Hypothalamic Leptin Resistance: Causes and Mechanisms (Prof Ashford)

Question 1

What does CNS disruption of STAT3 induce

Answer 1

Hyperphagia, obesity, diabetes andninfertility (resembles ob/ob and db/db mice)

Question 2

What tyrosine residue on LEP-Rb undergoes phosphorylation to activate STAT3

Answer 2

Y1138

Question 3

What happens when Y1138 is changed to S1138

Answer 3

Hyperphagia (reduced energy expenditure-like db/db mice), become less hyperglycaemia (unlike db/db mice) and no increase in NPY mRNA (unlike db/db mice)

Question 4

What does STAT3 not control in terms of leptins properties

Answer 4

Glucose homeostasis and reproduction control

Question 5

What is phosphorylated y1077 associated with and what is its action

Answer 5

STAT5 and not much

Question 6

What does phosphorylated y985 recruit

Answer 6

tyrosine phosphatase (SHP-2)

Question 7

Look over the y985 pathway

Answer 7

dae it

Question 8

What do mutant y985 mice show

Answer 8

Reduced feeding, adiposity and ARC orexigenic neuropeptide expression
Increased leptin sensitivity and this site plays a role in the inhibition of leptin receptor signalling

Question 9

What is the PI3K pathway important for

Answer 9

Glucose homeostasis and NPY mRNA production

Question 10

Why is Fox01 important in terms of insulin

Answer 10

It mediates many of the metabolic actions of insulin

Question 11

What does fox01 and STAT3 do in relation to transcription of AgRP and POMC

Answer 11

Fox01 increases AgRP transcription and decreases POMC transcription
STAT3 increases POMC transcription and decreases AgRP transcription

Question 12

What inhibits the JAK-STAT signalling

Answer 12

Suppressor of the cytokine signalling (SOCS)

Question 13

How does leptin induced JAK2 phosphorylation introduce a negative feedback loop

Answer 13

Phosphorylation of Y1138 and STAT3 activation results in SOCS3 mRNA induction

Question 14

What other things inhibit STAT3 (apart from SOCS)

Answer 14

TCPTP

Question 15

What chromosome is the FTO on and what is it

Answer 15

Fat mass and obesity associated SNP cluster

Question 16

What does FTO code for

Answer 16

2-oxyglutarate demethylase

Question 17

What are the importances of gut microbiota

Answer 17

Digestion, metabolism, nutrient extraction and immunomodulation

Question 18

What are the three types of gut bacteria and its gram stain

Answer 18

Firmacutes (G+ve), bacteroidetes (G-ve) and actinobacteria

Question 19

What does an increase of fat intake do to gut microbiota

Answer 19

Increase abundance of firmacutes and decreased bacteroidetes

Question 20

How long does it take to change gut microbiota by diet

Answer 20

24 hours

Question 21

What medication can change gut microbiota

Answer 21

Antibiotics

Question 22

What is the connection to obesity and diabetes

Answer 22

Altered LPS (lipopolysaccharides which are endotoxins of gram -ve bacteria) driving inflammation (TLR4 and NFkB)

Question 23

What is the connection between leptin resistance and obesity

Answer 23

Obesity causes increased leptin resistance. Also reduced leptin in CSF compared to plasma (reduced crossing in the BBB)

Question 24

What is the relationship between age and leptin resistance

Answer 24

Humans demonstrate a steady increase in body weight and adiposity when ageing and so too does leptin

Question 25

What can short term fat intake induce in the liver

Answer 25

Steatosis

Question 26

What negative regulators rise in ageing an obesity

Answer 26

SOCS3 (overexpression of SOCS3 in POMC neurons cause leptin resistance and obesity) PTP1B (overexpression inhibits cells leptin-driven STAT3 phosphorylation) and TCPTP

Question 27

What does deletion of SOCS3 in the brain do in relation to leptin sensitivity

Answer 27

Causes a high leptin sensitivity

Question 28

What does leptin administration do to insulin function

Answer 28

Improves insulin function in peripheral tissues

Question 29

What three tissues are mainly attenuated by leptin resistance

Answer 29

Adipose, liver and skeletal

Question 30

What are leptin’s impacts on adipose tissues

Answer 30

Has large effect on adipocyte number
Directly inhibits lipid synthesis (suppresses fatty acid synthase)
Inhibits insulin responsiveness

Question 31

What does leptin resistance do in adipocytes

Answer 31

Leptin resistance leads to proliferation of bigger adipocytes and this leads to excessive fat mass in obese individuals

Question 32

What two pro inflammatory immune cells cause inflammation in obesity

Answer 32

M1 macrophages and CD8+ T cells

Question 33

A high fat diet increases what immunoglobulins in the arcuate nucleus

Answer 33

IgG

Question 34

What is a neuroprotective response to a high fat diet and what can this end up becoming in chronic high fat feeding

Answer 34

Early microglial activation is considered a neuroprotective response to a high fat diet

Question 35

What receptors do free fatty acids bind to to cause obesity, type 2 diabetes and hypertension

Answer 35

Toll like receptor (4)

Question 36

What part of the cell is highly responsive to nutrient and energy status

Answer 36

Endoplasmic reticulum

Question 37

What is switched on in the endoplasmic reticulum under high fat feeding

Answer 37

ER-mediated stress signalling and adaption pathways

Question 38

Give a brief description of ER stress in high fat diet situations

Answer 38

ER processing