endrocrine - ghrelin, obesity, prader-willi Flashcards
what the main phenotypic features of PWS?
hyperphagia because of hyperghrelinameia
GH deficient = short stature
cognative disability
obesity after puberty
hypotonia
can PWS symptoms improve?
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
what is the basic genetic basis of PWS?
imprinting disorder so abberent methylation results in repression of paternal alleles (which are normally monoallelically expressed)
where is the PWS locus?
region of chromosome 15q11-13 in humans
and chromosome 7 PWS locus equivalent in mice
how does the PWS locus differ from normal in disease?
there can be deletion of paternal locus
mutation of paternal locus
can lead to expression of maternal allele (UPD)
which is the main genetic issue of PWS?
A uniparental paternal disomy
B imprinting centre defects
C deletions
D loss of paternal expression
deletions within locus account for 70% of causes of PWS
majority is de novo deletion of paternal 15q11-13
1% from chromosome rearrangement
describe a normal PWS locus
> alleles
at the locus, under the action of the imprinting centre,
the maternal allele is silenced and paternal is expressed
why is UPD of maternal disomy bad on PWS locus?
because the imprinting centre is acting to SILENCE maternal allele
therefore no expression of genes at PWS locus
what is the issue with many of mouse models of full PWS?
often the deletion of PWS locus results in embryonic lethality
prevents PHENOTYPE of mice to be studied?
how can we study phenotype of PWS?
create mouse models deleting specific genes only
what genes can we delete in PWS?
necdin and magel2 (polypeptides)
also snoRNA genes
what could be a possible reason behind the low birthweight and reduced growth curve seen in mice models of full PWS?
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
why do mouse models of PWS not appear obese?
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
what has mouse models told us about PWS?
given insight into thermogenesis, metabolism and bone fracture risk
why is fracture risk high in PWS patients? (molecularly)
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
what is the relationship between adipocytes and osteoblasts?
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
what do osteoblasts do?
cells that form and deposit bone matrix
able to form new bone tissue
Which of the following hormone(s) causes a decrease in fat mass?
A Insulin
B Oestrogen
C Leptin
D Adiponectin
E Growth hormone
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
how does ghrelin affect body mass
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`
where can brown fat be found? what it do?
brown fat found in intrascapluar region, around neck
perirenal and pericardial
around blood vessels too
involved in diet induced + non-shivering thermogenesis
why is is called brown adipose tissue?
BROWN as its full of mitochondria
» needed for nonshivering thermogenesis to regulate body temperature
> very profound in newborn
where are GLUT4 receptors found? how do they get activated?
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
describe the link between adiponectin and diabetes
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
describe link between obesity and diabetes
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
Maybe link to oscillations
why is growth hormone secreted in pulses whilst other hormones like TSH and GnRH have regular secretion?
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
for GH experiemtns, we can take ‘automated serial blood samples’ to track hormone levels. why can’t we just take one sample?
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
why does GH have so many effects on the body? (pleiotrophic actions
because GH- receptors are widely distributed in body and present in many tissue
> liver, chondrocytes, adipose, bone, cartilage
- brain, skeletal muscle. kidney
how does patterns of GH release affect lipolysis?
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
which of these are anorexogenic signals
NPY
POMC
GABA
AgRP
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
what are PPARgamma and C/EPB alpha
markers of adipogenesis// increase in number of fat cells within adipose tissue
Genes of terminal adipocyte differentiation
why is thermogenesis more important in small rodents
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
how does thermogenesis (either diet induced or nonshivering) affect the WAT depots?
can decrease the size of the fat depots!
how does diet induced thermogenesis occur?
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!
why does physical activity burn more energy than it needs to
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
what an adipokine?
cytokine released by adipose tissue to regulate energy metabolism
> leptin, adiponectin, resistin
