Peripheral-specific Y1 receptor antagonism increases thermogenesis and protects against diet-induced obesity

Obesity is caused by an imbalance between food intake and energy expenditure (EE). Here we identify a conserved pathway that links signalling through peripheral Y1 receptors (Y1R) to the control of EE. Selective antagonism of peripheral Y1R, via the non-brain penetrable antagonist BIBO3304, leads to...

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Published in:Nature communications Vol. 12; no. 1; pp. 2622 - 20
Main Authors: Yan, Chenxu, Zeng, Tianshu, Lee, Kailun, Nobis, Max, Loh, Kim, Gou, Luoning, Xia, Zefeng, Gao, Zhongmin, Bensellam, Mohammed, Hughes, Will, Lau, Jackie, Zhang, Lei, Ip, Chi Kin, Enriquez, Ronaldo, Gao, Hanyu, Wang, Qiao-Ping, Wu, Qi, Haigh, Jody J., Laybutt, D. Ross, Timpson, Paul, Herzog, Herbert, Shi, Yan-Chuan
Format: Journal Article
Language:English
Published: London Nature Publishing Group UK 11.05.2021
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Ablation
Adipocytes
Adipose tissue
Adipose tissue (brown)
AKT protein
Body fat
Body weight
Body weight gain
Browning
Diet
Energy balance
Energy expenditure
Food intake
Glucose
Glucose metabolism
Homeostasis
Humanities and Social Sciences
multidisciplinary
Neuropeptide Y
Obesity
Receptors
Science
Science (multidisciplinary)
Signal transduction
Signaling
Thermogenesis
ISSN:2041-1723, 2041-1723
Online Access:Get full text
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Summary:Obesity is caused by an imbalance between food intake and energy expenditure (EE). Here we identify a conserved pathway that links signalling through peripheral Y1 receptors (Y1R) to the control of EE. Selective antagonism of peripheral Y1R, via the non-brain penetrable antagonist BIBO3304, leads to a significant reduction in body weight gain due to enhanced EE thereby reducing fat mass. Specifically thermogenesis in brown adipose tissue (BAT) due to elevated UCP1 is enhanced accompanied by extensive browning of white adipose tissue both in mice and humans. Importantly, selective ablation of Y1R from adipocytes protects against diet-induced obesity. Furthermore, peripheral specific Y1R antagonism also improves glucose homeostasis mainly driven by dynamic changes in Akt activity in BAT. Together, these data suggest that selective peripheral only Y1R antagonism via BIBO3304, or a functional analogue, could be developed as a safer and more effective treatment option to mitigate diet-induced obesity. Neuropeptide Y signalling in the periphery contributes to the regulation of metabolic and energy homeostasis. Here the authors show that blocking Y1R signalling in peripheral tissues using the selective antagonist BIBO3304 ameliorates diet-induced obesity and improves whole-body glucose metabolism.
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ISSN:2041-1723
2041-1723
DOI:10.1038/s41467-021-22925-3