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biochem term 2 quiz 4 > signaling pathways for energy balance > Flashcards

signaling pathways for energy balance Flashcards

1
Q

what is the key region of the brain for metabolic control?

A

the arcuate nucleus of the hypothalamus

particularly true for control of appetite

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2
Q

where do signals to the arcuate nucleus come from? how does it exert control?

A

receives hormonal input from the periphery in the form of insulin, leptin, ghrelin and others
signals to the periphery in turn to exert metabolic control

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3
Q

what are the types of neurons in the arcuate nucleus? what does each type do to appetite? What NT do they release and what is the receptor for the NT?

A

POMC neurons = anorexigenic (appetite-suppressing) - release alpha-MSH (melanocyte-stimulating hormone) to activate downstream neurons that express MC4 receptor

NPY neurons = orexigenic (appetite-stimulating) - release several NT, including NPY

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4
Q

how do NPY neurons inhibit appetite?

A

1: by inhibiting downstream neurons that the POMC neurons activate
2: by inhibiting POMC neurons

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5
Q

how do fuel sources affect activation of appetite?

A

POMC neurons can be activated by glucose

NPY neurons can be activated by FA

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6
Q

how do pancreatic beta cells sense glucose? (review)

A

1: glucose enters cell via GLUT2 channel
2: glucokinase phosporylates glucose to glucose-6-phosphate
3: glucose metabolized through glycolysis - citric acid cycle begins
4: electron transport chain in mitochondria generates ATP from the NADH and FADH2 generated by citric acid cycle
5: ATP can inhibit plasma membrane K channel => membrane depolarization
6: depolarization activates V-G Ca channel => Ca enters cell
7: Ca entry triggers secretion of insulin via fusion of vesicles with plasma membrane

in step 3, the amount of glucose-6-phosphate made depends on the amount of glucose present (since the Km of the kinase is in the physiological range, it should be able to convert all the glucose that comes into the cell), and the GLUT2 transporter is not regulated, so the amount of glucose entering the cell should always be directly proportional to the amount in the blood

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7
Q

How do POMC neurons sense glucose levels?

A

use part of pathway that pancreatic beta cells use - part where ATP inhibits K channel
inhibition => depolarization of plasma membrane => action potential

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8
Q

what are potassium, sodium, and calcium levels inside and outside of cells?

A

K: high in cytoplasm (>100 mM) and low in cells (100 mM)

Ca: very low in cytoplasm (<100 nM) and high extracellularly (1-2 mM) plus lots of Ca in ER

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9
Q

how do NPY neurons sense FA levels?

A

despite that brain doesn’t synthesize or oxidize FA, NPY neurons have enzymes from the FA synthesis/oxidation pathways including CAT-1, ACC, FAS, and AMPK
interplay between ACC and CAT-1 regulates NPY activity:
- low CAT-1 activity is anorexigenic => decreased NPY activity
- high CAT-1 activity is orexigenic => increased NPY activty

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10
Q

what does it mean for something to be anorexigenic?

A

it decreases appetite and increases energy utilization

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11
Q

what does it mean for something to be orexigenic?

A

it increases appetite and decreases energy utilization

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12
Q

what does CAT-1 do? (review)

A

converts Acyl-CoA to carnitine-CoA

first step in FA transport into mitochondiral matrix for oxidation

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13
Q

what does ACC do? (review)

A

produces malonyl-CoA
key step in FA synthesis
the malonyl-CoA inhibits CAT-1 activity => inhibited FA oxidation

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14
Q

what does FAS do? (review)

A

uses malonyl-CoA to synthesize FA
high activity depletes malonyl-CoA => increased CAT-1 activity (since malonyl-CoA inhibits CAT-1) => increased FA oxidation

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15
Q

what does AMPK do? (review)

A

can phosphorylate ACC => reduced ACC activity => decreased malonyl-CoA levels => increased CAT-1 activity => increased FA oxidation

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16
Q

how do neuronal ACC inhibitors affect appetite?

A

increase neuronal CAT-1 activity

increases appetite

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17
Q

how do neuronal FAS inhibitors affect appetite?

A

decrease neuronal CAT-1 activity

decreases appetite

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18
Q

how do neuronal CAT-1 inhibitors affect appetite?

A

decrease neuronal CAT-1 activity

decreases appetite

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19
Q

how do neuronal AMPK activators affect appetite?

A

increase neuronal CAT-1 activity

increases appetite

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20
Q

what is leptin? what cells secrete it?

A

peptide hormone secreted by adipose tissue

21
Q

how do leptin levels relate to fat?

A

blood leptin levels are proportional to adipose tissue mass

22
Q

where does leptin act?

A

on the arcuate nucleus of the hypothalamus

23
Q

what is the action of leptin on arcuate nucleus neurons?

A

inhibits NPY neurons

activates POMC neurons

24
Q

what are the affects of leptin on neuronal circuitry?

A

appears to affect two aspects:

1: direct neural signaling in the short-term
2: neuronal wiring patterns in the long-term - creates more stimulatory POMC synapses and less stimulatory NPY synapses

25
Q

what is the end result of leptin activity?

A 
decreased appetite (anorexigenic) and increased energy expenditure
keeps amount of adipose tissue within a certain range
26
Q

what happens in individuals that don’t produce leptin? can this be treated?

A

this is rare, but does happen
will result in morbid obesity
but can be treated with leptin

27
Q

what mutations can occur in the leptin pathway (beside not producing leptin)?

A

mutations in:

1: leptin receptor
2: alpha-MSH (the NT released from POMC neurons)
3: MC4R (major alpha-MSH receptor on neurons down-stream of POMC neurons)

28
Q

what are the blood levels of leptin in most people with obesity?

A

most have higher than normal blood leptin levels

29
Q

how does leptin’s creation of a set-point affect the ability of diets to be effective?

A

dieting causes loss of adipose tissue => decrease in leptin levels => increased NPY and decreased POMC neuron activity => hunger
plus longer-term wiring patterns in brain still geared toward heavier set point
dieter therefore fighting against strong biological desire to eat more and strong biological desire to reduce energy expenditure

30
Q

what type of hormone is ghrelin and what organ secretes it?

A

peptide hormone secreted by the stomach

31
Q

how is ghrelin secretion related to the amount that you eat?

A

secretion is inversely proportional to stomach distension (empty stomach means lots of ghrelin)

32
Q

how does ghrelin affect appetite?

A

activates NPY neurons of hypothalamus (as opposed to leptin, which inhibits them)

33
Q

how do gastric bypass surgeries affect ghrelin levels?

A

they can reduce ghrelin levels but more than 70%

34
Q

what is the major endocannabinoid? what are they made from?

A

major ones = anandamide
made from specific low-abundance phospholipids
anandamide contains arachidonic acid

35
Q

what kind of hormone are endocannabinoids?

A

paracrine

36
Q

how do endocanabinoids affect appetite? (receptor, effect)

A

binds to cannabinoid type 1 receptor (CB1R) in hypothalamus

has strong orexigenic effect (appetite-inducing)

37
Q

how has the endocannabinoid pathway been used in drug development?

A

Rimonablant (Acomplia) is a CB1R antagonist
approved in europe but not FDA approved
appetite suppressant
may have psychological side effects

38
Q

what does PPAR stand for?

A

peroxisome proliferator-activated receptor because first known effect was to cause peroxisome amplification in liver

39
Q

what cellular process do PPAR proteins affect?

A

transcription factors

40
Q

how do PPAR proteins interact with retinoic acid receptors (RXR)?

A

they form heterodimers

41
Q

what are the ligands for PPARs?

A

FA or their metabolites thought to be endogenous ligands

variety of fatty compounds can activate

42
Q

what are the two isoforms of PPARs?

A

alpha and beta

both targets clinically

43
Q

where is the PPAR-alpha isoform found?

A

in liver, heart, and skeletal muscle

note: these are all tissues that burn fat well

44
Q

what is the action of PPAR-alpha? what is the mechanism behind this action?

A

activates FA oxidation by increasing transcription of proteins involved in beta-oxidation and proteins involved in FA import to mitochondrial matrix (CAT1, CAT2)

45
Q

how are PPAR-alpha proteins targeted clinically?

A

tehy bind to the fibrate family of synthetic ligands
use these to therapeutically lower blood lipid levels
fibrates increase FA utilization

46
Q

where is the PPAR-gamma isoform found?

A

in adipose tissue

47
Q

what does the PPAR-gamma isoform do?

A 
activates adipogenesis (creation of new adipocytes)
activates increased FA up-take into adipocytes
48
Q

how is PPAR-gamma targeted clinically?

A

binds to thiazolidinedione (TZD) family of synthetic ligands
TZDs can be used as insulin sensitizers - likely through indirect mechanism
but can cause weight gain as side effect
avandia = commercially available - has significant side effects (cardiovascular problems, osteoporosis)

biochem term 2 quiz 4 (7 decks)

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