Pathways of action of the potent anorexigenic gut hormones pancreatic polypeptide and peptide YY.
Lead Research Organisation:
Imperial College London
Department Name: Dept of Medicine
Abstract
Obesity is the major cause of early death in the UK, accounting for an estimated 600 premature
deaths per week. As yet there are no effective treatments and the factors which regulate appetite
and body weight are largely unknown.
Pancreatic polypeptide (PP) and Peptide YY (PYY) are hormones released from the gut in
response to food intake. Recently they have both been shown to act in the brain to reduce
appetite, and can therefore be thought of as part of the body‘s mechanism of feeling full after a
meal. Infusions of these hormones into humans have consistently shown powerful and sustained
effects in lowering food intake. Exciting work is already underway to develop analogues that can
be effectively administered as weight-loss drugs.
There remains a large gap in our understanding of how PP and PYY exert their appetite-reducing
effects in the brain. Although their structure and effects are very similar, we know that they each
have a strong preference for different receptors and therefore stimulate different appetite signals in
the brain. By comparing and contrasting the effects of PP and PYY, I will contribute to our overall
understanding of the pathways that control of food intake.
deaths per week. As yet there are no effective treatments and the factors which regulate appetite
and body weight are largely unknown.
Pancreatic polypeptide (PP) and Peptide YY (PYY) are hormones released from the gut in
response to food intake. Recently they have both been shown to act in the brain to reduce
appetite, and can therefore be thought of as part of the body‘s mechanism of feeling full after a
meal. Infusions of these hormones into humans have consistently shown powerful and sustained
effects in lowering food intake. Exciting work is already underway to develop analogues that can
be effectively administered as weight-loss drugs.
There remains a large gap in our understanding of how PP and PYY exert their appetite-reducing
effects in the brain. Although their structure and effects are very similar, we know that they each
have a strong preference for different receptors and therefore stimulate different appetite signals in
the brain. By comparing and contrasting the effects of PP and PYY, I will contribute to our overall
understanding of the pathways that control of food intake.
Technical Summary
Pancreatic polypeptide (PP) and peptide YY 3-36 (PYY3-36) potently inhibit food intake and may
be the basis for anti-obesity therapies. Although both are members of the NPY family of peptides,
they mediate their effects via different receptor systems and their effects on food intake are
additive. Initial findings suggested that the anorexigenic effects of PYY3-36 were mediated
exclusively in the arcuate nucleus whilst those of PP were via the area postrema in the brainstem.
However, new evidence shows that this is an over-simplistic model. The actual neuronal targets of
PP and PYY3-36 are unknown. I will therefore:
1) Identify the phenotype and location of neurones activated in response to PP and PYY3-36.
2) Determine the brain regions which mediate the anorexigenic effects of PP and PYY3-36.
3) Identify which are the most important neurones mediating the anorectic effects of PP and
PYY3-36.
Understanding this system will allow development of more effective agents to moderate appetite.
be the basis for anti-obesity therapies. Although both are members of the NPY family of peptides,
they mediate their effects via different receptor systems and their effects on food intake are
additive. Initial findings suggested that the anorexigenic effects of PYY3-36 were mediated
exclusively in the arcuate nucleus whilst those of PP were via the area postrema in the brainstem.
However, new evidence shows that this is an over-simplistic model. The actual neuronal targets of
PP and PYY3-36 are unknown. I will therefore:
1) Identify the phenotype and location of neurones activated in response to PP and PYY3-36.
2) Determine the brain regions which mediate the anorexigenic effects of PP and PYY3-36.
3) Identify which are the most important neurones mediating the anorectic effects of PP and
PYY3-36.
Understanding this system will allow development of more effective agents to moderate appetite.