Leptin signalling

Question 1

what are the actions of leptin?

Answer 1

prevents obesity and diabetes

synthesis and release of; insulin, glucocorticoids, growth hormone

enhance angiogenesis

regulates onset of puberty and reproductive capabilty

immune system repsonse

hyperinsulinaemia

reduces food intake

stops development of lipodystrophy

shares many characteristics with T2DM

reduces accumulation of lipids in adipocytes

Question 2

describe the leptin receptor

Answer 2

abundant in the hypothalamus particularly localised to ARC neurons

has multiple splice site variants

leptin is transported across the BBB

Question 3

describe the interaction with the leptin receptor and JAK2

Answer 3

the leptin receptor has a specific docking site for JAK2 which phosphorylates tyrosine residues and creates a docking site for STAT3.

this leads to altered POMC transcription

Question 4

describe STAT3

Answer 4

stat3 signalling participates in energy homestasis via the melanocortin pathway (regulates transcription of POMC)

Question 5

what is the link between leptin and adiposity?

Answer 5

plasma leptin levels are highly correlated with adipose tissue mass. circulating leptin levels fluctuate with nutritional state. fasting = low leptin

giving leptin lowers food intake and body weight

obesity causes leptin resistance and therefore more is produced

Question 6

what is the primary effect of leptin?

Answer 6

reduces gluconeogenesis & glycogenolysis

suppresses lipogenesis in WAT

Leptin: important for regulation of blood pressure (central - via sympathetic output

Question 7

what happens to leptin signalling in the brain in obesity?

Answer 7

leptin signalling involves pathways between ARC and PVN which is disrupted in ob/ob mice

diet and hormones alter ARC neurones synaptic plasticity

ARC neurones/ circuits are crucial for fat and glucose homoestasis

Question 8

what does leptin deficiency do to brain development?

Answer 8

decreases brain size and hinders CNA development

Question 9

what does lack of leptin do to synapses of neurons?

Answer 9

lack of leptin is associated with altered number of excitatory and inhibitory synapses of neurons - leptin being added back in restores this

Question 10

In a normal fasted state describe melanocortins

Answer 10

increased NPY/AgRP
decreased POMV/CART

Question 11

what does leptin do to melanocortins?

Answer 11

decreases NPY/AgRP
increases POMC/CART

Question 12

what causes disrupted leptin signalling?

Answer 12

limitation of leptin transport across the BBB

decreased leptin signalling in ARC

hyperleptinaemia drives leptin resistance. expression of STAT3 in POMC neurones causes leptin resistance, hyperphagia and obesity

(selective to some tissues)

Question 13

what pathways are utilised in leptin signalling?

Answer 13

IRS-PI3K pathways in the brain. SH2B1 (implicated in obesity) and IRS2 are both crucial for insulin leptin signalling

Question 14

describe PTP1B

Answer 14

a negative regulator of leptin signalling, it dephosphorylates and inhibits JAK2

Question 15

what does SH2B1 do?

Answer 15

amplifies JAK2 signals and allows coupling to IRS proteins

Question 16

what do both JAK-STAT and PI3K-Fox01 do?

Answer 16

act as downstream transcription factors for leptin and insulin

Question 17

what does SOCS do?

Answer 17

inhibit JAK-STAT signalling

it is a leptin targeted and STAT3 regulated gene that mediates a negative feedback loop

Question 18

where do NPY and POMC neurones originate and insert?

Answer 18

originate in the ARC and project to the PVN and LHA/PFA

Question 19

describe CART

Answer 19

CART is found in the hypothalamic centres ARC, VMH and PVN

it is co-expressed with alpha-MSH in ARC POMC neurones

Question 20

what is the PVN?

Answer 20

principle hypothalamic MOTOR output system

regulates oxytocin, vasopressin, CRH, TRH

Question 21

what are positive transcription factors in leptin signalling

Answer 21

SH2B1
IRS-PI3K
FOX01

Question 22

what are inhibitory factors in leptin signalling?

Answer 22

SOCS
TCPTP
PTP1B