Obesity Therapies Flashcards
How does insulin affect weight lose
Decreased insulin = increased weight loss
Disadvantages of liposuction
Fluid accumulation
Nerve damage
Risk of infection
Expensive
May not be covered by insurance
Not permanent
describe gastric bypass surgery
small pouch is created at the top of the stomach so you feel full with less food
Decrease ghrelin which reduces hunger
Which steps of the TG biosynthetic pathway make good drug targets for obesity therapy
GPATs- maybe
AGPATs- maybe, but not AGPAT2
Lipins- probably not
DGATs- DGAT1, not DGAT2
DGAT1 ko mouse vs DGAT2 ko mouse
DGAT1 ko: viable and healthy, reduced TG and adipose tissue, obesity resistance, no fatty liver
DGAT2 ko: Lethal, no energy store, skin defect/dehydration
Which tissues does DGAT1 affect
Liver and small intestines
Where does dietary fat absorption occur
Small intestine
What are enterocytes
absorptive cells in intestines
T/F Dietary TG cannot be absorbed by enterocytes intact
True
Dietary cannot be absorbed by enterocytes intact, how does the body get around this? (how does dietary TG get to CM in circulation)
TG are disassembled by pancreatic lipase to fatty acids and 2-monoacylglycerol
Transporters move fatty acids and 2-MG into enterocytes from the intestinal lumen
TG are packaged into CM with phospholipids and specific proteins
CM is then secreted into the lymph then circulation
What is the role of DGAT1 in the small intestine
Catalyzes the resynthesis of dietary TG
What is the pathway responsible for the resynthesis of dietary TG
Monoacylglycerol acyltransferase (MGAT) pathway
What is monoacylglycerol acyltransferase-2 for? (what is the substrate)
It is produced in the small intestine by pancreatic lipase and transported into intestinal cells (enterocytes)
2-monoacylglycerol is the substrate by MGAT to synthesize 1,2-DG
Role of 1,2-DG
DGAT1 uses 1,2-DG to synthesize TG that are packaged into chylomicrons and released into the circulation
What is the postprandial triglyceridemic response when subjects are given a drink high in fat and blood is taken every hour? Why is this the response?
Blood TG levels increase after 1 hour then decrease after 2 hours
This represents TG secretion from the small intestines and TG clearance by other tissues (CM clearance)
What does clearance of chylomicrons from the circulation require?
Lipoprotein lipase
Describe the activity and function of LPL? What happens to the chylomicron remnant?
Anchored to muscle/adipose tissue and is exposed to circulation
Normally, LPL is inactive. But is activated by apoCII on chylomicrons
LPL breaks down TG in CM to fatty acids, which are taken up by tissues
Chylomicron remnant is taken up by the liver
If you treat a person with the DGAT1 inhibitor, is TG absorption by the small intestine reduced? Would this lead to weight loss? Short-term vs Long-term? Is it a useful drug target?
Overall, the DGAT1 inhibitor should reduce amount of TG absorbed in the diet
Theoretically, this should activate lipolysis in adipose tissue decreasing TG in adipose tissue and weight loss
Short-term there was a concentration dependent decrease in blood TG after 8 hours
Drug inhibited dietary TG absorption
Long-term DGAT1 inhibitor reduced TG absorption, but results in adverse gastrointestinal effects
It is not useful because of side effects
What is the effect of inhibition of MGAT2? Does it reduce obesity?
Resulted in a reduction in TG absorbed and decreased CM
Protected against diet-induced obesity
Decreased body fat
MGAT2 inhibitor decreased blood TG after a meal
Blocked chylomicron assembly/secretion
Dietary TG absorption is reduced and had no adverse intestinal issues
Body fat decreased by almost 50% and had no adverse effects
How do the following drugs promote weight loss: Saxenda, contrave, orlistat, ozempic
Saxenda- Appetite suppressant
Contrave- Appetite suppressant
Orlistat- inhibits fat absorption
Ozempic- appetite suppressant
What is the goal of obesity therapies?
Reduce the amount of dietary fat absorbed
Promote lipolysis in adipocytes to reduce adipose tissue mass
Describe the route of dietary fat absorption from the intestine
TG uses pancreatic lipase to break down into fatty acidsand 2-MG
2-MG are converted to TG in enterocytes through the MGAT pathway it is then packaged into CM and circulated through the blood to get taken to adipose tissue
What is orlistat
An inhibitor of dietary fat absorption derived from bacteria (natural compound)
Pancreatic lipase inhibitors (binds to activate site)
Prevents pancreatic lipase from breaking TG to fatty acids in the small intestine which decreases adipose tissue
What is the active site in pancreatic lipase? Where does orlistat bind
Ser-His-Asp –> catalytic triad that is part of the active site
Ser is essential for catalysis
orlistat binds to Serine152
Effects of orlistat?
Caloric intake
Absorption of drug
Efficiency of fat digestion and absorption
Weight loss
Side effect
Reduces caloric intake
Not an appetite suppressant
Drug is not absorbed
Lowers the efficiency of fat digestion and absorption by the small intestine
Modest weight loss
Fatty stool side effect
What is olestra?
Fat replacement approved by FDA
Adds no calories and cannot be broken down or absorbed
Side effects: Cramps, gas, bloating, diarrhea
Banned in Canada but still approved in USA
