Obesity Therapies

Question 1

How does insulin affect weight lose

Answer 1

Decreased insulin = increased weight loss

Question 2

Disadvantages of liposuction

Answer 2

Fluid accumulation
Nerve damage
Risk of infection
Expensive
May not be covered by insurance
Not permanent

Question 3

describe gastric bypass surgery

Answer 3

small pouch is created at the top of the stomach so you feel full with less food
Decrease ghrelin which reduces hunger

Question 4

Which steps of the TG biosynthetic pathway make good drug targets for obesity therapy

Answer 4

GPATs- maybe
AGPATs- maybe, but not AGPAT2
Lipins- probably not
DGATs- DGAT1, not DGAT2

Question 5

DGAT1 ko mouse vs DGAT2 ko mouse

Answer 5

DGAT1 ko: viable and healthy, reduced TG and adipose tissue, obesity resistance, no fatty liver

DGAT2 ko: Lethal, no energy store, skin defect/dehydration

Question 6

Which tissues does DGAT1 affect

Answer 6

Liver and small intestines

Question 7

Where does dietary fat absorption occur

Answer 7

Small intestine

Question 8

What are enterocytes

Answer 8

absorptive cells in intestines

Question 9

T/F Dietary TG cannot be absorbed by enterocytes intact

Answer 9

True

Question 10

Dietary cannot be absorbed by enterocytes intact, how does the body get around this? (how does dietary TG get to CM in circulation)

Answer 10

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

Question 11

What is the role of DGAT1 in the small intestine

Answer 11

Catalyzes the resynthesis of dietary TG

Question 12

What is the pathway responsible for the resynthesis of dietary TG

Answer 12

Monoacylglycerol acyltransferase (MGAT) pathway

Question 13

What is monoacylglycerol acyltransferase-2 for? (what is the substrate)

Answer 13

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

Question 14

Role of 1,2-DG

Answer 14

DGAT1 uses 1,2-DG to synthesize TG that are packaged into chylomicrons and released into the circulation

Question 15

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?

Answer 15

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)

Question 16

What does clearance of chylomicrons from the circulation require?

Answer 16

Lipoprotein lipase

Question 17

Describe the activity and function of LPL? What happens to the chylomicron remnant?

Answer 17

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

Question 18

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?

Answer 18

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

Question 19

What is the effect of inhibition of MGAT2? Does it reduce obesity?

Answer 19

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

Question 20

How do the following drugs promote weight loss: Saxenda, contrave, orlistat, ozempic

Answer 20

Saxenda- Appetite suppressant
Contrave- Appetite suppressant
Orlistat- inhibits fat absorption
Ozempic- appetite suppressant

Question 21

What is the goal of obesity therapies?

Answer 21

Reduce the amount of dietary fat absorbed
Promote lipolysis in adipocytes to reduce adipose tissue mass

Question 22

Describe the route of dietary fat absorption from the intestine

Answer 22

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

Question 23

What is orlistat

Answer 23

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

Question 24

What is the active site in pancreatic lipase? Where does orlistat bind

Answer 24

Ser-His-Asp –> catalytic triad that is part of the active site

Ser is essential for catalysis

orlistat binds to Serine152

Question 25

Effects of orlistat?
Caloric intake
Absorption of drug
Efficiency of fat digestion and absorption
Weight loss
Side effect

Answer 25

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

Question 26

What is olestra?

Answer 26

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