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?

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

Describe cholecystokinin (CCK) Source Action Release

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

Describe Ghrelin Source Release Action

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

Describe Leptin Source Release Action

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

Describe NPY Source Release Action

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

Describe POMC Receptors Release Action

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

Describe α-MSH Source Release Action

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

Describe AGRP Source Release Action

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

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

Lecture 32 - Feeding & Weight Control Flashcards by Eleanor Nicklason

Outline the metabolic syndrome

Obesity →

Hypertension
Dyslipidaemia
Insulin resistance

How well did you know this?

Not at all

Perfectly

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

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
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

How well did you know this?

Not at all

Perfectly

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?

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

How well did you know this?

Not at all

Perfectly

Describe cholecystokinin (CCK)

Source
Action
Release

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

How well did you know this?

Not at all

Perfectly

Describe Ghrelin

Source
Release
Action

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

How well did you know this?

Not at all

Perfectly

Describe Leptin

Source
Release
Action

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

How well did you know this?

Not at all

Perfectly

Compare circulating levels of Ghrelin and Leptin

Ghrelin: inversely proportional to BMI & weight

Leptin: proportional to BMI & weight

How well did you know this?

Not at all

Perfectly

What is the role of Leptin in obesity?

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

How well did you know this?

Not at all

Perfectly

Compare the sources of Leptin & Ghrelin

Leptin: adipocytes

Ghrelin: stomach

How well did you know this?

Not at all

Perfectly

Describe how Leptin regulates energy balance

Leptin released from white adipose cells
Leptin crosses BBB and binds to Leptin receptors on the hypothalamus
- Stimulation of POMC/CART neurons
- Inhibition of: **NPY/AGRP **neurons
Release of neuropeptides:
Control of food intake & energy usage

How well did you know this?

Not at all

Perfectly

Describe NPY

Source
Release
Action

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

How well did you know this?

Not at all

Perfectly

Describe POMC

Receptors
Release
Action

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

How well did you know this?

Not at all

Perfectly

Describe α-MSH

Source
Release
Action

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

How well did you know this?

Not at all

Perfectly

Describe AGRP

Source
Release
Action

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

How well did you know this?

Not at all

Perfectly

What is ARC?

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

How well did you know this?

Not at all

Perfectly

Describe the effect of changed fat mass

Decreased fat mass
Decreased leptin
Decreased inhibition of NPY/AGRP neurons in ARC
Expression of NPY/AGRP
Release of NPY & AGRP in PVN
Effects:
1. Stimulation of feeding behaviour
2. Decreased energy expenditure
3. Inhibition of α-MSH at MC4R
  - Decreased activity of the anorexigenic pathway
Increased body weight
Increased fat mass
Increased Leptin
Leptin crosses BBB to ARC in hypothalamus
Actions:
1. Inhibition of NPY/AGRP neurons
  1. Decreased expression of NPY & AGRP
2. Stimulation of POMC neurons
Expression and release of** α-MSH**
α-MSH acts on MC4R
Increased energy expenditure
Decreased feeding
Reduced bodyweight

What is PVN?

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

Outline factors that affect generation of obesity

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

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

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

Describe the evolutionary factors of obesity

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

Describe the current ‘obesogenic’ environment

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

Describe the neurobiology of consumption of palatable food

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

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

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

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

Leptin

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

Ghrelin

Binds Ghrelin receptors on VTA neurons
Increases activity
Increased ‘reward’ signal from food

Which is the most important acutely acting satiety signals?

CCK

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

**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_

Which is the more important cause of genetic obesity?

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

Which molecules act on MC4R?

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

Why is there increased motivation to consume palatable food?

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

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

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**