Energy Balance Flashcards
(18 cards)
What experiments have been done that show parts of the hypothalamus contribute to energy balance?
- Contributing to energy balance by regulating food intake
- Lesioning hypothalamus in rats showed its the central coordinator of food intake
- ARCH nucleus lesioned = complicated phenotypes, some starved some overate
- Show that the tuberal hypothalamus is responsible for energy balance via food intake
What is the modern understanding of controlling food intake?
- Set of hypothalamic neurons in various nuclei that operate together to generate an appropriate response related to body’s energy storage
Two sets of neurons:
1. ‘Fasting situation’
2. ‘obese situation’ - Other neurons can respond to acute signals such as ‘hungry’ or ‘full’
- These neurons are in the ARCH nucleus of the tuberal hypothalamus and work antagonistically
Explain the processes of energy homeostasis in the ARCH nucleus regarding leptin and its receptor
Leptin: A hormone secreted by adipose tissue that provides information about the body’s energy stores.
Leptin Receptors: Expressed on two key types of neurons in the ARC: NPY/AgRP neurons and POMC neurons.
Leptin’s Effects:
Inhibits NPY/AgRP neurons: These neurons promote food intake and reduce energy expenditure.
Stimulates POMC neurons: These neurons release α-MSH (alpha-melanocyte-stimulating hormone), which reduces food intake and increases energy expenditure.
NPY/AgRP Neurons:
Release neuropeptide Y (NPY) and agouti-related peptide (AgRP), which activate pathways that drive hunger and conserve energy.
POMC Neurons:
Project to the same downstream neurons targeted by NPY/AgRP neurons.
Their activation by leptin leads to downstream signaling that decreases food intake and increases energy expenditure.
How can we observe the journey from FGF-10 expressing cells to tuberal progenitors and neurons?
- Integrating uMAPs to observe trajectories
Process:
1. expression of FGF-10
2. Follow trajectory to neurogenic progenitors upregulating Delta-like1 (notch)
3. They then regulate AT0H7
4. They then express Islet1
5. Finally upregulate POMC and NPY
How can we ensure this process to neurons is accurate and essential?
-GOF and LOF experiments
- KO mature and immature genes can affect the progression to neurons
In what condition is POMC differentiation altered?
type 2 diabetes
What do progenitor cells in the tuberic neurogenic region become?
precursors of neurons that occupy the ARCH nucleus
Who wrote the paper which hypothesised if islet1 is important for the development of POMC expressing neurons?
Nasif et al, 2015
What did figure 1 of his paper show? (expression)
Technique = immunofluorescence assays using antibodies
Prediction: Iselt 1 is expressed before POMC
- Looked at protein expression
- Found no islet1 expression at E9.5
- At E10 there are some islet1 and no POMC precursor
- Co-expression of both implies that Islet1 expression predicts POMC expression
What did Fig.2 of the paper show? (enhancers)
Hypothesis: Islet1 when translated goes back in to the cell it was produced and upregulates PomC
- Mutated the sequences of the enhancers needed for POMC expression (nPE1 and nPE2) so not recognised by Islet1
- Make a transgenic animal to observe expression
- Control = POMC expression, mutated = no POMC expression
What did Fig.3 show? (KO)
Hypothesis: Islet1 is ESSNEITAL
- KO of islet1 gene itself, relevant in lots of early processes so used a conditional KO
- Temporal conditional deletion using the Cre-Lox system and tamoxifen
- Found no POMC expression in Islet1 KOs
ALSO!! found inducible Islet1 KO does not affect future hypothalamus development apart from POMC
What did Fig.6 show? (phenotypical changes)
- Normal POMC= awareness of when to reduce food intake
- No POMC = body will not get the right signals
- Conditional KO of Isl1/pomc means the mice experience early onset obesity
- Many Labradors have mutations in POMC meaning they are always hungry
How is Islet1’s role found to be generalisable?
Same findings were found across mice and zebrafish, predict this is a process occurring for over 450my in jawed vertebrates
WR: What neurons are referred to as orexigenic and anorexigenic?
orexigenic = NPY- AgRP
anorexigenic = POMC
WR: Where do POMC and NPY neurons project to and what else do they respond to?
Project to neurons in the PVN and respond to ghrelin
WR: Where does AgRP have extra projections to?
feeding related structures in the brain stem such as the parabrachial nucleus of the pons
WR: What typical TFs are seen in the tuberal neurogenic progenitors that charactersie this region?
ATOH7 + Islet1 - characteristic of POMC and ARCH nucleus
WR: What can maternal obesity and overfeeding lead to in offspring mice?
- Reduced levels of neurogenesis and disruption of leptin signalling disrupting the formation of POMC neurons
