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A BMS 381 - Developmental neurobiology > Hypothalamus and the control of energy balance > Flashcards

Hypothalamus and the control of energy balance Flashcards

1
Q

When looking at the hypothalamus, what is widely used as an animal model?

How is this model used?

A

The mouse

Manipulate the genome
Dissect out the brain

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2
Q

What did early lesion studies of the mouse brain show?

A

The hypothalamus regulates food intake (to regulate energy balance)

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3
Q

What did lesions of the VMN lead to?
What did lesions of the lateral hypothalamus lead to?

What were the conclusions?

Why can these conclusions not be entirely trusted

A

VMN: Hyperphagia (over eating) and obesity
Lateral hypothalamus: Aphagia and starvation

Conclusion: Hypothalamus contains a ‘feeding centre’ and a ‘satiety center’

Not trusted: Lesion studies lead to damage of other parts of the hypothalamus

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4
Q

What is satiety?

A

Feeling of being full

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5
Q

What is the modern view of energy homeostasis?

What is central to this view?

A

INTEGRATED system:

Complicated sets of neurons in different nuclei of the hypothalamus operate TOGETHER to generate appropriate responses related to the bodies energy STATE/STORAGE

Central to this view:
- Some neurons in the Arc are activated in a ‘fasting’ situation and some in an ‘over-eaten’ situation (eg, feeding and satiety centres are the neurons that respond)

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6
Q

In regards to food intake and energy balance, what does the hypothalamus respond and control? (modern)

A

The ENERGY STATE of the body:

  • How much energy is STORED
  • How much energy is CIRCULATING in the blood
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7
Q

What signals is the hypothalamus sensitive to?

A

ADIPOSITY signals: hormones leptin and insulin (signals for energy)

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8
Q

Where is leptin secreted from?

A

Adipose tissue (fat cells)

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9
Q

Where is insulin secreted from?

A

The pancreas

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10
Q

What neurons detect how much leptin is circulating in the body?

How?

A

Neurons of the Arc

Contain leptin receptors

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11
Q

How do leptin and insulin signal to the hypothalamus?

A

Modulate neuronal activity in the Arc –> transduce hormonal signals into neuronal response

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12
Q

How does leptin from the circulation reach the Arc?

A

Via 2 different types of tanycytes:

  • Leptin to the blood-hypothalamic interface
  • Through tanycytes to the medial eminence
  • Through other tanycytes to the Arc, where leptin binds to neurons with leptin receptors
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13
Q

Where are the tanycytes and where do they project?

A

Line the 3rd ventricle and project to either:

  • Nuclei of the hypothalamus (VMN, Arc)
  • Medial eminence - contact the periphery where the blood-hypothalamic interface is (fenestrated capillaries)
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14
Q

Where do neurons of the Arc project to?

Why?

A 
To other neurons of the hypothalamus:
- PVN
- LMN
- LH 
To elicit local responses

Or to the BRAINSTEM:
- Send neuronal signals back via efferent Vagus nerve to all necessary targets

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15
Q

What do the neurons within the PVN do?

A

Make hormone releasing factors and project back to the medial eminence to the anterior pituitary to regulate hormone release

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16
Q

What does the combined activity of all the neuronal targets that are signalled to by the Arc do?

How?

A

Elicits a FEEDBACK SYSTEM to the body –> to respond to the leptin trigger event

To control food intake and energy expenditure through neuronal and hormonal signals that regulate:

  • BEHAVIOUR
  • AUTONOMIC ACTIVITY
  • METABOLIC RATE
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17
Q

Why is food intake only PART of how energy balance is maintained?

A

Energy balance is involved in behaviours,

Eg. stressed –> don’t eat, staying in bed

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18
Q

What are the key neurons that act the antagonistic situations of ‘fasting’ and ‘over eating’?

A

Leptin responsive neurons in the Arc

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19
Q

What signals do the neurons in the Arc respond to?

A

Short term: hungry vs full

Long term: fasting vs over-eating

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20
Q

What are the 2 classes of neurons in the arc that are responsive to leptin (contain leptin receptors)?

A

1) Pomc

2) NPY

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21
Q

How many Arc nuclei are there in the body?

A

2 - one on either side of the head

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22
Q

Which Arc neurons are ACTIVATED by leptin/adiposity signals?

A

The POMC neurons

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23
Q

Which Arc neurons are INHIBITED by leptin/adiposity signals?

A

The NPY neurons

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24
Q

What do POMC neurons do?

What does this cause?

A

Release POMC:

Projects to neurons via local neuronal circuits and leads the brain to co-ordinate array of neuronal activities that REDUCES food intake and INCREASES energy expenditure (when full)

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25
What is POMC and NPY?
Neurohormones
26
What do NPY neurons do? What does this cause?
Release NPY: Projects to neurons via local neuronal circuits and leads the brain to co-ordinate array of neuronal activities that INCREASES food intake and REDUCES energy expenditure (when hungry)
27
What dictates the energy balance of the body?
BALANCE between the activities of POMC and NPY and their neuronal targets
28
When active, what neurons do the NPY neurons activate/inhibit?
Inhibit the PVN | Activate the LH area
29
When active, what neurons do the POMC neurons activate/inhibit?
Activate the PVN | Inhibit the LH area
30
What is the action of the PVN?
When active - net CATABOLIC ACTION: - Releases CRH and oxytocin - Decreases food intake
31
What is the action of the LH area?
When active - net ANABOLIC ACTION - Releases orexin and MCH - Stimulate food intake
32
What are the NPY neurons also called?
AgRP neurons
33
Describe the overall pathway of energy balance
1) TWO adiposity signals: LEPTIN and INSULIN - produced in the periphery and travel via TANYCYTES (x2) and the medial eminence to the ARC, where they influence NPY and POMC neurons 2) Different classes of Arc neurons are activated/inhibited due to the presence or absence of adiposity signals: POMC - activated by adiposity signals NPY - inhibited by adiposity signals 3) Arc neurons signals to the brainstem and different parts of the HyP (LH and PVN) activating them/inhibiting them to release hormones --> to control energy expenditure and food intake
34
What are the POMC neurons also called?
a-MSH or CART neurons
35
What pathway is the feeding pathway intimately linked with?
The stress pathway
36
What are the melanocortin neurons?
POMC and AgRP (NPY) neurons
37
What specifies the identity of hypothalamic melanocotin neurons? What is this critical for?
Islet 1 (HD transcription factor) Critical for NORMAL food intake and ADIPOSITY in adulthood
38
What is adiposity?
The condition of being severely overweight
39
What does Islet1 do? How is this seen?
Prefigures and predicts the expression of POMC (ATCH) Seen using: 1) An overlay of immunohistochemistry (antibodies) detection of Islet 1 (red) and ATCH (green) - where they are both present - see yellow in the EMBRYO - Shows the nuclei express both Islet 1 and POMC 2) Combination of immunohistochem and a transgenic reporter line (pomc-EGFP) in the ADULT - Show a number of the Islet1 cells are POMC+
40
How is POMC related to ATCH?
ATCH is a peptide produced from the protein POMC
41
Wha antibody recognises POMC neurons?
ATCH antibody
42
What does the TF Islet1 bind to?
Critical homeodomain binding DNA motifs in the neuronal POMC enhancers nPE1 and nPE2
43
How many enhancers drive the expression of the POMC gene? What is needed for the expression of the POMC gene?
2 enhancers: nPE1 and nPE2 Both nPE1 and nPE2 enhancer activity is needed for upregulation
44
How can it be proved that Islet1 is necessary to up regulate POMC?
Mutate the sequences within nPE1 and nPE2 --> see if Isl1 no longer recognises the DNA/no longer binds and poc is no longer upregulated
45
In the study, how were nPE1 and nPE2 mutated? How can the effect of these mutations be visualised?
Using POINT MUTATIONS: | - Transgenic animal with the point mutations in the enhancers and cross with a reporter animal (POMC-EGFP)
46
What is seen in nPE1 and nPE2 mutants and WT?
WT (cross WT with reporter animal): - Use reporter to look for the normal expression pattern of POMC --> normal - Islet1 able to bind and POMC upregulated MUTANTS: - No green - POMC not up regulated due to the failure of Islet1 to bind to enhancers
47
What experiments must be done to answer if Islet1 is REQUIRED for POC neurons? Why use this approach?
Make a CONDITIONAL KNOCK-OUT animal (where sequences encoding ISL1 are absent) Why use this approach: - Islet1 is required for vascular development - KO die very early in embryogenesis (even before Islet1 is expressed in the HyP) - So, KO Islet1 at a later time point or in SPECIFIC tissue (after jobs in development)
48
How can Islet1 be KO in a SPECIFIC STAGE of embryogenesis?
Using a CONDITIONAL KO and TAMOXIFEN
49
What is the process of making a temporal conditional KO?
2 transgenic mice MOUSE 1: - Contains Cre --> when translated and transcribed recognises the loxP sites and cuts them - deleting the gene - Cre fused to ERT2 (mutant estrogen ligand-binding domain that requires the presence of TAMOXIFEN to function --> CreERT (downstream of a general promoter) MOUSE 2: - Contains flanked Islet1 gene - loxP sites either side of exon2 BREED MICE and add tamoxifen at any stage in life --> recombine out exon 2 --> KO Islet1
50
What is the critical exon of Islet1? What occurs if this exon is deleted?
Exon 2 If deleted - aberrant Islet1 mRNA --> degraded/non-functional
51
What does KO of islet 1 at E9.5 and E11.5 show?
Absence of POMC - Islet1 required for POMC
52
What does conditional KO of islet1/Pomc show? Why?
Early onset obesity Normally: - POMC INHIBITS food intake and increases energy expenditure - if not functional --> will not inhibit food intake --> obese
53
How is Islet1 and the development of POMC neurons linked to the development of the hypothalamus?
Islet1+ progenitor cells that give rise to the POMC neurons differentiate from the anterior progenitors that differentiate from the Fgf10 expressing stem/progenitor cells
54
What happens to the Fgf10+ cells in the hypothalamus?
They change over embryogenesis from neuroepithelial cells to radial glial like cells (tanycytes) and are maintained into adulthood as radial-glial like cells (tanycytes) Continue to express Fgf10 SOME Fgf10+ expressing tancytes: - Retain 'stem like/progenitor cell activity' and give rise to Arc neurons throughout life
55
What are is the function of tanycytes that project to the ME and the Arc?
Allow the transport of leptin
56
How do the Arc neurons continue to develop over adult life?
When hypothalamic tancytyes (radial glial like cell with cell body at the ventricle) divide - give rise to: 1) 1 daughter that stays at the ventricle - tanycyte 2) 1 daughter that takes neuronal fate and migrates up the tanycyte scaffold to the Arc - Arc neuron
57
What happens to glucose (energy) requirements throughout life? What does this mean?
They CHANGE Need to alter the optimal set point of glucose in the body
58
How does the hypothalamus change the optimal set points of glucose requirement?
EMERGING IDEA: - NPY and POMC neurons can be generated from the hypothalamic stem cells (some Fgf10+ tanycytes) throughout life to ANTICIPATE and/or RESPOND to the changing needs of the body
59
What is allostasis?
Idea that optimal set points change throughout life
60
What is the working hypothesis about tanycyte stem cells?
Stimulated by metabolites/hormones provided by the components of the HYPOTHALAMIC NICHE --> and RESPOND to these signals --> Giving rise to NEW NEURONS (Respond to changes in energy needs)
61
What is the hypothesis leading to T2D?
Loss of hypothalamic neurons/circuits/ loss of function --> key event that leads to T2D
62
What do REPORTER LINES depend upon?
The fact that genes are DIFFERENTIALLY TRANSCRIBED as a function of the interaction of their PROMOTER/ENHANCER with CELL-SPECIFIC transcription factors/activators
63
How are reporter lines made?
1) Fuse tissue specific promoter to the coding sequence of the gene that fluoresces when shine UV light on them Eg. GFP (eGFP), Kaede - green RFP, tomato - red 2) Make a transgenic animal in which this extra gene is stably incorporated into the genome Mouse - Tg (promoter:flourescent gene)

A BMS 381 - Developmental neurobiology (17 decks)

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