A Transcriptomic Signature of the Hypothalamic Response to Fasting and BDNF Deficiency in Prader-Willi Syndrome.

Abstract:

:Transcriptional analysis of brain tissue from people with molecularly defined causes of obesity may highlight disease mechanisms and therapeutic targets. We performed RNA sequencing of hypothalamus from individuals with Prader-Willi syndrome (PWS), a genetic obesity syndrome characterized by severe hyperphagia. We found that upregulated genes overlap with the transcriptome of mouse Agrp neurons that signal hunger, while downregulated genes overlap with the expression profile of Pomc neurons activated by feeding. Downregulated genes are expressed mainly in neuronal cells and contribute to neurogenesis, neurotransmitter release, and synaptic plasticity, while upregulated, predominantly microglial genes are involved in inflammatory responses. This transcriptional signature may be mediated by reduced brain-derived neurotrophic factor expression. Additionally, we implicate disruption of alternative splicing as a potential molecular mechanism underlying neuronal dysfunction in PWS. Transcriptomic analysis of the human hypothalamus may identify neural mechanisms involved in energy homeostasis and potential therapeutic targets for weight loss.

journal_name

Cell Rep

journal_title

Cell reports

authors

Bochukova EG,Lawler K,Croizier S,Keogh JM,Patel N,Strohbehn G,Lo KK,Humphrey J,Hokken-Koelega A,Damen L,Donze S,Bouret SG,Plagnol V,Farooqi IS

doi

10.1016/j.celrep.2018.03.018

subject

Has Abstract

pub_date

2018-03-27 00:00:00

pages

3401-3408

issue

13

issn

2211-1247

pii

S2211-1247(18)30347-4

journal_volume

22

pub_type

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