Lecture 30: Neurocircuitry of Metabolism 2 Flashcards
What is AgRP synthesised by?
neuropeptide Y (NPY)-containing cell bodies located in the arcuate nucleus in the hypothalamus
What does AgRP or NPY promote when administered intracerebroventricularly?
food intake
How do the levels of AgRP and NPY in AgRP neurons change throughout the day?
increase during fasting and decrease after refeeding (regulated by metabolic status)
How is AgRP mRNA expression change in a fasted state?
elevated
What are AgRP neurons activated by?
energy deficit
What does neuronal activation lead to?
changes in intracellular calcium levels
Why does fasting increase c-Fos expression in AgRP / NPY neurons?
because the gene that codes for c-FOS is among the genes whose activity is altered by calcium levels
What are POMC neurons considered as?
the brakes of metabolism
What does genetic ablation of POMC neurons result in?
weight gain and hyperphagia
What does optogenic or chemogenic (DREADDS) activation of POMC neurons result in?
weight loss and hypophagia
What does the POMC gene encode?
the POMC precursor protein, which produces many biologically active peptides via a series of enzymatic steps in a tissue-specific manner
What does the POMC precursor protein produce?
melanocyte-stimulating hormones (MSHs), corticotropin (ACTH) and beta-endorphin
Where is POMC protein directed?
into secretory granules where post-translational processing yields many peptides by successive, cell-specific, enzymatic modifications
Where does cleavage by the pro-peptide convertases PC1 and PC2 occur?
at specific pairs of basic residues and cleaves alpha-MSH, beta-MSH and gamma-MSH
What does alpha-MSH, beta-MSH and gamma-MSH have in common?
are all agonists at the Melanocortin 4 receptor (MC4R)
What is melanocortin 4 receptor?
a Gs protein-coupled receptor that binds alpha-melanocyte stimulating hormone (alpha-MSH)
What are mutations in the MC4R gene associated with?
genome-wide association studies of BMI confirmed that they are associated with obesity
What does ICV administration of alpha-MSH result in?
weight loss and hypophagia
mice or humans lacking MC4R or alpha-MSH are…
obese and hyperphagic
Where are MC4R receptors heavily expressed?
on cell bodies of the PVH and LH
Where do neurons of the PVH project to and what do these projections govern?
preganglionic neurons in the spinal cord which in turn govern the innervation to peripheral tissues such as liver and fat to regulate energy stores
What do neurons of the LH regulate?
feeding behaviour and motivated behaviours
How does alpha-MSH and AgRP act on MC4R receptors?
alpha-MSH is an agonist at MC4R receptors and AgRP is an antagonist at MC4R receptors
What does POMC promote?
satiety
What happens to POMC in the neuron?
is cleaved producing the neuropeptide, alpha-MSH which is secreted from the neuron and acts as an agonist on MC4R on second order PVH or LH neurons to elicit effects on energy balance
What do defects in the melanocortin system underly?
human obesity
What is AgRP peptide secreted from?
AgRP / NPY neurons and acts as an antagonist at MC4R
What does the melanocortin circuit form?
the basics by which opposing neuronal populations of the ARC can elicit biphasic actions upon energy balance
What is the lipostatic hypothesis?
the brain monitors the amount body fat and acts to “defend” this
energy store against perturbations
What is parabiosis?
the surgical union of two animals to produce a common blood
supply and allows the investigation of bloodborne circulating factors
What happens when a db/db mouse is connected to a lean weight mouse?
db/db overproduces a satiety factor but does not respond to it
lean wt responds to the satiety factor and starves
What happens when a ob/ob mouse is connected to a lean weight mouse?
ob/ob mice respond to the satiety factor produced in the lean wt mice
production of a satiety factor in lean wt mice is not sufficient to cause starvation in ob/ob mice
