Regulation of Body Weight
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Regulation of Body Weight Regulation of body weight and set point theory. Leptin and body weight regulation. Melanocortin system: anorexigenic signaling. NPY and AGRP: orexigenic signaling. Putting it all together. Theories of Obesity

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Regulation of Body Weight

Regulation of body weight and set point theory.

Leptin and body weight regulation.

Melanocortin system: anorexigenic signaling.

NPY and AGRP: orexigenic signaling.

Putting it all together.


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Theories of Obesity

  • Can BW be regulated in the face of high or low caloric consumption (Jules Hirsch, early 1970’s)???

  • Subjects

  • 100 healthy male volunteers with stable body weight for at least 6 months

  • three groups: thin, healthy weight, and overweight

  • confined to a sedentary life in a metabolic ward of a hospital

  • Design

  • food availability was systematically varied to promote:

    • a 10% BW gain

    • a 10% BW loss

  • measurements:

    • body weight, body mass index

    • food intake

    • feelings of hunger/satiety

    • mood


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165 lbs

+ 10%

150 lbs

- 10%

135 lbs

“Fattening Phase”

  • forced to increase intake

  • hi fat diet

  • hi carbohydrate diet

“Slimming Phase”

  • caloric restriction

  • low fat diet

  • low carbohydrate diet


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165 lbs

+ 10%

150 lbs

- 10%

135 lbs

  • Results – Following a 10% body weight loss

    • increase in appetite

    • food obsessions

    • felt sluggish

    • decrease in metabolic rate

  • When given free access to food, subjects

    • consumed larger meals

    • consumed more frequent meals

    • re-gained the weight lost during the “slimming phase”


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165 lbs

+ 10%

150 lbs

- 10%

135 lbs

  • Results – Following a 10% body weight gain

    • decrease in appetite

    • food aversions

    • bloating, gastrointestinal distress

    • increase in metabolic rate

  • When given free access to food, subjects

    • consumed smaller meals

    • consumed less frequent meals

    • chose foods that were low in fat content

    • lost the weight gained during the “fattening” phase


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165 lbs

+ 10%

150 lbs

- 10%

135 lbs

  • Conclusions

    • body weight is a regulated variable

    • transient behavioral changes

    • (i.e., over/under-eating) induces

    • behavioral (appetite) and physiological

    • (metabolic) changes that help to “defend”

    • a person’s body weight

increased

satiety

signaling

  • The Big Question….

  • Well, there are actually 2….

    • How does the brain sense the body’s

    • level of adiposity stores?

    • If our body weights are regulated, how does

    • one become overweight/obese or maintain

    • a significant weight loss?

increased

orexigenic

signaling


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leptin

leptin

brain

Factors that Regulate Body Weight

  • Leptin

  • protein product of the ob gene (also called OB protein)

  • synthesized in white adipose tissue

  • secreted in proportion to body adiposity

  • functions as a hormone

  • binds to leptin receptor (OB-R) in the brain

  • acts on multiple brain regions (ARC, VMH, DMH)

  • expression is sexually dimorphic


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  • Melanocortin System

  • family of peptides cleaved from the proopiomelanoocortin (POMC) precursor

  • POMC neurons are expressed solely in the arcuate nucleus (ARC)

  • one product of POMC neurons is aMSH

aMSH

POMC protein

  • aMSH

  • alpha-melanocyte-stimulating hormone

  • synthesized within POMC neurons; secreted from the PVN

  • binds with melanocortin receptors in the PVN (MC4 receptor)

  • decreases food intake

  • release of aMSH is regulated by leptin

  • POMC neurons contain leptin receptors (OB-R)

  • melanocortin receptor knockout mice


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  • NPY

  • neuropeptide Y

  • neurotransmitter; widespread expression in the brain

  • multiple biological actions

    • suppress reproductive function

    • causes smooth muscle to relax

    • decreases grooming behavior (in rats!)

    • anxiolytic effects

    • increases food intake

  • synthesized in the arcuate nucleus (ARC)

  • secreted from the paraventricular nucleus (PVN) in

  • response to a decline in energy stores

  • central administration of NPY

    • increases food intake

    • increases fat storage

    • decreases metabolic energy expenditure

    • increases body weight


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    • AGRP

    • agouti-related protein

    • synthesized in the ARC (co-localized with NPY)

    • secreted in the PVN

    • endogenous antagonist of MC-4 receptor

    • stimulates food intake and weight gain

    • also regulated by leptin


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    Activation of the Melanocortin System Inhibits Food Intake

    Satiety Signal

    Decrease

    in Food Intake

    PVN

    MC4-R

    ARC


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    +

    +

    Melanocortin System Is Modulated by Leptin

    Increased Satiety Signal

    Decrease

    in Food Intake

    PVN

    MC4-R

    OB-R

    Increased

    Leptin Secretion

    ARC


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    Melanocortin System Is Modulated by Leptin

    Decreased Satiety Signal

    Increase

    in Food Intake

    PVN

    -

    MC4-R

    OB-R

    +

    Decreased

    Leptin Secretion

    ARC


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    Orexigenic Signal

    Increase

    in Food Intake

    • AGRP

    • agouti-related protein

    • synthesized in the ARC (co-localized with NPY)

    • secreted in the PVN

    • endogenous antagonist of MC-4 receptor

    • stimulates food intake and weight gain

    • also regulated by leptin

    PVN

    ARC


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    Satiety Signal

    Decrease

    in Food Intake

    PVN

    +

    -

    ARC

    Dual Systems Function to Keep Body Weight Stable


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    How Does Leptin Regulate Body Adiposity?

    % body fat

    A)Healthy BW:Leptin secretion is stable and supports energy balance (FI = EE).

    B)Healthy BW:Decrease in leptin secretion signals a decrease in adipose stores and produces a positive energy balance (FI > EE).

    C)Healthy BW:Increase in leptin secretion signals an increase in adipose stores and produces a negative energy balance (FI < EE).

    D)Obese:Set point is elevated. Increase in leptin secretion fails to signal an increase in adipose stores and, thereby, fails to produce a negative energy balance (FI = EE). ** WHY ???


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    OVEREAT

    brain senses

    rise in plasma leptin

    1) appetite is suppressed

    2) metabolism increases

    Increased

    Leptin Secretion

    In an Individual with a Healthy Body Weight….


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    In an Overweight Individual….

    OVEREAT

    brain senses

    rise in plasma leptin

    1) appetite is not suppressed

    2) metabolism doesn’t change

    Increased

    Leptin Secretion


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    In an Individual with a Healthy Body Weight….

    Increased release of a-MSH

    Decreased release of AGRP

    Decreased release of NPY

    OVEREAT

    brain senses

    excessive calories

    1) appetite is suppressed

    2) metabolism increases

    Increased

    Leptin Secretion


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