lecture 32: feeding and weight control

Question 1

What are features of the metabolic syndrome?

Answer 1

• obesity (excess body fat) → hypertension, insulin resistance/glucose intolerance, dyslipidaemia

Question 2

What is homeostatic control of appetite?

Answer 2

• adiposity signals (long-term) leptin and insulin → hypothalamus
• satiety signals (short-term) from liver and stomach via vagus and sympathetic nerves → medulla → hypothalamus
• CCK and ghrelin produced by stomach

Question 3

What are peptides regulating food intake?

Answer 3

• peptides that increase food intake
  
  • brain
    
    • neuropeptide U
    • melanin concentrating hormone
    • agouti-related peptide
    • orexin A and B
    • endocannabinoids
  • periphery
    
    • ghrelin
• peptides that decrease food intake
  
  • brain
    
    • alpha-melanocyte stimulating hormone
    • CART
    • urocortin
    • corticotrophin releasing hormone
    • serotonin
  • periphery
    
    • leptin
    • insulin
    • cholecystokinin
    • amylin

Question 4

What is cholecystokinin (CKK)?

Answer 4

• 33 amino acid peptide produced by gut
• satiety signal acts quickly
• released in response to digestion certain nutrients esp fat
• acts locally on CCK_A receptors on vagus nerve
  
  • transmits information to nucleus tractus solitarius in medulla
  • ascending messages to hypothalamus to terminate meal
  • may also act on CCK receptors in brain to terminate a meal
• antagonism of peripheripheral CCK receptors increases food intake

Question 5

What is ghrelin?

Answer 5

• circulating 28 amino acid peptide (1999)
• predominantly synthesised in the stomach
• plasma levels inversely proportional to BMI
• pre-prandial rise and post-prandial decrease
  
  • meal initiation
• receptors (GHSR-1a) located in hypothalamus

Question 6

What does ghrelin do?

Answer 6

• increases appetite and body weight
• induces adiposity in rodents

Question 7

What is leptin?

Answer 7

• derived from Greek ‘leptos’ meaning thin
• secreted predominantly from fat cells
• plasma levels proportional to BMI and fat
• crosses blood-brain barrier via a saturable process
• receptors located in the hypothalamus
• inhibits food intake via CNS mechanism

Question 8

Could leptin defects be a cause of human obesity?

Answer 8

• leptin deficient mice obese compared to normal leptin counterpart with same access to food
• but only relevant in very small number of patients
• e.g. missense mutation - no leptin made
• mutation in OB-R - no pubertal development

Question 9

What does leptin regulate?

Answer 9

• energy balance
• white adipose cells → leptin → binds to leptin receptors in hypothalamus → neuropeptides → food intake and energy usage
• leptin inhibits NPR/AGRP
• stimulates ARC POMC/CART

Question 10

What is neuropeptide Y (NPY)?

Answer 10

• 36 amino acid peptide, highly conserved
• discovered in 1981 (pig brain)
• member of pancreatic polypeptide family
  
  • peptide YY → GIT
  • pancreatic polypeptide → pancreatic islets
• various actions in CNS and periphery

Question 11

What is the relationship between NPY and body weight?

Answer 11

• stimulates feeding in satiated animals
• chronic administration causes obesity
• hypothalamic action
• Y1, Y2 and Y5 receptors implicated
• reduces energy expenditure
• level changes with feeding status
• level regulated by leptin

Question 12

What is pro-opopmelanocortin (POMC)?

Answer 12

• POMC 131 amino acid precursor protein
• five G-protein coupled melanocortin receptors (MC1-5R)
• within CNS POMC:
  
  • limited to ARC and Nucleus Tractus Solitarius
  • in ARC co-localised with other neuropeptides
• tissue specific post-translational processing
  
  • prohormone convertases (PC1 and PC2)

Question 13

What is alpha-melanocyte stimulating hormone (a-MSH)?

Answer 13

• endogenous agonist - 13 aa peptide
• released in the PVN
• inhibits food intake predominantly via MC4R
  
  • tonic inhibition of food intake
  • a-MSH constantly released act as agonist at MC4R
• increases energy expenditure
• level regulated by feeding status and leptin
• mutation in POMC or MC4R genes results in obesity
• MC4R accounts for ~4% human obesity

Question 14

What is agouti-related peptide (AGRP)?

Answer 14

• 132 aa protein
• within CNS AGRP:
  
  • synthesis limited to ARC
  • co-localised with NPY
• endogenous antagonist at MC4R
• inhibits a-MSH from binding to MC4R
  
  • increases food intake
  • reduces energy expenditure
• level regulated by feeding status and leptin
• over-expression results in obesity

Question 15

What are pathways that lead to increased body weight?

Answer 15

• decreased fat cell mass
• decreased leptin expression
• decreased leptin action in hypothalamus
  
  • POMC neuron
    
    • decreased a-MSH expression and release
  • NPY-AGRP neuron
    
    • increased NPY and AGRP expression
    • increased NPY release and AGRP release
      
      • AGRP blocks a-MSH binding to MC receptors
        
        • decreased activity of melanocortin anorexigenic pathway
      • increased food intake, reduced energy expenditure
        
        • increased body weight

Question 16

What are pathways that lead to reduced body weight?

Answer 16

• increased fat cell mass
• increased leptin expression
• increased leptin action in hypothalamus
  
  • inhibition of NPY/AGRP neuron
    
    • decreased NPY/AGRP release
      
      • AGRP no longer inhibits a-MSH
  • activation of POMC neuron
    
    • increased a-MSH expression and release
      
      • more a-MSH binds and activates MC receptors
        
        • reduced food intake, increaesed energy expenditure
          
          • reduced body weight

Question 17

What are things to remember?

Answer 17

• circulating leptin levels proportional to fat mass
• low leptin (decrease in fat mass):
  
  • NPY and AGRP increased
  • POMC decreased (less a-MSH released)
  • increased body weight
• elevated leptin (increase in fat mass):
  
  • NPY and AGRP decreased
  • POMC increased (more a-MSH released)
  • decreased body weight
• ghrelin increases NPY and AGRP synthesis and release

Question 18

What are factors influencing development of obesity?

Answer 18

• genetic factors
  
  • monogenic/inherited
  • susceptibility genes
• environmental factors
  
  • sleep deprivation
  • food intake
  • physical activity
  • socioeconomic status
  • cultural

Question 19

What is the importance of genetic differences?

Answer 19

• adoption studies - BMI of adopted child more strongly correlated with BMI of biological parent
• twin studies - heritability estimates ranging from 50-90%
  
  • highest for monozygote twins
• more than 250 genes and chromosomal regions associated with obesity
• while certain genes increase the susceptibility to obesity, the prevalence of obesity has almost doubled since 1980 making purely genetic causes unlikely

Question 20

What is the ‘obesogenic’ environment?

Answer 20

• historically availability of food inconsistent and exertion high to obtain
• evolutionary bias to protect against starvation
  
  • energy homeostasis more likely to prevent weight loss than obesity
• decline in physical activity
  
  • decrease in rates of exercise
  • increase in technology to complete activities of daily living, TV, computers
• food portion size - mistake quantity for quality
• consumption of sugar-sweetened beverages
• consumption of palatable energy-dense foods
  
  • high-fat and sugar content
  • high-fat food less poweful satiety response
  • cheaper than vegetables and whole grains

Question 21

What are hedonic (reward) systems involved in appetite?

Answer 21

• bland foods not eaten in excess but palatable foods consumed after energy demands met
  
  • well fed rats choose to suffer pain to have access to palatable foods
  • in some individuals pleasure overrides homeostatic signals
• major contributing factor to obesity epidemic
• mesolimbic dopaminergic (reward) pathway activated in response to palatable food
  
  • ventral tegmental area (VTA) to nucleus accumbens (NAc)
  • important for natural reward
• hedonic value of food influenced by metabolic state
  
  • hunger enhances good-induced activation of mesolimbic pathway
  • hunger increases ‘craving’ for palatable food
  • over feeding can reduce activation of palatable food
• leptin inhibits activity of VTA dopaminergic neurons
  
  • VTA neurons express leptin receptor
  • knockdown leptin receptors on BTA neurons increases food intake and preference for palatable food
• ghrelin stimulates activity of VTA dopaminergic neurons
  
  • VTA neurons express ghrelin receptor
  • increases rewarding value of food

Question 22

summary

Answer 22

• body weight homeostasis extremely complex
• hypothalamus major site for control of appetite and energy expenditure
• hypothalamus receives information from the periphery and other brain regions about energy status
• mesolimbic dopaminergic system important for reward obtained from food