Block C Lecture 3 - Complex Pharmacology of Free Fatty Acid Receptors

Question 1

What is a carboxylic acid?

Answer 1

An organic compound that contain at least one carboxyl group (-COOH)

(Slide 4)

Question 2

What is a fatty acid?

Answer 2

A carboxylic acid linked to an aliphatic tail (a hydrocarbon tail of varying length)

(Slide 4)

Question 3

What are the 3 categories of fatty acids based on size?

Answer 3

Short chain fatty acids (SCFA) - 6 or less carbon chain
Medium chain fatty acids (MCFA) - 7-12 carbon chain
Long chain fatty acids (LCFA) - > 13 carbon chain

(Slide 4)

Question 4

What are the 3 classifications of fatty acids based on saturation?

Answer 4

Saturated fatty acids (SFA) - fatty acids with no double bonds in them
Monounsaturated (MUFA) - fatty acids with one double bond in them
Polyunsaturated (PUFA) - contain more than one double bond

(Slide 4)

Question 5

Where are medium and long chain fatty acids obtained from and synthesised in?

Answer 5

They are obtained from dietary fat but can also be synthesised de novo (from scratch) in the liver

(Slide 5)

Question 6

What are essential fatty acids?

Answer 6

A group of polyunsaturated fatty acids (PUFAs) that must be obtained from the diet

(Slide 5)

Question 7

What do essential fatty acids help synthesise?

Answer 7

Polyunsaturated fatty acids

(Slide 5)

Question 8

What 2 signalling molecules are medium and long chain fatty acids precursors for?

Answer 8

Prostaglandins and leukotrienes

(Slide 5)

Question 9

When are short chain fatty acids produced?

Answer 9

When dietary fibre is fermented in the colon by microbiota of the gut

(Slide 5)

Question 10

What are the four family members of FFA GPCRs?

Answer 10

FFA1
FFA2
FFA3
FFA4
(creative I know)

(Side 6)

Question 11

What 2 FFA receptors do short chain fatty acids target?

Answer 11

FFA2 and 3 receptors

(Slide 6)

Question 12

What 2 FFA receptors do medium and long chain fatty acids target?

Answer 12

FFA1 and 4 receptors

(Slide 6)

Question 13

What cells are FFA2Rs expressed in and what is their function?

Answer 13

Immune cells - Act as neutrophil chemotaxis

Enteroendocrine cells - Gut hormone secretion

Adipocytes - Inhibition of Lipolysis

Pancreatic β-cells - regulation of insulin secretion

(Slide 7)

Question 14

What are cells FFA3Rs expressed in and what is their function?

Answer 14

Enteroendocrine cells - gut hormone secretion

Pancreatic β-cells - inhibition of insulin secretion

Sympathetic ganglia (unknown function)

(Slide 7)

Question 15

What are cells FFA4Rs expressed in and what is their function?

Answer 15

Enteroendocrine cells - gut hormone secretion

Adipocytes - stimulate glucose uptake

Immune cells - Inhibit cytokine secretion

Pancreas islets - Regulation of hormone secretion

(Slide 7)

Question 16

What has knowing the crystal structure of FFA1R allowed us to do?

Answer 16

Gain knowledge of the regions of ligand binding, and allowing us to design and develop new drugs based on this information

(Slide 8)

Question 17

What are 4 examples of where FFA1Rs are found and what are their functions in these different locations?

Answer 17

CNS - Modulates cognitive defects, chronic pain, emotional and maternal behaviour, epileptic seizures, reduction of energy efficiency and regulation of inflammation

Taste buds - taste perception

Pancreatic β-cells - insulin secretion

Enteroendocrine I, K, L - CCK, GIP and GLP-1 secretion (regulate digestion, metabolism and appetite)

Osteoclast and Osteoblast cells (in the bone) - Inhibition of osteoclastogenesis (formation of osteoclasts) and stimulation of bone formation

Bone-marrow-derived cells - induction of differentiation of M2 macrophages

(Slide 16)

Question 18

What fatty acids have the highest potency in activating the FFA1R?

Answer 18

Long chain poly-unsaturated fatty acids

(Slide 18)

Question 19

What fatty acids are considered poor agonists for the FFA1R?

Answer 19

Trans-unsaturated fatty acids

(Slide 18)

Question 20

What does acute long chain fatty acids treatment result in?

Answer 20

Enhanced - glucose-dependent insulin secretion (GSIS)

(Slide 18)

Question 21

What does chronic long chain fatty acid treatment result in?

Answer 21

Lipotoxicity and inhibition of insulin secretion

(Slide 18)

Question 22

What are 2 examples of endogenous FFA1R agonists?

Answer 22

α-linolenic acid (ALA)
Docosahexaenoic acid (DHA)

(Slide 19)

Question 23

What is TAK875 (Fasiglifam)?

Answer 23

A drug that acts as a FFA1 agonist, activating Arrestin 2/3 pathways

(Slide 20)

Question 24

What activity is reduced in Arrestin KO mice?

Answer 24

Insulintropic (the ability of the body to secrete insulin) activity

(Slide 20)

Question 25

What pathway do long chain fatty acids activate when they bind to FFA1 receptors?

Answer 25

Gq protein pathway (Slide 20)

Question 26

What does inhibition of Gq lead to?

Answer 26

Insulintropic activity being ablated (completed eliminated) (Slide 20)

Question 27

What are the properties of AM1638, especially when compared to TAK875 (Fasiglifam)?

Answer 27

It is a full agonist, which has a distinct binding profile from TAK, and has better preclinical data; being more effective in regulating blood glucose insulin levels, an showing effects with GLP-1, GIP and insulin levels which TAK doesn't. It transduces Gs and Gq pathways, meaning it activates them both (Slide 20)

Question 28

What are glitazones?

Answer 28

FFA1 agonists, which are used as anti-diabetic drugs. Examples include: Rosiglitazone Netoglitazone Troglitazone (Slide 22)

Question 29

Why have studies investing the possibility of synthetic ligands for FFA2 receptors been hampered?

Answer 29

As they've only done rodent based studies so far and there is no guarantee they'll work the same in humans (Slide 23)

Question 30

Why are scientists pursuing FFA2 agonism?

Answer 30

To limit obesity (Slide 23)

Question 31

Why have FFA2 antagonism studies using GLPG0974 been pursued and why did they fail?

Answer 31

For protection against ulcerative colitis, a chronic inflammatory disease that causes inflammation and ulcers in the colon and rectum. The drug failed as it showed no clinical benefit over a placebo (Slide 23)

Question 32

What issues have scientists had developing FFA3 allosteric agonists?

Answer 32

Potency issues (Slide 23)

Question 33

What is the problem with developing orthosteric agonists for FFA4Rs?

Answer 33

Spice variant genetic polymorphisms. There is a 3% polymorphism in the European cohort where the receptor loses the ability to couple with G proteins but can still activate the Arrestin 2/3 pathway. (Slide 23)

Question 34

What studies can provide insight into FFA4Rs feasibility as a drug target?

Answer 34

Population studies (to determine how many variants there are and if they act differently, if they influence disease risk etc) (Slide 23)