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

Chenxu Yan, Tianshu Zeng, Kailun Lee, Max Nobis, Kim Loh, Luoning Gou, Zefeng Xia, Zhongmin Gao, Mohammed Bensellam, Will Hughes, Jackie Lau, Lei Zhang, Chi Kin Ip, Ronaldo Enriquez, Hanyu Gao, Qiao-Ping Wang, Qi Wu, Jody J. Haigh, D. Ross Laybutt, Paul Timpson, Herbert Herzog () and Yan-Chuan Shi ()
Additional contact information
Chenxu Yan: St Vincent’s Hospital
Tianshu Zeng: Huazhong University of Science and Technology
Kailun Lee: St Vincent’s Hospital
Max Nobis: St Vincent’s Hospital
Kim Loh: St Vincent’s Hospital
Luoning Gou: Huazhong University of Science and Technology
Zefeng Xia: Huazhong University of Science and Technology
Zhongmin Gao: St Vincent’s Hospital
Mohammed Bensellam: St Vincent’s Hospital
Will Hughes: St Vincent’s Hospital
Jackie Lau: St Vincent’s Hospital
Lei Zhang: St Vincent’s Hospital
Chi Kin Ip: St Vincent’s Hospital
Ronaldo Enriquez: St Vincent’s Hospital
Hanyu Gao: St Vincent’s Hospital
Qiao-Ping Wang: Sun Yat-sen University
Qi Wu: St Vincent’s Hospital
Jody J. Haigh: University of Manitoba
D. Ross Laybutt: St Vincent’s Hospital
Paul Timpson: St Vincent’s Hospital
Herbert Herzog: St Vincent’s Hospital
Yan-Chuan Shi: St Vincent’s Hospital

Nature Communications, 2021, vol. 12, issue 1, 1-20

Abstract: Abstract 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.

Date: 2021
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DOI: 10.1038/s41467-021-22925-3

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