 2024 25
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Obesity Trends Among U.S. AdultsBRFSS, 2002
(BMI 30, or 30 lbs overweight for 5 4
person)
No Data lt10 1014
1519 2024 25
23
Obesity Trends Among U.S. AdultsBRFSS, 2003
(BMI 30, or 30 lbs overweight for 5 4
person)
No Data lt10 1014
1519 2024 25
24
Obesity Trends Among U.S. AdultsBRFSS, 2004
(BMI 30, or 30 lbs overweight for 5 4
person)
No Data lt10 1014
1519 2024 25
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Obesity Trends Among U.S. AdultsBRFSS, 2005
(BMI 30, or 30 lbs overweight for 5 4
person)
No Data lt10 1014
1519 2024 2529
30
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Obesity Trends Among U.S. AdultsBRFSS, 2006
(BMI 30, or 30 lbs. overweight for 5 4
person)
No Data lt10 1014
1519 2024 2529
30
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Obesity Trends Among U.S. AdultsBRFSS, 2007
(BMI 30, or 30 lbs. overweight for 5 4
person)
No Data lt10 1014
1519 2024 2529
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
• Type II diabetes
• Hypertension
• Atheroschlerosis
• Some types of cancer
• Asthma
• Gall bladder problems
• Gastroesophageal reflux
• Sleep apnea
• Fertility problems
• Osteoarthritis

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Prevalence of type II diabetes by BMI
From Handbook of obesity, Marcel Dekker Inc, 2004
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Diabetes Trends Among Adults in the
U.S.,(Includes Gestational Diabetes) BRFSS,
1990,1995 and 2001
Source Mokdad et al., Diabetes Care
2000231278-83 J Am Med Assoc 200128610.
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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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Risk of premature death
20 25 30 35
15
BMI
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From Ludwig, D.S. New England Journal Of
Medicine 3572325-27, 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 Americans, 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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Wildtype (C57BL/6J)
Ob/Ob
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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 Americans, 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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Association of a SNP in the FTO gene with obesity
From Frayling, TM et al Science 316889, 2007
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Short sleep duration increases BMI
From Taheri et al, PLoS Med 3e62, 2004
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Sleep and Obesity

• Elevations of BMI are observed in subjects who
  sleep fewer than
• 6 h per night
• Experimental acute sleep curtailment increases
  hunger and appetite
• especially for energy rich foods
• -Mice in which circadian rhythms are disrupted
  become obese
• More than 33 of adolescents get less sleep than
  recommended

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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
  genes
• that 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
  related
• to waist circumference gain
• Total amount of fat in diet is not

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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 3562017-2021, 2007
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Consumption of trans fats increases the risk of
heart disease
Mozaffarian et al NEJM 3541601-1613, 2007
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HOW IS BODY WEIGHT REGULATED? Body weight
represents a balance between calorie input and
calorie expenditure. Inputs Expenditures food
eaten basal metabolic rate cost 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
  inhibits
• glucose uptake in muscle and fat

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Ghrelin is produced in the stomach
Normal
Gastric Resection
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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
  dont increase
• to 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. 349941-948, 2003

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Calorie intake after PYY infusion
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What is actually regulated? Data suggest that
input is matched to expenditures over long
periods of time (weeks to months) but not over
shorter periods (days). Suggests something that
doesnt change much acutely, for example, body
energy stores are what is regulated. Body fat!
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What is actually regulated? Data suggest that
input is matched to expenditures over long
periods of time (weeks to months) but not over
shorter periods (days). Suggests that
something that doesnt change much acutely, for
example, body energy stores, is what is
regulated. Body fat!
Weekly energy expenditure
Daily energy expenditure
Daily food intake
Weekly food intake
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An extra 10 calories a day results in an
approximate 12 pound weight 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
  promote
• utilization of fatty acids to produce ATP

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Wildtype (C57BL/6J)
Ob/Ob
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Leptin and human obesity

• 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
  they
• have more fat and fat makes leptin)
• How come the leptin doesnt prevent them from
  eating?
• - leptin resistance just like insulin resistance
  in type II
• diabetes?
• - leptin doesnt get across the blood brain
  barrier

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Short sleep duration is associated with
increased grelin and decreased leptin
leptin
ghrelin
From Taheri et al, PLoS Med 3e62, 2004
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CYTOKINES TNFa IL-6 IL-1 PBEF TGFb IL-10
OTHER FACTORS Angiotensinogen Complement B, C3,
D Acylation-stimulating protein VEGF IL-1RA Retino
l-binding protein-4
CHEMOKINES IL-8 Eotaxin MCP-1 MIP-1a
ADIPOSE TISSUE
ACUTE PHASE REACTANTS Serum amyloid A C-reactive
protein PAI-1 a1-acid glycoprotein
ENERGY REGULATING HORMONES Leptin Adiponectin Res
istin
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Macrophage specific antigen F4/80 in adipose tisse
Agouti female
Lean female
Ob/ob
Lean male
DIO male
Ob/ob male
Weisberg et al, JCI 1121796-1808,2003
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Macrophage specific antigen F4/80 in skeletal
muscle
muscle
Ob/ob
Lean
liver
Ob/ob
Lean
Weisberg et al, JCI 1121796-1808,2003
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Abdominal fat is more important than subcutaneous
fat for type 2 diabetes
Wang et al, Am. J. Clin. Nutr. 81555-63, 2005
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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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HMW Adiponectin
Bobbert et al, Diabetes 547212-9, 2005
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Mice overexpressing Adiponectin using a Liver
specific promoter
Yamauchi et al, J. Biol. Chem. 2782461, 2003
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Yamauchi et al, J. Biol. Chem. 2782461, 2003
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Adiponectin knockout mice are susceptible to
atheroschlerosis
From Kubota et al, J. Biol. Chem. 27725863,
2002.
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Rosiglitazone induced changes in insulin
sensitivity correlate with changes in adiponectin
Pajvani et al, J Biol Chem 27912152-62, 2004
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• TREATMENT OF OBESITY
• Liposuction
• Gastric reduction surgery (side effects)
• Wiring of the jaw
• Drugs (side effects)
• Diet and exercise
• Behavior modification