21+22 Flashcards
1
Q
What happens to NE injected into paraventricular nucleus (PVN)
A
- increases feeding behavior
- effects mediated by post-syn a2 R (agonist = increase feeding and antagonist = decrease feeding)
2
Q
what is the role of a1 R in PVN
A
- activation = decreases feeding
3
Q
what is the role of a2 R in PVN
A
- activation = inhibit a1(decrease feeding) (net increase)
4
Q
what are the main CNS neuropeptides involved in feeding?
A
- neuropep Y
- POMC peptide (MSHs)
- agouti related peptide (AgRP)
5
Q
what is the role of NPY in feeding (expression/secretion)
A
- NPY = powerful appetite stim
- rats injected with NPY exhibit: increased feeding + weight gain
- expressed in neurons projecting from ARC to PVN
- expression and secretion is increase by food deprivation
- hypoglycemic = increase secretion > increased feeding
6
Q
describe NPY R
A
- GPCR (Y1R-Y6R)
- couples to inhibition of AC
- R1-5 implicated in mediating feeding effects
- Y5 agonist > increase feeding behavior (increase food intake = directly related to agonist affinity)
- inhibition of PVN increases feeding behavior
(basically NPY R expressed at PVN and neuron project from ARC > send NPY to PVN)
7
Q
describe melanocortin R
A
- 5 subtypes cloned
- coupled through Gs to AC
- MC3R/4R expressed in CNS both involved in feeding
8
Q
describe the function of melanocortin R
A
- inhibits feeding
- mice lacking MC4R increase feeding > obese
- inhibition of melanocortin R = stimulate feeding
9
Q
describe the agouti-related peptide (AgRP)
A
- expressed with NPY in neurons of ARC
- endogenous inhibitor of MCRs (3/4)
- agouti mice develop obesity, hyperinsulinemia,
hyperglycemia, hyperphagia, yellow coat color - agouti protein antagonize MCR
10
Q
describe NPY and POMC neurons and expression of serotonergic R
A
- NPY neurons express 5HT 1B R
- inhibit AC > serotonin binding = inhibit neuron act
- POMC neurons express 5HT 2C R
- couples with PLC > serotonin binding increases neuron activity
11
Q
what is lorcaserin
A
5HT 2C agonist > weight lost
12
Q
describe the role of ghrelin in feeding
A
- stim feeding
- synthesized in stomach
- levels increase with food deprivation and decrease w/ food intake
- decrease release of insulin + antagonize effects of leptin
13
Q
describe ghrelin R
A
ghrelin binds to GHS-R1a
- couples to Gq
- expressed in ARC and present on NPY neurons
14
Q
describe effect of ghrelin at R site
A
- activates NPY neurons
- increase release of NPY and AgRP
- induces feeding behavior
- increase transcription of NPY and AgRP
- effects is blocked by NPY antagonist
- thus effects are mediated by NPY
15
Q
what’s evidence for ghrelin’s effects
A
- obese pateints who lost weight dieting > exaggerated peaks of ghrelin before meals
- obese patients with gastric bypass = reduce levels of ghrelin
16
Q
what is prader-willi syndrome
A
- increased ghrelin levels in patients with this syndro
- pt exhibit voracious app
- profoundly obese
17
Q
describe leptin effect on feeding
A
- inhibit feeding
- synthesized in white adipose
- secreted into blood stream
- levels increase with food intake and decrease with food deprv
18
Q
describe the evidence for leptin effect
A
- leptin cloned from obsese mice that do not express functional leptin ob/ob mice
- mice that do not express functional leptin R increase food intake fa/fa zucker rats
19
Q
describe the leptin R
A
- belongs to cytokine superfam of R
- ligand binding > dimerization = signal transduction
- activates the Jak-STAT second mess pathway
- leptin activation of R > tyrosine phos of Jak2
- phos of Jak2 > tyrosine phos of STAT3 (transcription factor)
- phos of STAT3 > dimerize and affect transcription
20
Q
describe leptin effect at R level
A
- leptin effect both NPY and POMC (both expresses leptin R)
- activates POMC neurons > increase release of aMSH
- inhibit NPY neurons > decrease release NPY + decrease levels of NPY in ARC
21
Q
describe the effect of sleep on feeding
A
- subjects with sleep deprivation showed
Leptin decreased 18%
Ghrelin increased 28%
Hunger increased 24% - Especially for calorie-dense foods
22
Q
describe insulin effect on feeding
A
- inhibit feeding
- expressed in pancreas
- increase blood sugar > release insulin
(review insulin release mec)
23
Q
review insulin release mec
A
- glucose enter GLUT2 > ATP increase > ATPsensitive Kch opens > depol > calcium ch open > insulin secretion
- Binding of insulin to its receptor causes
activation of its tyrosine kinase activity (insulin receptor is a tyrosine kinase receptor) - Phosphorylation of insulin receptor activates
signal transduction pathway - Result is translocation of GLUT4 glucose
transporters to cell surface
24
Q
how does insulin effect at R level
A
- decrease feeding by inhibiting neurons that expresses NPY
- synergizes with leptin
- decrease release of NPY
- inhibition of NPY relieves inhibition of POMC
- decrease transcription of NPY
25
how does leptin and insulin work together
- signaling synergize to decrease the release of NPY
- increase opening of K+ channels to cause
hyperpolarization of NPY neurons
- signaling synergize to decrease transcription of NPY and increase transcription of MSHs
- High insulin levels = Phosphorylation of transcription factor FOX01 leads to inhibition
- Decreased transcription of NPY and AgRP = High leptin levels > Phosphorylation of transcription factor STAT3 leads to activation> Increased transcription of MSHs
26
what does FOX01 normally do
- increases the expression of NPY and
AgRP
- Normally decreases the
transcription of POMC
27
what does STAT3 normally do
STAT3 normally increases the expression of POMC > Normally decreases the transcription of NPY and AgRP
28
review slide 51
29
describe how cholecystokinin (CCK) is synthesized and released and how it effects feeding
- synthesized in small intestine and released when food present
- fats and proteins in intestine are potent stim
- CCK cells repond to bitter tastants
- CCK inhibits feeding
30
describe CCK at the R level
- GPCR = CCK1/2
- KO animals w/o CCK R are obese (OLETF rats)
- has peripheral and central actions
31
describe peripheral action of CCK
- inhibits gastric emptying, increase release of bile from liver, stim insulin release by pancreas
- decrease gastric emptying (can synergi with other signals to decrease feeding ie. low doses CCK + gastric distention = satiety)
32
describe central activity of CCK
- increase satiety
- increases expression of NPY Y2R R in ARC (inhibitory)
- activation of Y2R decreases release of NPY > inhibition of NPY neurons release inhibition of POMC neurons > increase POMC activities
33
how does CCK interact with regulatory hormones
- CCK increase release of leptin into bloodstream
- CCK + leptin synergize to decrease feeding
- full satiety signal from CCK is dependent of leptin R in ARC (leptin may increase reponsiveness of NPY/POMC neurons in ARC to CCK signalling)
34
describe how peptide PYY is synthesized and released and how it effects feeding
- expressed in lower small intestine and colon
- released into blood steam in relation of caloric content of meal
- higher secretion when proteins are ingested
- inhibit feeding
35
describe PYY peripheral and central actions
Peripheral activity
- Inhibits gastric emptying
- Inhibits gut motility
- PYY decreases the release of ghrelin
Central activity
- PYY inhibits NPY neurons to decrease feeding
- Binds receptors in arcuate nucleus
36
describe central activity of PYY at R level
- PYY binds NPY Y2R R in ARC (inhib)
- activation of Y2R > decrease release of NPY > inhibition of NPY neurons relieves inhibition of POMC > increase activity of POMC neurons.
37
describe the role of glucagon-like peptide1 in feeding (express/release)
- expressed in small intestine and colon
- released in response to ingestion of food from enteroendocrine cell of small intest
- can be enhanced by concetration of glucose
- mec of release thought to be similar to glucose-mediated release of insulin from pan B cells
- decreases feeding
38
describe GLP1 effects at the R level
- GLP1R is GPCR
- couples to Gs
- expressed in several tissues
GI tract, heart, pancreas
39
describe the action of GLP1
- decrease rate of gastric emptying
- increase production of ANP1 (hypertension common in T2 diabetes)
- increase the release of insulin from pancreas
- decrease release of glucagon
- has short half life in blood stream but analogs can be made resistant to degradation by peptidases
40
describe GLP1 effect on pancreatic function
- enhances release of insulin from beta cells (incretin hormone)
- decreases glucagon from alpha cells
41
describe evidence for incretin hormones' effect
- glucose given orally causes a greater increase in insulin release and given IV
- incretin released from endocrine cells in intestine in response to ingestion of glucose
- this increase in insulin release anticipates the rise of blood glucose
42
what is exenatide (byetta)
- treatment for T2 diabetes
- reduce plasma glucose levels and causes weight loss
43
what is victoza
- treatment for T2 diabetes
- GLP-1 agonist
44
what is trulicity
- treatment for type 2 diabetes
- GLP1 R agonist
- subcutaneously injected (slow absorption allows for 1 a week dosing)
- decreases A1C levels
45
what is ozempic
- GLP1 analog with 3 key amino acid residues changes > decrease proteolysis and renal clearance > extends the half-life
- administered by injection 1 a weeks
46
what is januvia
- T2 diabetes treatment
- Dipeptidyl peptidase-4 (DPP-4) inhibitor
- GLP-1 is a peptide hormone that is degraded rapidly
after release > DPP-4 inactivates GLP-1 > Januvia inhibits DPP-4 > extend the duration of action of endogenous GLP-1
- also decreases HbA1C levels
47
what is metformin
- insulin resistance T2 diabetes
- Metformin activates AMP-Activated Protein
Kinase (AMPK) > Increases sensitivity to insulin > translocation of GLUT4 vesicles to cell membrane
(aka insulin independent GLUT4 translocation)
48
what is invokana
- T2 diabetes treatment
- inhibitor of sodium-glucose co-
transporter 2 (SGLT2) = SGLT2 is expressed in the proximal renal tubules + responsible for the reuptake of the majority of glucose filtered in the glomerulus
- Inhibition of SGLT2 reduces the reuptake of
glucose in the kidneys > Results in loss of glucose (and Na) from the body through urine
- (more effective than Januvia at reducing HbA1C in T2 pt)
49
what is Jardiance
- approved for pt w/ T2 diabetes
- SGLT2 inhibitor
50
what is the role of ENS
- regulates function of the GI tract
- has intrinsic activity
- May be modulated by input from sympathetic or
parasympathetic nervous systems
- The number of neurons in the ENS is similar to
the number of neurons in the spinal cord
51
what r the functions of the GI tract
- digestion
- absorption
- fluid exchange
- immune function
52
describe the Gl tract
Mouth
Esophagus
Stomach
Small intestine
Large intestine (colon)
Rectum
Anus
53
describe the swallowing reflex
- coordinated by brainstem
- muscles in esophagus move food in an aboral direction
54
describe digestion in the stomach
- stomach stores food and digest food
- secretory cells produce acidic environment
- kneads large clumps of food into small particles
- produce chyme
55
describe digestion and absorption in the small intestine
- pancreas and liver produce and secrete digestive enzymes
- enterocytes in the small intestine produce enzymes for digestion
- final step in digestion occurs at the site of transporter on microvilli which absorb nutrients
56
describe gut motility through small intestine
- propulsion and mixing
- longitudinal and circular smooth muscle fibers
57
describe large intestine functions
- gut motility (separate from defecation reflex)
- water absorption
