Role of Leptin in Energy Balance (2)

Question 1

What do satiety signals do?

Answer 1

Control food intake
Whilst eating, food interacts with receptors on the tongue, oropharynx, stomach and duodenum, as well as liver and other organs
The detection, processing and absorption of food generate satiety signals that provide negative feedback to the CNS
These signals accumulate and interact to bring a meal to an end
The signals reach the brain through visceral afferent nerve fibres and through the blood

Question 2

Is leptin a satiety hormone?

Answer 2

No

Question 3

What does leptin deficiency lead to?

Answer 3

Overeating

Question 4

Which cells synthesise leptin?

Answer 4

Adipocytes

Question 5

How does leptin work?

Answer 5

Senses when adipose tissue mass is decreased - signals to eat
Reduces food intake and increasers activity of sympathetic nervous system
Does not increase after a meal - more long-term effects

Question 6

How does leptin relate to obesity?

Answer 6

Leptin increases with increasing adipose tissue mass (elevated levels in obesity) (levels fall after weight loss)

Question 7

How does leptin deficiency relate to obesity?

Answer 7

Associated with massive obesity
Absence of its receptor in the hypothalamus also causes obesity

Question 8

How many leptin receptor isoforms are there?

Answer 8

5: LRa, LRb, LRc, LRd, LRe

Question 9

What is characteristic of leptin receptor LRa?

Answer 9

Lacks intracellular domain and is highly abundantly expressed in brain capillary endothelium and peripheral organs
It is proposed to mediate leptin transport across endothelial barriers

Question 10

What is characteristic of leptin receptor LRb?

Answer 10

Restricted to the hypothalamus, brainstem and key regions of the brain that control feeding, metabolism and neuroendrocine systems
Signals into the cell

Question 11

How does leptin signal into cells?

Answer 11

Leptin receptors contain JAK2 domains

When activated by leptin binding, the leptin receptor combines with its co-receptor

JAK2 autophosphorylates and:

JAK-2 mediated phosphorylation of transcription factors (e.g., STAT3) and translocation into the nucleus

Question 12

What is the role of SOCS-3 in leptin signalling?

Answer 12

STAT3 translocation into the nucleus regulates the expression of SOCS-3
It will exit the nucleus and inhibit phosphorylation

Negative feedback loop

Question 13

Which signal does POMC expression relate to?

Answer 13

Satiety signal

When leptin is present, STAT3 will lead to the transcription of POMC to induce a satiety signal

Question 14

Which signal does AgRP expression relate to?

Answer 14

Hunger

When leptin is not bound, FOXO1 will lead to the transcription of AgRP to induce a hunger signal.

Question 15

How do the actions of STAT3 and FOXO1 differ?

Answer 15

When leptin and insulin are not bound, FOXO1 translocates into the nucleus to transcribe AgRP and NPY, to induce a hunger signal. FOXO1 also inhibits the transcription of POMC/CART

When leptin and insulin are bound, STAT3 translocates into the nucleus to transcribe POMC and CART, to induce a satiety signal. STAT3 also inhibits the transcription of AgRP/NPY

Question 16

How does leptin affect the PI3K signalling pathway?

Answer 16

JAK2-mediated phosphorylation of IRS2 mobilises the PI3K pathway
PKB will phosphorylate FOXO1 and STAT3 will enter the nucleus to induce a satiety signal

Question 17

How is leptin signalling regulated?

Answer 17

A lack of glucose - stimulates a rescue pathway: ADP + ADP -> ATP + 5’ AMP

5’ AMP activates AMPK (conformational change)
AMPK is phosphorylated by LKB1 when active
Phosphorylated AMPK activates mTOR by phosphorylating TSC to activate RhebGTPase
Activated mTOR causes a hunger signal

Question 18

How does leptin influence energy homeostasis and weight?

Answer 18

By regulating a melanocortin circuit

Downstream signalling affects of AgRP, NPY, POMC and CART include endocrine effectors (e.g., thyroid, growth and reproduction), autonomic output (e.g., regulating energy expenditure, insulin secretion, and glucose homeostasis)