An amyloid-β/APP regulatory layer in human brown adipocyte recruitment identifies repurposable drugs for thermogenic fat expansion
- 1University of Cambridge
Abstract
Brown adipose tissue (BAT) increases energy expenditure but is scarce in adults, yet most strategies focus on activating existing thermogenic adipocytes rather than recruiting new ones. We integrate human single-nucleus transcriptomics with protein-interaction and knowledge-graph analyses to identify stage-specific, druggable programmes governing brown adipogenesis. This pipeline resolved four ordered transcriptional states and three transitions, revealing an amyloid-{beta}/APP regulatory layer and nominating APP as a central signalling hub. Most prioritised compounds altered differentiation or metabolic phenotype, several substantially. Phenserine (APP-lowering) and sacubitril (neprilysin inhibitor) promoted differentiation through distinct mechanisms and stages and could be combined sequentially for benefit. Phenserine increased differentiation across three human models and, in mice, expanded BAT mass and increased thermogenic capacity. Together, these findings reveal targetable control points in human brown adipocyte recruitment, nominate repurposable drugs for BAT expansion, and establish a generalisable framework coupling single-cell transcriptomics with network-based drug repurposing across staged biological systems.
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BibTeX
@misc{bazin2026amyloidβapp,
title = {{An amyloid-β/APP regulatory layer in human brown adipocyte recruitment identifies repurposable drugs for thermogenic fat expansion}},
author = {H. M. L. Bazin and S. Rodriguez-Fdez and F. Baldo and I. D. Mali and N. Gupta and M. Maimaiti and T. L. Simonian and M. Campbell and P. Prasertsuk and N. Han and A. Vidal-Puig},
howpublished = {bioRxiv},
year = {2026},
month = oct,
doi = {10.64898/2026.10.02.754417},
url = {https://www.biorxiv.org/content/10.64898/2026.10.02.754417v1},
note = {CC BY-NC},
}
RIS
TY - UNPB
TI - An amyloid-β/APP regulatory layer in human brown adipocyte recruitment identifies repurposable drugs for thermogenic fat expansion
AU - H. M. L. Bazin
AU - S. Rodriguez-Fdez
AU - F. Baldo
AU - I. D. Mali
AU - N. Gupta
AU - M. Maimaiti
AU - T. L. Simonian
AU - M. Campbell
AU - P. Prasertsuk
AU - N. Han
AU - A. Vidal-Puig
PY - 2026
DA - 2026/10/02
PB - bioRxiv
DO - 10.64898/2026.10.02.754417
UR - https://www.biorxiv.org/content/10.64898/2026.10.02.754417v1
AB - Brown adipose tissue (BAT) increases energy expenditure but is scarce in adults, yet most strategies focus on activating existing thermogenic adipocytes rather than recruiting new ones. We integrate human single-nucleus transcriptomics with protein-interaction and knowledge-graph analyses to identify stage-specific, druggable programmes governing brown adipogenesis. This pipeline resolved four ordered transcriptional states and three transitions, revealing an amyloid-{beta}/APP regulatory layer and nominating APP as a central signalling hub. Most prioritised compounds altered differentiation or metabolic phenotype, several substantially. Phenserine (APP-lowering) and sacubitril (neprilysin inhibitor) promoted differentiation through distinct mechanisms and stages and could be combined sequentially for benefit. Phenserine increased differentiation across three human models and, in mice, expanded BAT mass and increased thermogenic capacity. Together, these findings reveal targetable control points in human brown adipocyte recruitment, nominate repurposable drugs for BAT expansion, and establish a generalisable framework coupling single-cell transcriptomics with network-based drug repurposing across staged biological systems.
ER -