L12 - Energy Balance Flashcards
What were the early studies performed to implicated hypothalamus in energy balance
Ealy lessioning stidues
Lesions to the VMN –>
Hyperphagia
Over eating and obestity
Lesions to the LH –>
Aphagia leading to starvation
What were the conclusions of the lesioning experiments
How does this compare to the modern view
Lead to a theory that the hypothalamus contains a feeding centre and a satiety centre
Modern view is that of a mor eintegrated system - complex set of neurons in various nuclei are invovled
Hypothalamus is sensnisitve to ______ signals
What are these
Adiposy signals
Leptin and Insulin
What secretes leptin and insulin
Fat cells and pancrease
Where does leptin and insulin act at the hypothalmus
Arcuate nucelus
How does leptin reach the arcuate nucelus
Through TANYCYTES
Secribe the model of hypothalamuc control of hepatic glucose production
Leptin sensing neurones in ARC recieve input regarading energy sotres - in response input pathways that increase hepatic vagal tone which increases hepatic insulin sensitivity
The ARC neurones elicit local responses by connecting to
What is the effect of this
How do they do this
PVN VMN LH
Feedback to body via hormonal and nerual outputs to control food intake and energy expenditure
Regulating behaivour, autoomic activty nd metabolical rate
How many classes of LepR+ neurones
Two
NPY and Pomc neurones
LepR+ means what
Have leptin receptor
So are able to respond to leptin
Leptin ______ NPY nuerones
Inhibits
Describe NPY function
NPY is a neuropeptide (Y) whose action leads coordination of a vast array of activities to stimulate food intake and reduce energy expenditure
Leptin __________ Pomc neurones
Stimulates
Describe pomc function
POmc neurohormone.
Reduce food intake and increase energy expendityre
When are leptin levels high
When dont need any more food
Two adiposity signals _____________ produced in periphery and travel via ______________ to influence neurones in the ___________
Leptin and insulin
ME and tanycytes
Arcuate nucelus
NPY arcuated neurones ______________ and are ________________ inhibited by ______________
Synthesise and release
Neuropeptide Y
Inhibited by adipositry signals
Pomc arcute neurones sythnesise and release _______________________
a-melanocyte-stimulating-hormone (a-MSH)
NPY (NPY/AgRP) neurones inhibit the _______ and stimulate the _________
INIHIBT PVN
STIMULATE LHA
Pomc (a-MSH/CART) stimulates the _________ and inhibits the _____________
PVN
LHA (inhibit)
PVN has net _________
Causes the release of —— (2)
The net effect is …
Catabolic action
Release oxytocin and CRH
Decreases food intake and increases energy expenditure
LHA has net __________
Causes the release of ………. (2)
The net effect is …… (2)
Anabolic action
Releases orexinA and melanin-concentrating hormone (MCH)
Stimulate food intake and decrease energy expenditure
The paper used in the lecture aimed to …
Understand the genetic program the establishes the neuronal melanocortingergic phenotype and maintains and fully functional neuronal POMC phenotype
title of paper used in lecture
Islet 1 specifies the identity of hypothalamic melanocortin neurones and is critical for normal food intake and adiposity in adulthood
Transcription factor Islet1 __________________
Predicts and prefigures expression of pomc (ACTH)
How was it concluded that islet1 predicts and prefigures expression of pomc (ACTH)
IHC
Combination of IHC and transgenic reporter line (pomc-EGFP) in the adult
Islet two binds
To critical homeodomain binding motifs present in the neuronal Pomc enhancers nPE1 and nPE2
How did they study the binding of Isl1
Mutate sequences with nPE1 and nPE2 show isl1 no longer recognises mutated DNA and no longer binds
So ___- and _____ needed for activity of ___________
nPE1 and nPE2
Pomc transcription
What are the two binding motifs in pomc GENE
nPE1
nPE2
Mutations of nPE1 and nPE2 completely _________________
How was this studied
Prevents the ability of these enahners to drive reported gene expression to hypothalamic pomc neurons in transgenic animals
Reporter line - pomc driving expression of EGFP
How would you determine if Isl1 required for pomc neurons
Isl1 required for formation of many other other structures ealrier
SO need to use a conditonal KO
How was the conditional KO made
Mouse 1 - CreERT
Mouse 2 - Isl1/LoxP mouse
Add tamoxifen at any stage in life to recombine out Exon2 and coditonaly KO ISl1
What was seeen in the conditional KO for Isl1
Pomc neurones fail to differentiate
Why would you need to analyse expression of both Isl1 and ACTH by immunohistochemistry
To make sure that KO of exon 2 resulted in the absence of Isl1 protein
What is the phenotypic effect of KO Isl1
No Pomc
Leads to early onset obesity
…
Pomc a neurohormone – reduce food intake
What is the model fo rthe development of the hypothalamus
Describe it
Sequential anisotropic growth model of hypothalamic development
Anterior and mammary regions grow seqentially and in opposite direction from centrally retained FGF10+ pHyp cels
Islet1 progenitors differentiate from
Anterior progenitors
Isl1+ progenitors give rise to pomc neurones derive from
FGF10+ ‘stem’ pool
FGF10+ cells are retained in _______ as ________
Adulthood
Radial glial cells called tanycytes
What is special about some of the FGF10+ tanycytes
Some retain their stem cell actiivity and can give rise to Arc neurones throughout life
Potentially throughout life Arc neurones are generated from
Hypothalamic stem cells
What is the imolication of the stem cell theory with the idea that glucose requirements can chancge considerably throguhiut life
Pomc and NPY neurones can be generated from hypithalamic stem cells throughout life to anticipate of respond to changes
ALLOSTASIS
What is the working hypothesis regarding hypothalamic stem cells
Stem cells are stimulated by metabolites/horomones provided by components of the hypothalamic niche and can respond by giving rise to new neurones
