Adipocytes Energy Balance 2 Flashcards
What is Hepatic Steatosis?
Fatty Liver
What is the effect of insulin resistance on…
Muscle?
Adipose?
Liver?
Muscles – less glucose up-take (less GLUT4 on surface)
Adipose:
- less TG synthesis (less LPL, GLUT4 on surface) - more FA released (less HSL inhibition)
Liver – “selective” insulin resistance:
- FA synthesis still up-regulated by insulin - gluconeogenesis not inhibited by insulin
What are the two theories on insulin resistance?
1) Intramuscular fat inhibits IRS phosphorylation
2) Inflammatory cytokines cause inhibitory IRS phosphorylation
What is the intramuscular fat inhibits IRS phosphorylation theory of insulin resistance?
- Excess TG in muscle
- Leads to excess of other lipids in muscle (DG, other lipids)
- these lipids activate serine/threonine kinases
- these kinases phosphorylate IRS-1
- this S/T phosphorylation inhibits insulin receptor phosphorylation of IRS-1
- insulin signaling is reduced
What is the Inflammatory cytokines cause inhibitory IRS phosphorylation theory of insulin resistance?
Adipose tissue contains resident immune cells (macrophages, others)
- Increased adipose and/or adipocyte stress increases immune cells (especially visceral fat)
- Inflammatory cytokine secretion (TNF-a and others) increases
- cytokine signaling increases S/T phosphorylation of IRS-1
- this S/T phosphorylation inhibits insulin receptor phosphorylation of IRS-1
- insulin signaling is reduced
What are the three sources of FA intake for the LV?
What are the two sources of FA disposal for the liver?
3 sources of FA for liver:
Chylomicrons (diet)
Serum FA (adipose)
Endogenous synthesis
2 sinks for FA:
Oxidation
VLDL export
How are each affected by insulin? 3 sources of FA for liver: Chylomicrons (diet)? Serum FA (adipose)? Endogenous synthesis?
2 sinks for FA:
Oxidation?
VLDL export?
3 sources of FA for liver:
Chylomicrons (diet) increased by positive energy balance
Serum FA (adipose) not decreased, due to insulin resistance (Adipocytes are insulin resistant and therefore adipocyte HSL is still active, in spite of insulin)
Endogenous synthesis high, due to selective hepatic insulin resistance (Ie insulin still activates FA synthesis)
2 sinks for FA:
Oxidation low, due to selective hepatic insulin resistance
VLDL export overwhelmed
What effect does increased pancreatic TG have on insulin release?
Higher expression of Uncoupling Proteins (UCP2)
Higher activity of UCP2
Therefore, less ATP
Therefore, less glucose-induced insulin secretion
What is Orlistat?
binds to Lipase in the intestines and leaks undigested fat out of the butt
What is Rimonabant?
New Anti-Obesity Drug
-CB1R antagonist
-inhibits endocannabinoid signaling
-strong appetite suppressant
-also considered for smoking cessation
But… psychiatric side-effects
-taken off market in Europe,
never approved in US
What is Sibutramine?
appetite suppressant with CV side effects
Removed from market
FYI: Rimonabant (endocannabinoid antagonist). Withdrawn.
Sibutramine (serotonin/noradrenaline re-uptake inhibitor). Withdrawn.
Fenfluramine (serotonin enhancer). Withdrawn.
Phentermine (noradrenaline, serotonin, dopamine enhancer). Short-term.
Lorcaserin/Belviq (specific serotonin receptor agonist). Recently approved.
Contrave (combo therapy: noradrenaline re-uptake, opioid antagonist). Recently approved.
Qsymia (combo therapy: phentermine, and anti-epilepsy med). Recently approved.
Rimonabant (endocannabinoid antagonist). Withdrawn.
Sibutramine (serotonin/noradrenaline re-uptake inhibitor). Withdrawn.
Fenfluramine (serotonin enhancer). Withdrawn.
Phentermine (noradrenaline, serotonin, dopamine enhancer). Short-term.
Lorcaserin/Belviq (specific serotonin receptor agonist). Recently approved.
Contrave (combo therapy: noradrenaline re-uptake, opioid antagonist). Recently approved.
Qsymia (combo therapy: phentermine, and anti-epilepsy med). Recently approved.
Prior treatment plan for diabetes in 2006
Keep A1C levels re less aggressive)
Order of treatment:
a) Lifestyle changes/metformin
b) insulin (now with caution)
c) Sulfonoureas (incretin therapy has replaced)
d) Thiazolidinediones (not used much anymore)
What are the effects of metformin?
In liver:
a) decreases gluconeogenesis b) decreases FA synthesis c) increases FA oxidation 2. In muscle - Increases GLUT4 on PM/glucose up-take
Don’t need to know the mechanism for Metformin
Don’t need to know the mechanism for Metformin
Probably inhibits Adenyl cyclase and counters the counterregulatory compounds of insulin
