Hypothalamus, Leptin Signalling and Resistance Flashcards
What neurons does the melanocortin circuit comprise?
First order neurons:
Neuropeptide Y, AGRP, POMC
Roles of leptin in whole body homeostasis
Feeding - eating
Anorexia - starvation
Hedonic feeding - motivation to eat
Energy expenditure - thermoregulation
Glucose homeostasis - insulin sensitivity
True or false:
ARC neurons/circuits are crucial for fat (energy) and glucose homeostasis
True
What hormones are involved in surveillance of total body energy stores?
Leptin and Insulin by targeting the ARC neurons
Leptin and insulin are increased/decreased in the fasted state
Decreased
Leads to activation of NPY/AGRP and inhibits POMC
Leptin and insulin are increased/decreased in the fed state
Increased
Leads to inhibition of NPY/AGRP and activates POMC
What does ghrelin act in opposition to?
Acts in opposition to leptin/insulin in the ARC
What secretes ghrelin?
Endocrine cells lining the stomach
What is the enzyme that makes ghrelin active?
GOAT - ghrelin-O-acetyltransferase
Are ghrelin levels high before or after a meal?
Before, they rapidly fall after eating.
Is ghrelin the direct cause of obesity?
No
What are the results of chronic ghrelin infusion to the CNS?
Increased lipogenesis, decreased lipid oxidation
Increases blood glucose and decreases insulin secretion
DIO increases/reduces ghrelin secretion, plasma ghrelin, GOAD mRNA and transport across the BBB
Reduces
What becomes resistant to ghrelin during obesity?
The hypothalamic circuitry (ARC: NPY/ARGP neurons) that controls food intake
True or false:
Ghrelin levels normalise quickly when weight loss is achieved
False
They take a very long time to normalise
What is the physiological role of ghrelin?
To defend the body weight and glucose homeostasis during times of food shortage to prevent weight loss
What does LEAP2 do?
Blocks the effects of ghrelin in a dose dependent manner
Does fasting reduce or increase LEAP2 levels?
Reduces
Re-feeding increases
In obesity there is higher/lower LEAP2 and higher/lower ghrelin
There is higher LEAP2 and lower ghrelin
Leptin, insulin and ghrelin activate signalling pathways to trigger responses by what?
Transcription of neuropeptides
Electrical activity
Synaptic plasticity
Key signalling pathways in energy and glucose homeostasis
JAK-STAT
PI3K-FoxO1
AMPK
Shp-MAPK
True or false:
Leptin receptors do not have intrinsic tyrosine kinase
True
Describe the structure of leptin receptors
Single transmembrane domain cytokine-like protein
Has to have a dimer
End-terminal domain
What happens when leptin binds to the leptin receptor?
You get dimerisation
What allows association of JAK2 to leptin?
Leptin binds to LEP-Rb which is a dimer that allows the association of JAK2
What does JAK2 do?
Elicits autophosphorylation and transactivation of kinase
Rapidly phosphorylates tyrosine residues
What does activated JAK2 phosphorylate?
STAT3 which then dissociates from LEP-R
What happens when there is CNS specific interruption of STAT3 signalling?
There is induction of hyperphagia, diabetes, obesity and infertility
What is the docking site for STAT5?
pY1077
Does Y1077-STAT5 play a major role in food intake and energy expenditure?
No, it plays a minor role
By what system does insulin activate downstream signalling kinases?
PI3 kinase sytem
As well as insulin, what other hormone couples to the PI3K system?
Leptin
What does FOX-O1 do?
Mediates many of the metabolic actions of insulin
Increased/reduced FOX-O1 activity in POMC neurons and hypothalamus increases food intake and body weight
Increased activity increases food intake and body weight, reduced activity reduces food intake and body weight
True or false:
Monogenic causes of obesity are common
False - monogenic causes are rare
True or false:
Humans without detectable leptin exist
True, although it is more common to have individuals with reduced leptin levels
Genes associated with obesity
Mutations in MC4-R and POMC
Rare mutations in leptin signalling
Is the flow of information between the brain and the body unidirectional or bidirectional
Bidirectional
What signals control meal size?
Satiety signals - information from upper GI tract via vagus and sympathetic afferents
What 3 factors underlie regulation of food intake?
Satiety signalling
Adiposity negative feedback signalling
Food reward
What is satiation?
Sense of fullness generated during a meal
What is satiety?
The period of time between termination of one meal and the start of the next
What are PYY3-36 produced from and what do they do?
Produced from L-cells of gut
Inhibits gastric motility and reduces food intake
What is GLP-1 released from and what is its function?
Released from L-cells
Inhibits gastric emptying and reduces food intake
Where does OXM come from and what does it do?
Comes from oxyntic cells in stomach and suppresses appetite
How is leptin transported into the brain?
Via the BBB
The more fat you have, the more/less leptin you have
The more leptin you have
Fasting increases/decreases plasma leptin?
Decreases
CNS/PNS is the main leptin target?
CNS
If you inject leptin intracerebrovascularly what is the effect on food intake?
Decreases food intake
Obese humans have high levels of leptin, what does this tell us about leptin?
That leptin stops working
What is lipodystrophy?
Rare disorder in which individuals have few or no fat cells and store lipids elsewhere, and have high levels of lipids in the blood
Is lipodystrophy congenital or acquired?
Can be either
Patients with what virus are more prone to lipodystrophy?
HIV
Fasting increases what neuronal mRNAs and decreases what neuronal mRNAs?
Why is this?
Increases NPY/AgRP mRNA and decreases POMC/CART mRNA
You want the drive to eat to be increased and the drive to stop eating to be decreased
Why do you need to stick to a diet for a period of time for it to work?
For the changes in the synapses to occur
What does deletion of the brain insulin receptor result in?
An obese state
What is the effect on injected or infused insulin icv?
Inhibits food intake and reduces body weight
Effects of insulin delivery to the hypothalamus
Modulates hypothalamic neuronal activity
Improves whole body insulin sensitivity
Promotes lipogenesis and peripheral fat accumulation
Increases adaptive theromogenesis
Insulin resistant individuals have a lower/higher CSF:plasma insulin ratio compared to insulin sensitive subjects?
Lower ratio
How does insulin reduce hepatic glucose production?
By acting in the ARC to inhibit gluconeogenesis
