Lecture 32 - Feeding & Weight Control Flashcards

1
Q

Outline the metabolic syndrome

A

Obesity →

  • Hypertension
  • Dyslipidaemia
  • Insulin resistance
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2
Q

Outline the two types of peripheral signals involved in homeostasis of body weight

A
  1. Satiety signals
    • ​​CCK, Ghrelin
    • Short acting
    • Produced in the gut, stomach & liver
    • Action:
      • ​Acts on Vagus & sympathetic nerves
      • Transmission to medulla
      • Further transmission to hypothalamus
  2. Adiposity signals
    • Leptin, insulin
    • ​​Long term
    • Released from pancreas / leptin
    • Circulate in levels proportional to fat mass
      • ​Inform the hypothalamus about peripheral energy stores
    • Action
      • ​Released into blood stream
      • Actively transported across the BBB
      • Acts on neurons in the ARC
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3
Q

State the overall action of the following peptides:

  • Cholecystokinin
  • Agouti-related peptide
  • Ghrelin
  • α-melanocyte stimulating hormone
  • Leptin
  • Neuropeptide Y

What is the source of these?

A

Appetite stimulating:

  • Neuropeptide Y
  • Agouti-related peptide
  • Ghrelin

Appetite suppressing:

  • α-melanocyte stimulating hormone
  • Leptin
  • Cholecystokinin

​Source:

  • Brain:
    • ​NPY
    • α-MSH
    • ARP
  • Periphery:
    • ​Ghrelin
    • Leptin
    • Cholecytokinin
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4
Q

Describe cholecystokinin (CCK)

  • Source
  • Action
  • Release
A
  • 33 AA
  • Source:
    • ​Cells in the intestine
  • Release:
    • ​In response to nutrients esp. fat in the lumen of the gut
  • Action
    • ​Overall: Satiety (decreased food intake)
    • Acts locally on CCKA receptors on vagus nerves
    • Signal transmitted to Nucleus tractus solitarius in medulla
    • Ascending transmission to medulla
    • Termination of meal
  • Doesn’t have an overall effect on body weight
    • Increased frequency of meals to compensate
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5
Q

Describe Ghrelin

  • Source
  • Release
  • Action
A
  • 28 AA peptide
  • Source
    • Predominantly synthesised in the stomach
  • Release
    • ​Pre-prandially, when the stomach is empty
    • Decreases post-prandially
  • Action
    • ​Overall: increase appetite & body weight
    • Acts on GHSR-1a receptors in hypothalamus
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6
Q

Describe Leptin

  • Source
  • Release
  • Action
A
  • Source:
    • ​Predominantly adipocytes
  • Release
    • ​Post-prandially
  • Action
    • ​Crosses BBB
    • Acts on receptors in the hypothalamus (ARC)
    • Inhibits food intake
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7
Q

Compare circulating levels of Ghrelin and Leptin

A

Ghrelin: inversely proportional to BMI & weight

Leptin: proportional to BMI & weight

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8
Q

What is the role of Leptin in obesity?

A
  • Initially thought that Leptin defects could play a role in the pathogenesis of obesity
  • This is only the case for a low number of individuals
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9
Q

Compare the sources of Leptin & Ghrelin

A

Leptin: adipocytes

Ghrelin: stomach

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10
Q

Describe how Leptin regulates energy balance

A
  1. Leptin released from white adipose cells
  2. Leptin crosses BBB and binds to Leptin receptors on the hypothalamus
    • ​Stimulation of POMC/CART neurons
    • Inhibition of: **NPY/AGRP **neurons
  3. Release of neuropeptides:
  4. Control of food intake & energy usage
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11
Q

Describe NPY

  • Source
  • Release
  • Action
A
  • 36 AA peptide
  • Source:
    • ​NPY/AGRP neurons in hypothalamus
  • Release:
    • ​Regulated by Leptin:
      • ​Leptin signalling inhibits release
    • Ghrelin stimulates release
  • Action
    • Binds Y1, Y2 & Y5 receptors
      • GPCRs
      • ​Y1/2
        • ​Located post-synaptically
      • Y5
        • ​Located pre-synaptically
        • Auto-receptors
    • ​Stimulates feeding behaviour
    • Reduces energy expenditure
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12
Q

Describe POMC

  • Receptors
  • Release
  • Action
A
  • Pro-opiomelanocortin
  • 131 AA precursor protein
    • Cleaved into a-MSH (amongst other peptides)
  • Action
    • Binds receptors in PVN
      • MC(1-5) R
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13
Q

Describe α-MSH

  • Source
  • Release
  • Action
A
  • 13 AA peptide
  • Source
  • Release:
    • ​Regulated by leptin
      • ​Leptin stimulates release
    • Released into PVN
  • Action:
    • Tonically released:
      • Acts on **MC4R **
        • ​Inhibits food intake
      • Increases energy expenditure
    • ​→ tonic inhibition of food intake
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14
Q

Describe AGRP

  • Source
  • Release
  • Action
A
  • Agouti-related peptide
  • 132 AA protein
  • Source
    • ​ARC neurons
  • Release
    • ​Regulated by leptin
      • ​Leptin signalling inhibits release
    • Ghrelin stimulates release
  • Action
    • ​Antagonist at MC4R
      • Inhibits action of α-MSH
      • Increases food intake
      • Decreases energy expenditure
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15
Q

What is ARC?

A
  • Arcuate nucleus
  • Located in the hypothalamus
  • Contains NPY/AGRP & POMC/CART neurons
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16
Q

Describe the effect of changed fat mass

A
  1. Decreased fat mass
  2. Decreased leptin
  3. Decreased inhibition of NPY/AGRP neurons in ARC
  4. Expression of NPY/AGRP
  5. Release of NPY & AGRP in PVN
  6. Effects:
    1. Stimulation of feeding behaviour
    2. Decreased energy expenditure
    3. Inhibition of α-MSH at MC4R
      • ​Decreased activity of the anorexigenic pathway
  7. Increased body weight
  8. Increased fat mass
  9. Increased Leptin
  10. Leptin crosses BBB to ARC in hypothalamus
  11. Actions:
    1. ​Inhibition of NPY/AGRP neurons
      1. ​Decreased expression of NPY & AGRP
    2. Stimulation of POMC neurons
  12. Expression and release of** α-MSH**
  13. α-MSH acts on MC4R
  14. Increased energy expenditure
  15. Decreased feeding
  16. Reduced bodyweight
17
Q

What is PVN?

A
  • Paraventricular nucleus
  • Located in the hypothalamus
  • Location of release of NPY & AGRP
18
Q

Outline factors that affect generation of obesity

A
  • Genetic factors
    • Susceptibility genes
    • Monogenic/inherited
  • Environmental factors
    • ​Low physical activity
    • High calorie diet
    • Ethnicity
    • Socioeconomic status
    • Sleep deprivation
19
Q

Describe evidence for the role of genetics in the generation of obesity

A
  • Empirical evidence
    • ​BMI of adopted child more strongly correlated with biological parents
    • ​High concordance for monozygotic twins
      • ​50-90%
    • >250 genes associated with obesity
  • Evidence against
    • ​The increase in obesity since 1980 is too great to be purely genetic
20
Q

Describe the evolutionary factors of obesity

A
  • Historically, food was:
    • Inconsistent
    • Hard to obtain
  • There was a bias towards weight gain and against loss
  • Protective mechanism against starvation
21
Q

Describe the current ‘obesogenic’ environment

A
  • Decreased physical activity
    • Technology
    • Changing occupations
  • Increased high-calorie, palatable food
    • ​Addition of sugar
    • Increased portion size
    • High fat content
22
Q

Describe the neurobiology of consumption of palatable food

A
  • Palatable food consumed even after energy demands are met
    • ​In contrast to bland food
  • Mesolimbic dopaminergic (reward) pathway
    • Release of dopamine from dopaminergic neurons from VTA into the NAc
    • Activated in response to consumption of palatable food
    • ‘Reward’ / pleasure signal
23
Q

Describe the role of the metabolic state in the reward of palatable food consumption

A
  • Hunger:
    • ​Enhanced food-induced activation of the mesolimbic pathway
    • Increases craving for palatable food
24
Q

Describe the role of Leptin and Ghrelin in food-induced activation of the mesolimbic system

A

Leptin

  1. Binds Leptin receptors on VTA neurons
  2. Inhibits activity of VTA neurons
  3. Decreased ‘reward’ signal from palatable food

Ghrelin

  1. Binds Ghrelin receptors on VTA neurons
  2. Increases activity
  3. Increased ‘reward’ signal from food
25
Q

Which is the most important acutely acting satiety signals?

A

CCK

26
Q

Where do the following hormones act:

  • CCK
  • Ghrelin
  • Leptin
A

CCK:

  • **CCKA **receptors on vagal nerve
  • (ie locally acting)

**Ghrelin: **

  • Receptors (GHSR-1a) on the hypothalamus

Leptin:

  • Leptin receptors in the hypothalamus (ARC)
    • NPY/​AGRP & POMC neurons
27
Q

Which is the more important cause of genetic obesity?

A
  • Mutation in a-MSH
  • Accounts for 4% of obesity cases
28
Q

Which molecules act on MC4R?

A
  • Endogenous agonist: α-MSH
  • Endogenous antagonist: AGRP
29
Q

Why is there increased motivation to consume palatable food?

A

Because consumption of this food results in enhanced release of dopamine in the NAc

30
Q

Compare motivation to eat palatable food in non-obese and obese individuals

A

Study

  • Obese women had increased activation of the mesolimbic dopaminergic pathway than non-obese women when shown images of palatable food
  • However, it is not known whether this is **cause **or effect