Sunday, December 2, 2018

Obesity in Prader-Willi syndrome and WAGR syndrome

The delicate balance between food consumption and energy expenditure involves the modulation of orexigenic and anorexigenic signals at the 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 the 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 an alpha-melanocyte-stimulating hormone which in turn stimulates second-order neurons that release TRH, CRH and hence mediate catabolism.
They also simultaneously inhibit the anabolic pathway.

Now back to the pathogenesis of obesity in these syndromes.

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

In WAGR syndrome there is haploinsufficiency of BDNF(Brain-derived neurotrophic factor).
Alpha melanocyte-stimulating hormone in the catabolic pathway acts through melanocortin receptors(MC4R) on second-order neurons.
Downstream signaling pathways of MC4R involve 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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