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.
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Theories of Obesity

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

increased satiety signaling

• The Big Question.
• Well, there are actually 2.
• How does the brain sense the bodys
• 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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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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• 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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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 gt EE). C) Healthy
BW Increase in leptin secretion signals an
increase in adipose stores and produces a
negative energy balance (FI lt 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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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
doesnt 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
1) appetite is suppressed 2) metabolism increases
brain senses excessive calories
Increased Leptin Secretion