Lecture 32 - Feeding & Weight Control

Question 1

Outline the metabolic syndrome

Answer 1

Obesity →

• Hypertension
• Dyslipidaemia
• Insulin resistance

Question 2

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

Answer 2

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

Question 3

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?

Answer 3

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

Question 4

Describe cholecystokinin (CCK)

• Source
• Action
• Release

Answer 4

• 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 CCK_A 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

Question 5

Describe Ghrelin

• Source
• Release
• Action

Answer 5

• 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

Question 6

Describe Leptin

• Source
• Release
• Action

Answer 6

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

Question 7

Compare circulating levels of Ghrelin and Leptin

Answer 7

Ghrelin: inversely proportional to BMI & weight

Leptin: proportional to BMI & weight

Question 8

What is the role of Leptin in obesity?

Answer 8

• 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

Question 9

Compare the sources of Leptin & Ghrelin

Answer 9

Leptin: adipocytes

Ghrelin: stomach

Question 10

Describe how Leptin regulates energy balance

Answer 10

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

Question 11

Describe NPY

• Source
• Release
• Action

Answer 11

• 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

Question 12

Describe POMC

• Receptors
• Release
• Action

Answer 12

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

Question 13

Describe α-MSH

• Source
• Release
• Action

Answer 13

• 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

Question 14

Describe AGRP

• Source
• Release
• Action

Answer 14

• 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

Question 15

What is ARC?

Answer 15

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

Question 16

Describe the effect of changed fat mass

Answer 16

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

Question 17

What is PVN?

Answer 17

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

Question 18

Outline factors that affect generation of obesity

Answer 18

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

Question 19

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

Answer 19

• 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

Question 20

Describe the evolutionary factors of obesity

Answer 20

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

Question 21

Describe the current ‘obesogenic’ environment

Answer 21

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

Question 22

Describe the neurobiology of consumption of palatable food

Answer 22

• 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

Question 23

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

Answer 23

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

Question 24

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

Answer 24

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

Question 25

Which is the most important acutely acting satiety signals?

Answer 25

CCK

Question 26

Where do the following hormones act: * CCK * Ghrelin * Leptin

Answer 26

**CCK:** * **CCK_A **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_

Question 27

Which is the more important cause of genetic obesity?

Answer 27

* Mutation in a-MSH * Accounts for 4% of obesity cases

Question 28

Which molecules act on MC4R?

Answer 28

* Endogenous agonist: α-MSH * Endogenous antagonist: AGRP

Question 29

Why is there increased motivation to consume palatable food?

Answer 29

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

Question 30

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

Answer 30

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**