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Obesity Epidemic?. Detail of chromosome 15 From the obesity map database. Bacchus, Peter Paul Reubens, 1638. Recent Increases in Obesity. 1985: <15% obese 2000: >30% obese. Is obesity a disease?. -not all obese people have poor health. What’s causing this unusual Increase in obesity?.

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Obesity epidemic l.jpg

Obesity Epidemic?

Detail of chromosome 15

From the obesity map database

Bacchus, Peter Paul Reubens, 1638


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Recent Increases in Obesity

1985: <15% obese

2000: >30% obese

Is obesity a disease?

-not all obese people have poor health

What’s causing this unusual

Increase in obesity?

-Our genes?

-Environment?

fast foods

sedentary lifestyle

-Dieting, especially low fat diets

-Food choices that blind our natural ability to monitor our food intake


Obesity environment l.jpg

Obesity: Environment

It’s those damn corporations


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again shall be king


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Obesity: Environment

Sedentary Lifestyle


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Obesity: Ridiculousness


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Let’s poke

carbohydrates

in the eyeball

Dave Barry

Obesity: Environment

  • Diets too high in fat?

    • Too much meat and dairy?

  • Diets too high in carbohydrates?

    • Too much sugar

    • Refined flour

    • Soft drinks

  • Diet drinks make you hungry!


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Good Mouse

Bad Mouse

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


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Obesity Genes


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Recent Increases in Obesity

1985: <15% obese

2000: >30% obese


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Sexually Dimorphic Mammalian Species


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Humans are Dimorphic

  • Males

    • Taller, heavier

    • Broader shoulder

    • Smaller hips, buttocks

    • Smaller breasts

    • More facial hair

    • Deeper voice

    • Larger phallus

    • Less stamina due to lower subcutaneous fat

    • More heart disease due to tendency to gain abdominal body fat


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Sexual Dimorphism in Body Fat Distribution in HumansAbdominal vs. Subcutaneous FatResults in Apple vs. Pear Shape


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Diabetes and Heart Risks if. .

 150 mg/dL

< 40 mg/dL

< 50 mg/dL

  • Triglycerides

  • “Good Cholesterol” = High-Density Lipoprotein Cholesterol

    • Men

    • Women

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


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Plasma Triglycerides and HDL-Cin Lean Men and Women and in Obese Subjects with High or Low Visceral Adipose Tissue (AT)

1.50

1.25

1.00

0.75

0.00

1

1

Low

High

Low

High

Lean Men

Lean Men

HDL Cholesterol (mmol/L)

Visceral AT AreaObese Men

Visceral AT AreaObese Men

Triglycerides (mmol/L)

1.2

1.50

1.25

1.00

0.75

0.00

1

1.2

Low

High

Low

High

Lean Women

Lean Women

Visceral AT AreaObese Women

Visceral AT AreaObese Women

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


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Traits Associated with WTH in Women

  • TraitWTH HighWHT LowRef.

    Puberty onsetlateearly1

    Testosteronehighlow2

    Triglycerideshighlow1,3

    Insulin resistancehighlow1,4

    Risk for Type II

    diabeteshighmod-low1,5

    For gallbladder

    diseasehighmod-low6

    Risk for cancer

    (ovar.,breast, uterine)highmod-low7,8

    Hypertension, stroke

    heart disease,

    mortalityhighmod-low3,5,9


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Adaptive significance of Sexual Dimorphism in Body Fat Distribution

related to female lactation

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


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An enzyme active in weight gain is high in thighs prior to lactation.High LPL = gaining fatLow LPL = losing fat

Gaining in thighs

Losing in thighs

Rebuffe’-Scrive et al., 1974


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Nonabdominal fat critical for reproduction

And it’s not unhealthy!

It might even be “protective”

against diabetes and heart disease


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Regardless of female body weight(whether the females are very fat, very lean or in between)

A large body of data supports the notion that males of North or South American or Europe strongly prefer a LOW W.T.H. ratio


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Health 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


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obese

Bad

Cholesterol

lean

low

high

WHT

What kind of epidemic has so many healthy people?

Marilyn Monroe

BMI = overweight to obese


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Obesity Genes


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Leptin


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Significance of Leptin

  • It appears that body weight is regulated

  • By a “lipostat”

  • Leptin commonly thought to be the lipostatic signal

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


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The Seductive Lipostatic Hypothesis

Food Intake

Mystery Signal

Body FAT


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It’s OK to sleep with a hypothesis.

You should never marry one.


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History

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

  • Ob/ob mouse

  • Db/db mouse

    • Mutation in a single gene on an autosome

    • Obese (more than 30% heavier than wild type)

    • Hyperphagic (ate significantly more than wild type

    • Diabetic (hyperglycemic)

    • Infertile (does not undergo puberty, does not mate or have estrous cycles or spermatogenesis, decreases gonadal steroids)


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Parabiosis

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


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How would you explain these results?

  • ob/ob - +/+mouse: ob/ob lost weight


  • db/db- +/+ :db/db obese, +/+ stopped eating and lost weight

  • ob/ob -db/db: ob/ob stopped eating and lost weight, whereas the db/db unaffected

  • An additional experiment showed that when one of a pair of +/+ parabiotic mice was overfed, its "twin" lost weight.


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Conclusion?


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Conclusion of Parabiosis Experiment

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

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


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Conclusions of Parabiosis Experiment

  • Ob/ob lacks a factor that stops eating

  • The db/db lacks the receptor for that factor


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Leptin (Ob protein)

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

Adipocyte protein secreted

in proportion to body fat content

in response to influx of fuels into adipocytes (

Plasma concentrations

high in fat, fed animals

low in lean or fasted animals

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

Ob/ob (leptin decreases food intake and bw)

Db/db (leptin treatment has no effect)

Wild type mouse (leptin decrease FI and BW)

Rats

Hamsters

Monkeys


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So Is leptin the cure for obesity?

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

  • Clinical trials a failure

    • gave daily leptin injections to obese patients.

    • Only a third of the patients lost weight.

    • Some patients dropped out of the study finding the injections irritating

    • Some reported decrdased appetite at first, and increased appetite after continued use (they developed leptin resistance).

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


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Why is Leptin Not The Miracle Cure for Obestiy?

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

Giving leptin alone does not curtail obesity

Obese people have higher leptin than normal weight people


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Some Factors Involved in Energy BalanceOrganizational 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


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RED = INHIBITORYGREEN = STIMULATORY

  • Leptin Insulin Ghrelin

  • NPY/AGRP POMC (MSH)

Decreases appetite

Increases appetite


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ARC

PVN

LEPTIN

INSULIN


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Leptin Re-wires the NPY and POMC Circuitry

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

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


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Increase Food Intake

  • Orexin (lateral hypothalamus)

  • NPY (arcuate and PVN)

  • AgRP (arcuate and PVN)

  • MCH (lateral hypothalamus)


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Decrease Food Intake

  • POMC (MSH) (arcuate and PVN)

  • CART (arcuate nucleus)

  • CRH (PVN)


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Current Research

  • Any particular obese individual might have mutations or variations at these obesity-related loci

  • You cannot assume any one obese person is just lazy

  • Many genes, peptides and neurocircuits involved

  • Redundancy in the system

  • A drug that influences one of these peptides can be overridden by the others

  • As soon as you stop taking the “antiobesity” drug, you gain all the weight back

  • Single gene approach unlikely to solve the obesity problem.


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A Pause That Refreshes


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Dieting Doesn’t Work

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


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Energy Balance

  • Intake

    • Motivational (appetite)

    • Consumption

  • Storage

    • Glycogen in muscle and liver

    • Lipid in adipose tissue and other tissues

    • Amino acids in muscle and bone (used with glycerol to make new glucose)

  • Expenditure

    • Resting

    • Thermogenesis

    • Reproduction

    • Immune function

    • Other cellular processes (mitosis, miosis, digestion, metabolism, cell repair)


Energy balance no free rides l.jpg

-

+

Energy Balance-No Free Rides

  • Intake

  • Storage

    • Glycogen in muscle and liver

    • Lipids in adipose tissue and other tissues

    • Protein (Amino acids )in muscle and bone (used with glycerol to make new glucose)

  • Expenditure

    • Resting (Basal Metabolic Rate)

    • Thermogenesis

    • Reproduction, Immune function


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Restricting Food IntakeDecreases Energy Expenditure


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Rebound results from increased appetite coupled with decreased expenditure


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Dieting Makes you Fat

eventually


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I’m sorry, Louis

Fat doesn’t make you fat!


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Diet low in simple carbsare more satisfying

You feel less hungry

You eat less


Good fats l.jpg

Good Fats

Linoleic Acid has two double bonds, can be hydrogenated and is a Polyunsaturated fat.

Its formula isCH3(CH2)4CH=CH2CH=CH(CH2)7COOH


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Bad Fats

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.


Given two meals with the same caloric value the low carb diet results in l.jpg

Given two meals with the same caloric value, the low carb diet results in

-Significantly more weight loss

-Happier people

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


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Don’t Diet

Make permanent changes

-no soft drinks

-Minimize bread and pasta

-eat carbs like vegetables and fruits and berries


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Diet Drinks Make You Hungry

Growing up on diet drinks

-precludes your ability to match taste with caloric intake

-makes you significantly fatter


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

  • Davidson and Swithers, International Journal of Obesity, 28, 933, 2004.

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

  • Consistent Group received flavors that consitently predicted the calorie content

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


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Good luck this weekend

-Don’t diet

-Don’t drink soft drinks, especially diet

-Eat a balance diet of real foods including polyunsaturated fat

-To Sir Mixalot with love

87!


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More References

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

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


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