endrocrine - ghrelin, obesity, prader-willi

Question 1

what the main phenotypic features of PWS?

Answer 1

hyperphagia because of hyperghrelinameia
GH deficient = short stature
cognative disability

obesity after puberty
hypotonia

Question 2

can PWS symptoms improve?

Answer 2

on the clinician scale, a score of 4 shows an improvement of appetite control by 20-30yrs

however no every PWS individual reaches this phase

Question 3

what is the basic genetic basis of PWS?

Answer 3

imprinting disorder so abberent methylation results in repression of paternal alleles (which are normally monoallelically expressed)

Question 4

where is the PWS locus?

Answer 4

region of chromosome 15q11-13 in humans

and chromosome 7 PWS locus equivalent in mice

Question 5

how does the PWS locus differ from normal in disease?

Answer 5

there can be deletion of paternal locus

mutation of paternal locus

can lead to expression of maternal allele (UPD)

Question 6

which is the main genetic issue of PWS?
A uniparental paternal disomy
B imprinting centre defects
C deletions
D loss of paternal expression

Answer 6

deletions within locus account for 70% of causes of PWS

majority is de novo deletion of paternal 15q11-13
1% from chromosome rearrangement

Question 7

describe a normal PWS locus
> alleles

Answer 7

at the locus, under the action of the imprinting centre,
the maternal allele is silenced and paternal is expressed

Question 8

why is UPD of maternal disomy bad on PWS locus?

Answer 8

because the imprinting centre is acting to SILENCE maternal allele

therefore no expression of genes at PWS locus

Question 9

what is the issue with many of mouse models of full PWS?

Answer 9

often the deletion of PWS locus results in embryonic lethality

prevents PHENOTYPE of mice to be studied?

Question 10

how can we study phenotype of PWS?

Answer 10

create mouse models deleting specific genes only

Question 11

what genes can we delete in PWS?

Answer 11

necdin and magel2 (polypeptides)

also snoRNA genes

Question 12

what could be a possible reason behind the low birthweight and reduced growth curve seen in mice models of full PWS?

Answer 12

the inability to suckle properly could be responsible for the low growth curve

it has been shown that mutant mice with good suckling mothers had increased survival

Question 13

why do mouse models of PWS not appear obese?

Answer 13

because mice have larger SA:V than humans
they will have increase in thermogenesis so fat depots are smaller

More utilisation of brown fat and beiging of white fat so more energy used

Question 14

what has mouse models told us about PWS?

Answer 14

given insight into thermogenesis, metabolism and bone fracture risk

Question 15

why is fracture risk high in PWS patients? (molecularly)

Answer 15

adipocytes and osteoblasts derive from same progenitor cells

PWS, less bone marrow fat storage so no. of osteoblasts increases (calcified tissue increases) making the bone
weaker

Question 16

what is the relationship between adipocytes and osteoblasts?

Answer 16

they are derived from same progenitor cell

they have an inverse relationship with each other

a fatty bone would have less osteoblasts so the bone is weaker

Question 17

what do osteoblasts do?

Answer 17

cells that form and deposit bone matrix
able to form new bone tissue

Question 18

Which of the following hormone(s) causes a decrease in fat mass?
A Insulin
B Oestrogen
C Leptin
D Adiponectin
E Growth hormone

Answer 18

GH + LEPTIN

GH - increase lipolysis and increases protein synthesis so we get increased muscle mass
Letpin is an adipokine released from fat cells and is a SATIETY SIGNAL, will pressures appetite by exciting POMC/CART neurons

inuslin, oestrogen and adiponectin will increase lipid storage

Question 19

how does ghrelin affect body mass

Answer 19

can stimulate adipogenesis/lipoplysis in the bone marrow and intraabdominal fat

so only specific fat depots are increased, not all
HUNGER SIGNAL released from stomach in response go undernutrition`

Question 20

where can brown fat be found? what it do?

Answer 20

brown fat found in intrascapluar region, around neck
perirenal and pericardial
around blood vessels too

involved in diet induced + non-shivering thermogenesis

Question 21

why is is called brown adipose tissue?

Answer 21

BROWN as its full of mitochondria
» needed for nonshivering thermogenesis to regulate body temperature

> very profound in newborn

Question 22

where are GLUT4 receptors found? how do they get activated?

Answer 22

so as we eat, our BSL increase
this stimulates insulin release to increase expression of GLUT4 transporters on adipocyte and skeletal tissue (myocytes)
uptakes glucose by facilitaed diffusion

FED STATE of the starve-feed daily cycle

Question 23

describe the link between adiponectin and diabetes

Answer 23

normal function of adiponectin is to increase glucose uptake by activating signal transduction cascades invovled in glygogenesis, lipogenesis, decrease gluconeogenesis

low adiponectin associated with increase in fat mass
so predisposes to type2 diabetes as increases INSULIN RESISTANCE risk

Question 24

describe link between obesity and diabetes

Answer 24

obesity involves ectopic storage of fat in liver and Skeletal muscle, this can activate inflammatory pathways

there is chronic low level inflammation and a high LDL and low adiponectin which can promote insulin resistance

Question 25

Maybe link to oscillations

why is growth hormone secreted in pulses whilst other hormones like TSH and GnRH have regular secretion?

Answer 25

GH is under both positive and negative control
(GHRH, ghrelin and somastatin) so this will lead to pulses of secretion

the other hormones are under primary single positive control so there will be regular release of the hormone

Question 26

for GH experiemtns, we can take ‘automated serial blood samples’ to track hormone levels. why can’t we just take one sample?

Answer 26

GH is secreted in pulses so we are unable to be certain if our single measurement represents peak or trough levels of GH so serial samples can help to track GH levels over a certain time period.

A single measurement would not be able to determine if that was a peak or low GH level

Question 27

why does GH have so many effects on the body? (pleiotrophic actions

Answer 27

because GH- receptors are widely distributed in body and present in many tissue
> liver, chondrocytes, adipose, bone, cartilage
- brain, skeletal muscle. kidney

Question 28

how does patterns of GH release affect lipolysis?

Answer 28

it seems that pulses of GH is more effective than continuous secretion at creating the lipolytic effect as there is an increase in glycerol release// an indicator of lipolysis

Interestly IGF1 release. Is increased in continuous exposure

Question 29

which of these are anorexogenic signals
NPY
POMC
GABA
AgRP

Answer 29

anoregenic is a satiety signal, it will mean you are full and inhibit appetite

POMC/CART is the anorexogenic signal. these neurons project from the arcuate nucleus to the PVN

Question 30

what are PPARgamma and C/EPB alpha

Answer 30

markers of adipogenesis// increase in number of fat cells within adipose tissue

Genes of terminal adipocyte differentiation

Question 31

why is thermogenesis more important in small rodents

Answer 31

they have a larger SA:V so will lose heat more easily compared to larger organisms so there is a greater need to thermoregulate and possesss brown or beige adipose tissue

Question 32

how does thermogenesis (either diet induced or nonshivering) affect the WAT depots?

Answer 32

can decrease the size of the fat depots!

Question 33

how does diet induced thermogenesis occur?

Answer 33

as we eat, satiety signals are relayed to the hypothalamus
this then prompts the SNS to be activated and release the neurotransmitter noradrenaline which acts on B3 adrenergic receptor present on BAT
this promotes lipolysis of BAT allowing the mitch to use this energy to create heat!

Question 34

why does physical activity burn more energy than it needs to

Answer 34

so energy is being used to generate heat from muscle contraction

but ALSO WAT is being converted to beige adipose tissue too (irisin) // browning of WAT
> mediated by hormone irisin which expression is induced during exercise

Question 35

what an adipokine?

Answer 35

cytokine released by adipose tissue to regulate energy metabolism
> leptin, adiponectin, resistin