Hypothalmic leptin resistance Flashcards
What does JAK-STAT act as?
It acts as a signalling node to alter transciption in the DNA.
Leptin signallin is a result of multiple singalling nodes like JAK-STAT. There is rarely singular linear signalling in biology.
What does CNS specific disruption of STAT3 cause?
Hyperphagia, obesity, diabetes and infertiliy - similar to ob/ob or db/db mouse mutants.
This is seen in mice where the essential roll of STAT3 on the phosphorylation of Y1138 is blocked.
- Hyperphagia, reduced energy expenditure and obese (like db/db
- Mice less hyperglycaemic with normal fertility (unlike db/db)
- No increase in NPY mRNA (unlike db/db)
What is observed in mice where the Y in Y1138 is replaced by an S (knock in mice), which prevents the phosphorylation and activation of STAT3.
- Hyperphagia, reduced energy expenditure and obese (like db/db
- Mice less hyperglycaemic with normal fertility (unlike db/db)
- No increase in NPY mRNA (unlike db/db)
Hence Y1138S does not replicate all the characteristics associated with loss of leptin signalling ie. there are important non-STAT3 signals.
Suggestion that STAT3 signalling participates in energy homestasis via melnocortin pathyway - regulates transciption of POMC
Also suggests that glycaemia and reproduction control are via non-STAT pathways.
How great is the contribution of Y1077 to leptin signalling? (ie the docking site for STAT5)
Little contribution
STAT5 KO mice develop late onset mild obesity
STAT5 deletion from LEP-Rb neurones has no bodyweight phenotype. Deletion of STAT3 and STAT5 equals STAT3 deletion alone.
LEP-Rb Y1077 mutant only develops mild increase in food intake
Therefore Y1077-STAT5 plays a minor role in food intake and energy expenditure but may link adiposity with reproductive potential in female mice
Outline the roles of Y985
Creates a binding site for SHP-2 (a tyrosine phosphatase). The p-Y residues on JAK2 also binf to SHP-2.
This leads to the activation of the ERK/MAPK pathway which drives the transciption of genes onvolved in prolifer`tion and differentiation.
This site plays a role in the inhibition of leptin receptor signalling - mutant Y985 mice show reduced feeding, adiposity and ARC orexogenic neuropeptide expression, with increased in vivo leptin.
What does PI3K activate in the insulin signalling pathway?
AKT - see photo
The leptin receptor also couples to PI3K signalling. Explain how this works.
Protein SH2B1 contribute to leptin signalling. It amplifies JAK2 signals and allows the coupling of IRS proteins which control the PI3K pathway, production of PIP3 and further signalling.
- SH2B1 null mice display severe obesity and hyperphagia.
- IRS2 deletion in LEP-Rb neurons cause obesity
- icv administration of PI3K inhibitors reduces leptins anorexogenic actions
Do leptin and insulin receptors have discreet or overlapping receptor pathways in the brain?
Overlapping - Leptin and imsulin receptors utilise IRS-PI3K pathways in the brain. Pathway overlap occurs in hypothalamic neuronal signalling.
IRS2 and SH2B1 are both crucial for insulin signalling as well as leptin signalling.
It is probable that leprin and insulin act on subets of ARC neurons
What is Fox01 and describe its effects as well as its relationship with STAT3 and PI3K? - photo very good at explaining this
FoxO1 mediates many of the metabolic actions of insulin.
Increased FoxO1 activity in hypothalamus increases food intake and body weight.
Leptin and insulin require FoxO1 signalling for anorexogenic effects.
in POMC neurons, FoxO1 competes with STAT3 for promoter site, reducing STAT3 transciption.
Increased PI3K signalling drives phophorylation of FoxO1 and leads to nuclear exclusion - anorexogenic
Both JAK-STAT and IRS-PI3K act as downstream transcription factors for leptin and insulin - true or false?
True
WHat mediates negative feedback control of LEP-Rb?
SOCS3 - Inhibits JAK-STAT signalling by binding to specific phosphyrlated tyrosine residues.
SOCS is a leptin targeted and STAT3 regulated gene. STAT3 activation results in SOCS3 mRNA induction.
Descrivbe how SOCS3 works to inhibit LEP-Rb (-ve feedback)
SOCS3 binds to Y985 - likely involved in Y985 mediated reduction on leptin signalling
SOCS3 inhibits JAK2 kinase activity by binding to it.
SOCS3 is induced in multiple LEP-Rb neuron populations.
Deletion of SOCS3 results in increased leptin sensitivity and rediced obesity.
What other mechanisms (apart form SOSC3) are used in the negative regulation of LEP-Rb?
Proteins that cause the dephosphorylation of intrinsic tyrosine residues - Protein tyrosine phosphatases (PTPs)
Example 1 - TCPTP (T cell protein tyrosine phosphatase) dephosphorylates STAT3 - inhibition of this improves leptin sensitivity in obese mice.
Example 2 - PTP1B dephosphorylates and inhibits JAK2 - Deletion of this results in decreased food intake and increased eneergy expenditure.
What is FTO? What is its role in obesity??
FTO (Fat Mass and Obesity Associated) has been confirmed as an obesity susceptibility locus, with highest prevelance in european and east asian populations. It contains a cluster of SNPs (single nucleotide polymorphisms) linked with obesity.
Associated with ann increased food intake and reduced satiety. Doesn’t per se alter physical activity but exercise attenuates the association between FTO locus and obesity.
Recent work suggests that FTO facilitates weight gain by increased ghrelin od decreased thermogenesis.
