Obesity 2 Flashcards
What is NPY?
a 36aa peptide that stimulates food intake and reduces energy expenditure
What do high a-MSH levels do?
inhibit food intake
When is POMC gene expression increased?
when food intake
What does activation of MC3 and MC4 do?
suppresses food intake with agonists
enhances food intake with antagonists
What is the phenotype of the Ay mouse?
yellow obese hyperglycemic insulin resistant leptin resistant
What does the Ay gene encode?
AGOUTI - the natural antagonist of the MC receptors - (1 for hair colour, 4 for obesity)
What is agouti related protein?
co-expressed with NPY in ARC neurons and are antagonists to MC3 and MC4
causes long lasting increased food intake
What does the fa gene do?
results in leptin insensitivity
What is the mutation in the fa gene?
Q269P
What is the fat mutation?
mutation in CPE which is responsible for cleavage of POMC and thus a-MSH
What does the fat mutation cause?
massive obesity
What is the tubby mutation?
produces truncated protein modelling adult onset obesity
What are the obesity genes in humans?
rarely Ob occassionaly db Loss of function POMC mutations No CPE but PC1 Mutations in MC4
where does Leptin therapy work?
only in those who have no leptin
where does Leptin therapy work?
only in those who have no leptin
What are the two main theories in leptin resistance?
defective transport into the brain
altered signal transduction following binding to receptor
What is significant about the PTP-1B knockout mouse?
resistant to diet induced obesity and diabetes
What is PTP-1B?
an enzyme which curtails leptin and insulin signalling
What does the IRS-2 KO mouse display?
neuronal resistance to leptin and insulin
What is SOCS3?
a suppressor of cytokine signalling
What does SOC3 do?
inhibits JAK-STAT signalling, binds to Ob-Rb and prevents leptin signalling
What is associated with induction of SOCS3 in the hypothalamus?
leptin resistance
How does SOCS3 negatively regulate insulin signalling?
reduced IRS-mediated signalling
What else is considered to be contributors to hypothalamic resistance?
SHP2
Hyperleptinemia
ER stress
Inflammation
What are some previous drugs for treatment of obesity?
Noradrenergics - CV side effects, appetite suppressants
Serotonergics - appetite suppressants on 5-HT system
What was the problem with Sibutramine?
strokes and cardiovascular side effects
How did Orlistat work?
inhibited pancreatic lipase by decreased triglyceride absorption
reduces efficiency of fat absorption in sm. intestine
What is the problem with orlistat?
need supplements, can cause cramping and diarrhoea
What is signifcant about CB1 KO mice?
have decreased appetite and are lean
What is the issue with Rimonabant?
caused sever depression and anxiety and increased risk of suicide
What is Larcaserin?
5HT2c receptor agonist
What is Qsymia?
combination therapy - topiramate with phentermine - dosage reduced for approval
What is Contrave?
combination of opioid antagonist and dopamine uptake inhibiter - CV issues
What is Contrave?
combination of opioid antagonist and dopamine uptake inhibiter - CV issues
What is the most effective obesity treatment?
Bariatric Surgery
Why is Bariatric surgery so effective?
high level of resolution of T2DM
may affect peptide secretions
