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New Perspectives on the Pathogenesis of Obesity
Cardiometabolic Congress
Mark A. HermanApril 23, 2013
No Financial Disclosures
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Agenda
• Definitions and the Scope of the Problem
• Physiological Determinants of Body Weight
• Molecular Mediators of Body Weight
• Gene – Environment Interactions– The Role of Dietary Composition– The Social Environment
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Body Mass Index (BMI): weight (kg) / height (m2)
LeanBMI < 25
OverweightBMI 25 ‐ 30
ObeseBMI 30 ‐ 40
Morbidly ObeseBMI > 40
* Caveat: An athletic, fit person may have a high BMI without excess adiposity
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Obesity Increases the 10 Year Risk of Death in Men ages 50 ‐ 71
KF Adams et al., NEJM 355, 763–78 (2006).
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Obesity Increases the 10 Year Risk of Death in Women ages 50 ‐ 71
KF Adams et al., NEJM 355, 763–78 (2006).
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Age‐Adjusted Prevalence of Obesity and Diagnosed Diabetes Among U.S. Adults Aged 18 Years or older
Obesity (BMI ≥30 kg/m2)
Diabetes
1994
1994
2000
2000
No Data <14.0% 14.0‐17.9% 18.0‐21.9% 22.0‐25.9% >26.0%
No Data <4.5% 4.5‐5.9% 6.0‐7.4% 7.5‐8.9% >9.0%
CDC’s Division of Diabetes Translation. National Diabetes Surveillance System available at http://www.cdc.gov/diabetes/statistics
2010
2010
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Social Stigma of Obesity• Negative perception that obese people are lazy,
unmotivated, lacking self‐discipline, less competent
• The prevalence of weight discrimination is comparable to rates of racial discrimination, especially among women– Discrimination in hiring and employment decisions– Lower wages
• In a study of 600 primary care physicians in France– 30% considered overweight and obese patients to be lazier and
more self‐indulgent than normal weight people– 60% identified lack of patient motivation as the most common
problem in treating overweight and obese patients.
RM Puhl, Obesity 17, 941–64 (2009).A. Bocquier et al., Obesity 13, 787–95 (2005).
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Observations:• Obesity and its associated comorbidities have clear negative health consequences, yet they are also highly heritable.
Queries:• Why is the Prevalence of Obesity Increasing?
• How could natural selection favor the spread of genes with such negative consequences?
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Why is the Prevalence of Obesity Increasing?• The “thrifty gene” hypothesis? (J. Neel, 1962)
– In our early evolutionary development, genes that promoted efficient fat storage would be adaptive to protect against intermittent famine.
– In modern society, with an overabundance of cheap nutrients and absent famine, this efficiency is maladaptive and results in obesity
• The “predation release” hypothesis? (J. Speakman, 2007)– Genes favoring obesity have not been positively selected, but have
occurred due to random genetic “drift” as a result of the absence of selection
– ~ 2 million years ago, with the discovery of weapons and fire, the selection against obesity which might put us at risk for predation largely ceased
• Protection from chronic infections like tuberculosis? (J. Roth, 2009)– The thrifty hypothesis fails to explain why obesity predisposes to the
metabolic syndrome and why it is associated with increased “inflammation.”
– Increased adiposity associated with intensified proinflammatorydefenses may provide a survival benefit against infectious agents like tuberculosis
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Body Weight is Determined by Energy Balance
Energy Intake• Feeding
Energy Expenditure• Basal Metabolism• Physical Activity• Adaptive
Thermogenesis
* For body weight to increase such that obesity develops, energy intake must exceed energy expenditure
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Energy Expenditure• Resting Energy Expenditure: ~60% of total
– “Basal Metabolism”– Maintenance of transmembrane ion gradients– Resting cardiopulmonary activity
• The Thermic Effect of Feeding: ~10%– Digestion, transport, and deposition of nutrients
• Non‐Resting Energy Expenditure: ~ 30%– Physical activity
• Adaptive Thermogenesis: ? %– Major fraction of energy consumption in small mammals, but unclear in humans
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Can Small Changes in Energy Intake Cumulatively Produce Large Changes in Body Weight?
Example:• Average daily caloric intake: 2200 kcal / day
• If a person eats 1 extra Ritz Crackers per day (16 kcal / day)without changing energy expenditure– This is a 0.7% increase in daily energy intake
• 16 kcal / day for 5 years => 29,200 kcal– 1 gram of stored fat is equivalent to 9 kcal3.24 kg (7 pounds) of fat
** Without a change in energy expenditure, eating 1 extra Ritz Cracker per day would lead to a 7 pound weight gain over the course of 5 years.
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When Does Weight Gain Occur ‐ Slow Drift Versus Sudden Change?
• Sudden changes in weight?– “The Freshman 15” is largely a myth– Weight gain averages ~ 2.5 lbs during the freshman year
• ML. Morrow et al., Obesity 14, 1438–43 (2006); DJ Hoffman et al., J of ACH 55, 41–5 (2006).
• Weight generally increases slowly– In the Framingham Study, the body weight of the average adult increased by 10% over a 20‐year period [Belanger, AJ et al. The Framingham Study. Sect. 36. Government Printing Office, 1988 (NIH publication no. 88‐2970)]
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Common Experience: Energy Balance is Largely Self‐Regulating
• Despite short‐term and long‐term variability in energy consumption, body weight, in most people, remains generally stable over long periods of time A feedback system must exist to auto‐regulate energy consumption and energy expenditure
• The normal maintenance of body weight is not a matter of “willpower”=> We do not need to “think” about regulating our food intake or energy expenditure for the maintenance of energy balance on a meal to meal basis. This process occurs subconsciously.
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RL Leibel, et al. NEJM 332, 621–8 (1995).
Query:• Does Each Individual Have a Body Weight “Set Point?”
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RL Leibel, et al. NEJM 332, 621–8 (1995).
Energy Expenditure Increases Disproportionately with Weight Gain
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Energy Expenditure Increases Disproportionately with Weight Gain and Decreases Disproportionately with
Weight Loss
RL Leibel, et al. NEJM 332, 621–8 (1995).
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Weight Loss Increases Appetite Sensations
baseline 15 week drug tx
18 week low‐fat diet + exercise
“Desire to Eat” “Hunger”
baseline 15 week drug tx
18 week low‐fat diet + exercise
E. Doucet et al., International Journal of Obesity 24, 906–14 (2000).
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How is Unbalanced Energy Status Sensed and How is Rebalancing Controlled?
Energy Intake
Energy Expenditure
?
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Molecular / Genetic Evidence for the Regulation of Energy Balance
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Parabiosis Rescues Obesity in ob/ob Mice, but not db/db Mice
D. L. Coleman, Diabetologia 9, 294–8 (1973).
ob/ob mice: missing a circulating factor that regulates energy balance?
db/db mice: missing a receptor for a circulating factor that regulates energy balance?
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Fat Cell
Leptin
Leptin Receptor
ob/ob Mice are Deficient in the Adipose Secreted Hormone Leptin
• 1995: Positional Cloning of Leptin– Mutations of which cause the ob/ob obesity
phenotype (J. Freidman)
• 1995/6: Identification of the Leptin Receptor– Mutations of which cause the db/db obesity
phenotype
• 1997: Identification of human subjects with leptin mutations causing severe obesity
• 1998: Identification of human subjects with leptin receptor mutations causing severe obesityEnergy
ExpenditureFood Intake
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Child D Pre‐TreatmentAge 2.5 years
Child D Post‐Leptin Treatment Age 5.5 years
Recombinant Leptin Replacement Cures Obesity in a Leptin Deficient Child
IS Farooqi et al., NEJM 341, 879–84 (1999).
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7060504030201000
20
40
60
80
100
Body Fat (%)
Serum leptin (n
g/ml)
Obesity is a State of Leptin Resistance
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BM Spiegelman, et al., Cell 104, 531–43 (2001).
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Mutations in Members of the Leptin Signaling Pathway Cause Monogenic Forms of Severe
Obesity in Humans
FAT Hypothalamus HypothalamusOther areas of brain,
frontal cortex, hindbrain
Leptin Leptin Receptor Appetite Suppressing Neurons Expressing POMC
Effector Neurons Expressing MC4R
Leptin, Leptin Receptor, POMC MutationsSevere, early onset morbid obesityExtremely rare
MC4‐Receptor MutationsHeterozygous coding mutations in MC4R account for ~5‐7 % of early onset (before age 5) obesity
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adipocyte pancreas gut stomach sensory
NTS
PBN
leptin insulin CCK,PYY
ghrelin
Arcuate
Lateral Hypothalamus
NPYMSHAGRP
MCHOrexin
circulation
olfactorybulb
hypothalamuscortex
CNS
Periphery
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Queries:• Do Genetics Play a Role in Common Forms of Obesity?
• Is Adiposity a polygenic trait?– The predisposition to common obesity may be the result of relatively common mutations in many genes, each of which has individually a small impact on body weight.
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Changes in Adiposity with Overfeeding is Strongly Heritable
• 12 pairs of monozygotic twins overfed by 1000 kcal per day for 84 days
• ~ 10‐fold variation in adiposity with overfeeding across pairs
• Strong correlation within twin pairs (R = 0.72)
C. Bouchard et al., NEJM 322, 1477–82 (1990).
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Genome‐Wide Association Studies
• A large number of genetic loci contribute to the regulation of BMI
• Individually, each of these loci has a small effect
• The largest effect is for a loci that contains the gene FTO.– This polymorphism explains 0.34% of the variance in BMI
EK Speliotes et al., Nature Genetics 42, 937–948 (2010).
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Overweight
Overweight
On Average, People are Overweight Whether they have the Most or Least Number of Obesity Risk Alleles
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Observations:– Energy balance and body weight are tightly controlled by
genetic / molecular mechanisms. – However, the prevalence of obesity has increased
dramatically over the last four decades.– Our genes have not changed significantly over this time
period.
Conclusions:– Changes in Environmental Variables must account for the increase in obesity.
Queries: – What Environmental Variables have changed over the
last few decades contributing to the obesity epidemic?– How do these environmental variables alter the
homeostatic processes that normally regulates body weight within a narrow range?
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Environmental Variables• Decline in activity level
– Cars, decline in manual labor, sedentary lifestyles• Changes in Nutrient Intake / Composition
– Increased portion sizes– Increased availability and reduced cost of highly palatable, energy dense foods
• Social and Cultural Factors• Maternal‐Fetal Environment and Epigenetic Imprinting
– The Dutch Famine?• Viral or other Communicable Causes• Disrupted Sleep‐Wake Cycles and Circadian Rhythms• Changes in the Microbiome• Environmental Toxins
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Changes in Physical Activity Level?
• Occupation related physical activity has been slowly, but steadily trending down over the last 5 decades, inconsistent with the rapid increase in BW beginning in 1980
• “suburbanization” –cars, TV, washing machines and dishwashers, vacuums … became prevalent in the 1950s
Onset of obesity epidemic
TS Church et al., PloS one 6, e19657 (2011).
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Query:• Do Changes in Energy Intake or Dietary Composition Explain the Obesity Epidemic?
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ounces: 6.5 10 10 10 16 11.5calories: 70 120 120 120 192
511
384448+
Total 1337++ calories
• More food for the same amount of money is perceived as a positive value.
• “Supersizing” adds 1337 calories to the meal
• Expectation of larger portions evolved over time.
• Related to cheapness of food.
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Pepsi (20 ounces): • 259 calories• 69 grams of sugar
Dannon Frusion (10 ounces):• 240 calories• 3.4 grams of fat• 45 grams sugar
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Publication No. IP‐58g. University of Kentucky College of Agriculture.
http://www.ca.uky.edu/agc/pubs/ip/ip58g/ip58g.htm
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• Baseline consumption of sugar‐sweetened beverages (SSBs) correlated with BMI
• For each additional daily serving of SSB consumed over 19 months– BMI increased by 0.24 kg/m2– Odds ratio for obesity 1.6
Lancet 357, 505–8 (2001).
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New York Post
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Epigenetics / Maternal‐Fetal Environment?
GP Ravelli, et al., NEJM 295, 349–53 (1976).
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Queries:• Is There Hope for Effective Treatment of Obesity?
• Can we use our knowledge of genetics and molecular physiology to enhance weight loss?
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** Without a change in energy expenditure, eating 1 extra Ritz Cracker per day would lead to a 7 pound weight gain over the course of 5 years.
Sustained marginal reductions in energy intake coupled with maintenance of or small increases in energy expenditure should produce large cumulative weight losses over long periods of time
Short‐term we are capable of helping people reduce caloric intake and increase energy expenditure
We must learn to decouple weight loss from the compensatory homeostatic mechanisms
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The Journal of clinical endocrinology and metabolism 87, 2391–4 (2002).
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FDA Guidelines for Effective Anti‐Obesity Therapy
• In general, a product can be considered effective for weight management if after 1 year of treatment either of the following occurs:
– The difference in mean weight loss between the active‐product and placebo‐treated groups is at least 5 percent and the difference is statistically significant
• For a 250 pound person, that would require a 12.5 pound weight loss in 1 year
– The proportion of subjects who lose greater than or equal to 5 percent of baseline body weight in the active‐product group is at least 35 percent, is approximately double the proportion in the placebo‐treated group, and the difference between groups is statistically significant