Lecture 31: Neurocircuitry of Metabolism 3 Flashcards
What happens when a db/db mouse is connected to an ob/ob mouse?
the satiety factor in db/db mice acts on the factor receptor in the ob/ob mice causing them to lose weight and starve
What is the difference between db/db mice and ob/ob mice?
db/db mice do not produce the satiety factor’s receptor and are obese but they do produce the satiety factor
ob/ob mice do not produce the satiety factor but do produce the receptor
What is leptin?
a cytokine that is secreted from adipocytes and is encoded by the ob gene
What is the amount of leptin in the blood proportional to?
the amount of fat in the body
How does leptin regulate adiposity?
by communicating levels of adiposity to the brain
What is the leptin receptor encoded by? Which classes of isoforms are expressed?
the db gene
long, short and secretory
Where is the long, fully active isoform of LepR expressed?
mainly in the hypothalamus
What happens when leptin binds to the LepR?
this activates the Signal Transducer and Activator of Transcription 3 (STAT3) intracellular signalling pathway
What does leptin signalling result in?
the phosphorylation of STAT3 (pSTAT3), which is then translocated to the nucleus where it can regulate gene transcription
How does leptin influence AgRP and POMC neurons?
leptin inhibits AgRP neurons and activates POMC neurons
Where are leptin receptors expressed?
in AgRP and POMC neurons of the ARC as well as in neurons of the VMH
What does conditional deletion of LepR in AgRP neurons result in?
increased BW and adiposity
What does conditional deletion of LepR in POMC neurons result in?
increased BW and adiposity
What is insulin?
a peptide hormone secreted from beta-cells
in the pancreas in response to food intake
What does insulin signal muscle and fat to do?
to uptake glucose from the blood
What does insulin signal the liver to do?
to stop endogenous glucose production
Which receptor does insulin act on?
the insulin receptor (IR) encoded by the Insr gene
Which receptor family is the insulin receptor a member of?
the ligand-activated receptor and tyrosine kinase family of transmembrane receptors
What is the structure of the insulin receptor?
the single transmembrane polypeptide crosses the cell membrane once
the intracellular part of the receptor contains a tyrosine kinase domain
What happens when the insulin receptor is activated?
becomes phosphorylated and signals via the protein kinase B (Akt) pathway to modulate gene transcription and neuronal excitability
Where are insulin receptors expressed?
in AgRP and POMC neurons of the ARC as well as in neurons of the VMH
What does conditional deletion of the insulin receptor in AgRP / POMC neurons have profound effects upon?
body weight, ad`iposity and glucose homeostasis
What does exogenous insulin almost exclusively signal to?
AgRP and POMC neurons of the ARC
What is endogenous insulin?
the insulin after a meal which activates AgRP neurons
What is ghrelin?
a peptide hormone produced by ghrelinergic cells in the gastrointestinal tract
What is ghrelin encoded by and what is it produced from?
encoded by the Ghrl gene and is produced from the cleavage of the prepropeptide ghrelin
When is ghrelin secreted?
when the stomach is empty
when the stomach is stretched, secretion stops
How does ghrelin act on the brain?
travels via the blood where it crosses the BBB to interacts with neurons in the hypothalamus
Which receptor does ghrelin act upon and what is this receptor encoded by?
the ghrelin receptor (GPCR) which is encoded by the Ghs-r1 gene
Where is the ghrelin receptor expressed?
in AgRP neurons of the ARC (activates AgRP neurons in the ARC)
What does genetic deletion of ghrelin receptor in the brain result in?
weight loss and hypophagia
Deletion of the ____ receptor results in weight loss, whereas deletion of the ____ receptor results in weight gain.
ghrelin, insulin
What are circumventricular organs?
structures in the brain characterized by their extensive and highly permeable microvasculature, unlike those in the rest of the brain where there exists a blood brain barrier (BBB)
What do circumventricular organs allow for?
the linkage between the central nervous system and peripheral blood
Where is the median eminence located?
in the inferior portion of the hypothalamus and is ventral to the third ventricle
What is the role of the median eminence?
is rich in fenestrated capillaries and, therefore, allows the passage of factors (hormones, micronutrients) from the blood
What is the major cell type that makes up the median eminence?
specialised cells known as tanycytes
What do tanycytes exhibit when interacting with BBB vessles?
a diffuse pattern of tight junction complexes
What pattern do tanycytes display when interacting with fenestrated vessels?
a honeycomb pattern
How is ghrelin able to cross the BBB?
requires diffusion across the BBB to enter the ARC whereas leptin and insulin are less restrained
What is fasting-induced blood-ARC interface reorganisation associated with?
expansion of the ‘brain window’ so that it is accessible to bloodborne molecules
How does fasting influence the blood-ARC interface plasticity?
fasting induces the increase of VEGF expression in tanycytes and induces fenestration of microvessels
What is blood-ARC interface plasticity based on?
cell-cell communication
What is the purpose of glucose sensing in tanycytes?
closes the “brain window” (as this evokes a Ca2+ wave in the tanycyte layer)
What is the level of hormonal input into the ARC coordinated by?
nutritional status
You have just discovered a novel ghrelin receptor antagonist to treat obesity. What time of day would you recommend it to be administered for it to be most effective?
1h before meals
