obesity epidemic? bacchus, peter paul reubens, 1638 detail of chromosome 15 from the obesity map...

Obesity Epidemic?Obesity Epidemic?

Bacchus, Peter Paul Reubens, 1638

Detail of chromosome 15From the obesity map database

Recent Increases in Obesity1985: <15% obese2000: >30% obeseIs obesity a disease?

What’s causing this unusualIncrease in obesity?

-not all obese people have poor health

-Our genes?-Environment?

fast foodssedentary

lifestyle-Dieting, especially low fat diets-Food choices that blind our natural ability to monitor our food intake

Obesity: EnvironmentObesity: EnvironmentIt’s those damn corporationsIt’s those damn corporations

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again shall be kingagain shall be king

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Obesity: EnvironmentObesity: Environment

Sedentary LifestyleSedentary Lifestyle

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Obesity: Ridiculousness

Obesity: EnvironmentObesity: Environment Diets too high in fat?Diets too high in fat?

Too much meat and dairy?Too much meat and dairy? Diets too high in Diets too high in

carbohydrates?carbohydrates? Too much sugar Too much sugar Refined flourRefined flour Soft drinksSoft drinks

Diet drinks make you hungry!Diet drinks make you hungry!

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Let’s poke carbohydrates in the eyeball

Dave Barry

Avoiding Obesity: It’s all about self-discipline, will

power, determination

Bad Mouse

Good Mouse

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Recent Increases in Obesity

1985: <15% obese

2000: >30% obese

Sexually Dimorphic Mammalian SpeciesSexually Dimorphic Mammalian Species

Humans are DimorphicHumans are Dimorphic Males Males

Taller, heavierTaller, heavier Broader shoulderBroader shoulder Smaller hips, buttocksSmaller hips, buttocks Smaller breastsSmaller breasts More facial hairMore facial hair Deeper voiceDeeper voice Larger phallusLarger phallus Less stamina due to lower Less stamina due to lower

subcutaneous fatsubcutaneous fat More heart disease due to More heart disease due to

tendency to gain abdominal tendency to gain abdominal body fatbody fat

Sexual Dimorphism in Body Fat Sexual Dimorphism in Body Fat Distribution in HumansDistribution in Humans

Abdominal vs. Subcutaneous FatAbdominal vs. Subcutaneous FatResults in Apple vs. Pear ShapeResults in Apple vs. Pear Shape

Diabetes and Heart Risks if. .Diabetes and Heart Risks if. .

TriglyceridesTriglycerides

““Good Cholesterol” = High-Density Good Cholesterol” = High-Density Lipoprotein CholesterolLipoprotein Cholesterol

MenMen

WomenWomen

NCEP Expert Panel. JAMA. 2001;285:2486-2497.

150 mg/dL150 mg/dL

< 40 mg/dL< 40 mg/dL

< 50 mg/dL< 50 mg/dL

Plasma Triglycerides and HDL-CPlasma Triglycerides and HDL-C in Lean Men and Women and in Obese Subjects in Lean Men and Women and in Obese Subjects

with High or Low Visceral Adipose Tissue (AT)with High or Low Visceral Adipose Tissue (AT)

Despres JP, Krauss RM. Handbook of Obesity. 1998;651-675.

0.00.71.4

2.12.83.5

0.00.71.4

2.12.83.5

Trig

lyce

rides

(m

mol

/L)

Lean Women Visceral AT Area

Obese Women

Low High

Lean Men Visceral AT Area

Obese Men

Low High

HD

L C

hole

ster

ol (

mm

ol/L

)

Lean Women Visceral AT Area

Obese Women

Low High

Lean Men Visceral AT Area

Obese Men

Low High

1.50

1.25

1.00

0.750.00

1.50

1.25

1.00

0.750.00

1

1.2

1 1.2

1

Traits Associated with WTH in WomenTraits Associated with WTH in Women

TraitTrait WTH HighWTH High WHT LowWHT Low RefRef..Puberty onsetPuberty onset latelate earlyearly 11TestosteroneTestosterone highhigh lowlow 22TriglyceridesTriglycerides highhigh lowlow 1,31,3Insulin resistanceInsulin resistance highhigh lowlow 1,41,4Risk for Type IIRisk for Type II diabetesdiabetes highhigh mod-lowmod-low 1,51,5For gallbladderFor gallbladder

diseasedisease highhigh mod-lowmod-low 66Risk for cancerRisk for cancer (ovar.,breast, uterine)(ovar.,breast, uterine) highhigh mod-lowmod-low 7,87,8Hypertension, strokeHypertension, stroke

heart disease,heart disease,mortalitymortality highhigh mod-lowmod-low 3,5,93,5,9

Adaptive significance Adaptive significance of of

Sexual Dimorphism in Sexual Dimorphism in Body Fat DistributionBody Fat Distribution

related to female lactationrelated to female lactation

(fat is stored in the hips, thighs, (fat is stored in the hips, thighs, buttocks for use in making milk buttocks for use in making milk

during lactation)during lactation)

An enzyme active in weight gain is An enzyme active in weight gain is high in thighs prior to lactation.high in thighs prior to lactation.

High LPL = gaining fatHigh LPL = gaining fatLow LPL = losing fatLow LPL = losing fat

0

10

20

30

Menstruating Pregnant Lactating

Lipoprotein Lipase Activity

FemoralAbdominal

Rebuffe’-Scrive et al., 1974

Gaining in thighs

Losing in thighs

Nonabdominal Nonabdominal fatfat critical for critical for

reproductionreproductionAnd it’s not unhealthy!And it’s not unhealthy!

It might even be “protective”It might even be “protective”

against diabetes and heart against diabetes and heart diseasedisease

Regardless of female body Regardless of female body weightweight

(whether the females are very fat, very (whether the females are very fat, very lean or in between)lean or in between)

A large body of data supports the A large body of data supports the notion that males of North or South notion that males of North or South American or Europe strongly prefer American or Europe strongly prefer

a LOW W.T.H. ratioa LOW W.T.H. ratio

Health Risks and ObesityHealth Risks and Obesity

Abdominal (apple) Subcutaneous (pear)

Insulin resistance Hyperinsulinemia Hypercholesterolemia Low HDL cholesterol Diabetes mellitus Coronary artery disease Hypertension Stroke

No known health risks

Science sides with Sir MixAlot

What kind of epidemic has so What kind of epidemic has so many healthy people?many healthy people?

Marilyn MonroeBMI = overweight to obese

BadCholesterol

lean low high

obese

WHT

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LeptinLeptin

Significance of LeptinSignificance of Leptin

It appears that body weight is regulatedIt appears that body weight is regulated

By a “lipostat”By a “lipostat”

Leptin commonly thought to be the Leptin commonly thought to be the lipostatic signallipostatic signal

It is still hoped by many that our It is still hoped by many that our knowledge of leptin will lead to a cure for knowledge of leptin will lead to a cure for obesityobesity

Mystery SignalMystery Signal

Food Intake

Body FAT

The Seductive The Seductive Lipostatic Lipostatic HypothesisHypothesis

It’s OK to sleep with a It’s OK to sleep with a hypothesis.hypothesis.

You should never marry one.You should never marry one.

HistoryHistory

Early evidence (1970s) for a lipostat came from mutant Early evidence (1970s) for a lipostat came from mutant mice that were obesemice that were obese

Ob/ob mouseOb/ob mouse Db/db mouseDb/db mouse

Mutation in a single gene on an autosomeMutation in a single gene on an autosome Obese (more than 30% heavier than wild type)Obese (more than 30% heavier than wild type) Hyperphagic (ate significantly more than wild typeHyperphagic (ate significantly more than wild type Diabetic (hyperglycemic)Diabetic (hyperglycemic) Infertile (does not undergo puberty, does not mate or have Infertile (does not undergo puberty, does not mate or have

estrous cycles or spermatogenesis, decreases gonadal steroids)estrous cycles or spermatogenesis, decreases gonadal steroids)

ParabiosisParabiosis

An obese mouse (ob/ob) is sharing its An obese mouse (ob/ob) is sharing its circulation with a lean wild type mousecirculation with a lean wild type mouse

How would you explain these results?How would you explain these results?

ob/ob - +/+mouse: ob/ob lost weightob/ob - +/+mouse: ob/ob lost weight db/db- +/+ :db/db obese, +/+ stopped eating and lost weightdb/db- +/+ :db/db obese, +/+ stopped eating and lost weight ob/ob -db/db: ob/ob stopped eating and lost weight, whereas the ob/ob -db/db: ob/ob stopped eating and lost weight, whereas the

db/db unaffecteddb/db unaffected An additional experiment showed that when one of a pair of +/+ An additional experiment showed that when one of a pair of +/+

parabiotic mice was overfed, its "twin" lost weight.parabiotic mice was overfed, its "twin" lost weight.

Conclusion?Conclusion?

Conclusion of Parabiosis Conclusion of Parabiosis ExperimentExperiment

The ob/ob has a mutation in the gene that The ob/ob has a mutation in the gene that codes for a circulating factor that stops the codes for a circulating factor that stops the rat from eating.rat from eating.

The db/db has a mutation in the gene that The db/db has a mutation in the gene that codes for the receptor for this factorcodes for the receptor for this factor

Conclusions of Parabiosis Conclusions of Parabiosis ExperimentExperiment

Ob/ob lacks a factor that stops eatingOb/ob lacks a factor that stops eating The db/db lacks the receptor for that factorThe db/db lacks the receptor for that factor

Leptin (Ob protein)Leptin (Ob protein) Cloned by J. Friedman’s lab in 1994 (Zhang et al., 1995)Cloned by J. Friedman’s lab in 1994 (Zhang et al., 1995)

Adipocyte protein secretedAdipocyte protein secreted in proportion to body fat contentin proportion to body fat content in response to influx of fuels into adipocytes (in response to influx of fuels into adipocytes (

Plasma concentrationsPlasma concentrations high in fat, fed animalshigh in fat, fed animals low in lean or fasted animalslow in lean or fasted animals

Peripheral and central treatment decreases food intake (FI) Peripheral and central treatment decreases food intake (FI) and body weight (BW) in many different speciesand body weight (BW) in many different species

Ob/ob (leptin decreases food intake and bw)Ob/ob (leptin decreases food intake and bw) Db/db (leptin treatment has no effect)Db/db (leptin treatment has no effect) Wild type mouse (leptin decrease FI and BW)Wild type mouse (leptin decrease FI and BW) Rats Rats HamstersHamsters MonkeysMonkeys

So Is leptin the cure for So Is leptin the cure for obesity?obesity?

Percentage of people who are obese because they Percentage of people who are obese because they have a mutation in the gene for leptin = miniscule have a mutation in the gene for leptin = miniscule (only a few people in the world have this mutation)(only a few people in the world have this mutation)

Clinical trials a failureClinical trials a failure gave daily leptin injections to obese patients. gave daily leptin injections to obese patients. Only a third of the patients lost weight. Only a third of the patients lost weight. Some patients dropped out of the study finding the Some patients dropped out of the study finding the

injections irritatinginjections irritating Some reported decrdased appetite at first, and increased Some reported decrdased appetite at first, and increased

appetite after continued use (they developed leptin appetite after continued use (they developed leptin resistance).resistance).

The people gained back the weight they had lost when the The people gained back the weight they had lost when the leptin injections ceased.leptin injections ceased.

Why is Leptin Not The Miracle Cure for Why is Leptin Not The Miracle Cure for Obestiy?Obestiy?

In addtion to leptin, there are In addtion to leptin, there are manymany hormones and neuropeptides that hormones and neuropeptides that influence appetite and obesityinfluence appetite and obesity

Giving leptin alone does not curtail Giving leptin alone does not curtail obesityobesity

Obese people have higher leptin Obese people have higher leptin than normal weight peoplethan normal weight people

Some Factors Involved in Energy BalanceSome Factors Involved in Energy BalanceOrganizational SystemOrganizational System

Metabolic Stimuli glucose oxidation ffa oxidation ketone body formation, oxidation influx of fuels into adipocytes, muscles, liver, etc. lipolysis

Hormones insulin glucagon leptin glucocorticoids (cortisol, corticosterone) ghrelin growth hormone cholecystokinin (gut peptide)

Neuropeptides NPY AgRP Orexin CART a-MSH

RED = INHIBITORYRED = INHIBITORYGREEN = STIMULATORYGREEN = STIMULATORY

Leptin Insulin GhrelinLeptin Insulin Ghrelin

NPY/AGRP POMC (NPY/AGRP POMC (MSH)MSH)

Increases appetite Decreases appetite

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ARC PVN

Leptin Re-wires the NPY and POMC Circuitry

Wildtype mice tend to have more excitatory Wildtype mice tend to have more excitatory synapses in the leptin-to-POMC circuit, and more synapses in the leptin-to-POMC circuit, and more inhibitory synapses in the leptin-to-NPY circuitinhibitory synapses in the leptin-to-NPY circuit

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Ob/ob mice tend to have more excitatory synapses in Ob/ob mice tend to have more excitatory synapses in the leptin-to-NPY circuit and more inhibitory synapses the leptin-to-NPY circuit and more inhibitory synapses

in the leptin-to-POMC circuitin the leptin-to-POMC circuit

Increase Food IntakeIncrease Food Intake

Orexin (lateral hypothalamus)Orexin (lateral hypothalamus) NPY (arcuate and PVN)NPY (arcuate and PVN) AgRP (arcuate and PVN)AgRP (arcuate and PVN) MCH (lateral hypothalamus)MCH (lateral hypothalamus)

Decrease Food IntakeDecrease Food Intake

POMC (POMC (MSH) (arcuate and MSH) (arcuate and PVN)PVN)

CART (arcuate nucleus)CART (arcuate nucleus) CRH (PVN)CRH (PVN)

Current ResearchCurrent Research Any particular obese individual might have mutations or Any particular obese individual might have mutations or

variations at these obesity-related locivariations at these obesity-related loci You cannot assume any one obese person is just lazyYou cannot assume any one obese person is just lazy Many genes, peptides and neurocircuits involvedMany genes, peptides and neurocircuits involved Redundancy in the systemRedundancy in the system A drug that influences one of these peptides can be overridden A drug that influences one of these peptides can be overridden

by the othersby the others As soon as you stop taking the “antiobesity” drug, you gain all As soon as you stop taking the “antiobesity” drug, you gain all

the weight backthe weight back

Single gene approach unlikely to solve the obesity Single gene approach unlikely to solve the obesity problem.problem.

A Pause That Refreshes

Dieting Dieting Doesn’t WorkDoesn’t Work

Dieting is a signal to the brain to Dieting is a signal to the brain to become better at become better at storingstoring fat fat

Energy BalanceEnergy Balance IntakeIntake

Motivational (appetite)Motivational (appetite) ConsumptionConsumption

StorageStorage Glycogen in muscle and liverGlycogen in muscle and liver Lipid in adipose tissue and other tissuesLipid in adipose tissue and other tissues Amino acids in muscle and bone (used with glycerol to make new Amino acids in muscle and bone (used with glycerol to make new

glucose)glucose)

ExpenditureExpenditure RestingResting ThermogenesisThermogenesis ReproductionReproduction Immune functionImmune function Other cellular processes (mitosis, miosis, digestion, Other cellular processes (mitosis, miosis, digestion,

metabolism, cell repair)metabolism, cell repair)

Energy Balance-Energy Balance-No Free RidesNo Free Rides

IntakeIntake StorageStorage

Glycogen Glycogen in muscle and liverin muscle and liver LipidsLipids in adipose tissue and other tissues in adipose tissue and other tissues ProteinProtein (Amino acids )in muscle and bone (used with glycerol to (Amino acids )in muscle and bone (used with glycerol to

make new glucose)make new glucose)

ExpenditureExpenditure Resting (Basal Metabolic Rate)Resting (Basal Metabolic Rate) ThermogenesisThermogenesis Reproduction, Immune functionReproduction, Immune function

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- +

Restricting Food IntakeRestricting Food IntakeDecreases Energy ExpenditureDecreases Energy Expenditure

0

200

400

600

800

1000

1200

1st Qtr

Eating Regimen

Energy Expenditure

Ate Adlibitum

75%Restricted

50%Restricted

Rebound results from increased appetite Rebound results from increased appetite coupled with decreased expenditurecoupled with decreased expenditure

Dieting Makes you FatDieting Makes you Fat

eventuallyeventually

I’m sorry, LouisI’m sorry, Louis

Fat doesn’t make you Fat doesn’t make you fat!fat!

Diet low in simple Diet low in simple carbscarbs

are more satisfyingare more satisfying

You feel less hungryYou feel less hungry

You eat lessYou eat less

Good FatsGood Fats

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Linoleic Acid has two double bonds, can be hydrogenated and is a Polyunsaturated fat. Its formula is CH3(CH2)4CH=CH2CH=CH(CH2)7COOH

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Bad FatsBad Fats

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Water insoluble subatances. They have a relatively large nonpolar hydrocarbon part and a small oxygen containing polar part.

Stearic acid has a 17 atom hydrocarbon chain and a carboxylic acid group.

Its chemical formula is CH3(CH2)16COOH and it is a saturated fat.

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Given two meals with Given two meals with the same caloric value, the same caloric value,

the low carb diet the low carb diet results inresults in

-Significantly more weight loss-Significantly more weight loss

-Happier people-Happier people

-The weight will be gained back if -The weight will be gained back if you go back to eating carbsyou go back to eating carbs

Don’t DietDon’t DietMake permanent changesMake permanent changes

-no soft drinks-no soft drinks

-Minimize bread and pasta-Minimize bread and pasta

-eat carbs like vegetables and fruits -eat carbs like vegetables and fruits and berriesand berries

Diet Drinks Make You Diet Drinks Make You HungryHungry

Growing up on diet drinksGrowing up on diet drinks

-precludes your ability to match -precludes your ability to match taste with caloric intaketaste with caloric intake

-makes you significantly fatter-makes you significantly fatter

Diet Drinks decrease the ability to gauge Diet Drinks decrease the ability to gauge the caloric value of foodthe caloric value of food

Davidson and Swithers, Davidson and Swithers, International Journal of International Journal of ObesityObesity, 28, 933, 2004., 28, 933, 2004.

Rats were trained with a Rats were trained with a flavored premeal and flavored premeal and then later tested for their then later tested for their food intakefood intake

Consistent Group Consistent Group received flavors that received flavors that consitently predicted the consitently predicted the calorie contentcalorie content

Inconsistent Group Inconsistent Group received flavors that did received flavors that did not have any relation to not have any relation to their caloric valuetheir caloric value

Rats were given sweet flavored premeal that matched their

caloric value (consistent)or did not match (inconsistent)

0

10

20

Consistent Inconsistent

Caloric Intake

Flavored Premeal

Chow meal

Good luck this Good luck this weekendweekend

-Don’t diet-Don’t diet

-Don’t drink soft drinks, especially -Don’t drink soft drinks, especially dietdiet

-Eat a balance diet of real foods -Eat a balance diet of real foods including polyunsaturated fatincluding polyunsaturated fat

-To Sir Mixalot with love-To Sir Mixalot with love

87!

More ReferencesMore References

Taubes, Gary, What if it’s all been a big fat Taubes, Gary, What if it’s all been a big fat lie? lie? New York TimesNew York Times, Sept. 15, 2002., Sept. 15, 2002.

Pollen, Michael, Unhappy Meals, Pollen, Michael, Unhappy Meals, New New York TimesYork Times, January 28, 2007., January 28, 2007.