Smith-Magenis syndrome protein RAI1 regulates body weight homeostasis through hypothalamic BDNF-producing neurons and neurotrophin downstream signalling

Sehrish Javed; Ya-Ting Chang; Yoobin Cho; Yu-Ju Lee; Hao-Cheng Chang; Minza Haque; Yu Cheng Lin; Wei-Hsiang Huang

doi:10.7554/eLife.90333

Smith-Magenis syndrome protein RAI1 regulates body weight homeostasis through hypothalamic BDNF-producing neurons and neurotrophin downstream signalling

Elife. 2023 Nov 13:12:RP90333. doi: 10.7554/eLife.90333.

Authors

Sehrish Javed^{1

2}, Ya-Ting Chang^{1

2}, Yoobin Cho^{1

2}, Yu-Ju Lee^{1

2}, Hao-Cheng Chang^{1

2}, Minza Haque^{1

2}, Yu Cheng Lin^{1

2}, Wei-Hsiang Huang^{1

2}

Affiliations

¹ Department of Neurology and Neurosurgery, Centre for Research in Neuroscience, McGill University, Montréal, Canada.
² Brain Repair and Integrative Neuroscience Program, The Research Institute of the McGill University Health Centre, Montréal, Canada.

Abstract

Retinoic acid-induced 1 (RAI1) haploinsufficiency causes Smith-Magenis syndrome (SMS), a genetic disorder with symptoms including hyperphagia, hyperlipidemia, severe obesity, and autism phenotypes. RAI1 is a transcriptional regulator with a pan-neural expression pattern and hundreds of downstream targets. The mechanisms linking neural Rai1 to body weight regulation remain unclear. Here we find that hypothalamic brain-derived neurotrophic factor (BDNF) and its downstream signalling are disrupted in SMS (Rai1^+/-) mice. Selective Rai1 loss from all BDNF-producing cells or from BDNF-producing neurons in the paraventricular nucleus of the hypothalamus (PVH) induced obesity in mice. Electrophysiological recordings revealed that Rai1 ablation decreased the intrinsic excitability of PVH^BDNF neurons. Chronic treatment of SMS mice with LM22A-4 engages neurotrophin downstream signalling and delayed obesity onset. This treatment also partially rescued disrupted lipid profiles, insulin intolerance, and stereotypical repetitive behaviour in SMS mice. These data argue that RAI1 regulates body weight and metabolic function through hypothalamic BDNF-producing neurons and that targeting neurotrophin downstream signalling might improve associated SMS phenotypes.

Keywords: brain-derived neurotrophic factor; mouse; neuroscience; obesity; paraventricular nucleus of hypothalamus; retinoic acid induced 1.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Body Weight
Brain-Derived Neurotrophic Factor* / metabolism
Homeostasis
Hypothalamus / metabolism
Mice
Nerve Growth Factors / metabolism
Neurons / metabolism
Obesity / genetics
Smith-Magenis Syndrome* / genetics
Smith-Magenis Syndrome* / metabolism
Trans-Activators* / metabolism
Transcription Factors* / metabolism

Substances

Brain-Derived Neurotrophic Factor
Trans-Activators
Transcription Factors
Rai1 protein, mouse
Nerve Growth Factors

Grants and funding

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.