Sunday, December 2, 2018

Obesity in Prader-Willi syndrome and WAGR syndrome

Delicate balance between food consumption and energy expenditure involves modulation of orexigenic and anorexigenic signals at hypothalamus.

OREXIGENIC PATHWAY- It involves peripheral mediators like ghrelin and neuropeptide-Y. 
They act on NPY-AgRP(neuropeptide-Y and agouti related peptide) neurons which subsequently mediates orexigenic signals via second order neurons that release peptides like orexin at hypothalamus.

ANOREXIGENIC PATHWAY- It involves peripheral mediators like leptin, amylin and PYY(Peptide YY).
They act on POMC/CART(Pro-opio melanocortin/Cocaine and amphetamine regulated transcript) neurons.
These neurons release alpha melanocyte stimulating hormone which in turn stimulates second order neurons that release TRH ,CRH and hence mediates catabolism.
They also simultaneously inhibit anabolic pathway.

Now back to pathogenesis of obesity in these syndromes.

In Prader-Willi syndrome levels of PYY are low due loss of imprinted genes on chromosome 15q11-q13.
This results in reduced catabolism and enhanced unihibited anabolism.
It is not uncommon for such patients to have BMI above 40.

In WAGR syndrome there is haplo-insufficiency of BDNF(Brain derived neurotrophic factor).
Alpha melanocyte stimulating hormone in catabolic pathway acts through melanocortin receptors(MC4R) on second order neurons.
Downstream signalling pathways of MC4R involves BDNF hence explaining obesity in these patients.

In fact efforts are already underway to reduce PPY levels and modulate BDNF to control obesity in these disorders.

Kirtan Patolia

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