Whole-brain activation signatures of weight-lowering drugs

Molecular Metabolism

Johanna Perens¹  Henrik H. Hansen²  Jacob Jelsing³  Pernille Barkholt³  Jacob Hecksher-Sørensen³  Casper Gravesen Salinas³  Urmas Roostalu³  Kristoffer T.G. Rigbolt³  Niels Vrang³  Ditte Dencker Thorbek³  Jacob Lercke Skytte³ 

[1] Gubra, Hørsholm, Denmark;Corresponding author. Gubra, Hørsholm Kongevej 11B, DK-2970 Hørsholm, Denmark. Tel. [phone].;Gubra, Hørsholm, Denmark;

关键词: Imaging;    iDISCO;    Light sheet fluorescence microscopy;    c-Fos;    Obesity;    Anti-Obesity drugs;   

DOI  :  

来源: DOAJ

【 摘 要 】

Objective: The development of effective anti-obesity therapeutics relies heavily on the ability to target specific brain homeostatic and hedonic mechanisms controlling body weight. To obtain further insight into neurocircuits recruited by anti-obesity drug treatment, the present study aimed to determine whole-brain activation signatures of six different weight-lowering drug classes. Methods: Chow-fed C57BL/6J mice (n = 8 per group) received acute treatment with lorcaserin (7 mg/kg; i.p.), rimonabant (10 mg/kg; i.p.), bromocriptine (10 mg/kg; i.p.), sibutramine (10 mg/kg; p.o.), semaglutide (0.04 mg/kg; s.c.) or setmelanotide (4 mg/kg; s.c.). Brains were sampled two hours post-dosing and whole-brain neuronal activation patterns were analysed at single-cell resolution using c-Fos immunohistochemistry and automated quantitative three-dimensional (3D) imaging. Results: The whole-brain analysis comprised 308 atlas-defined mouse brain areas. To enable fast and efficient data mining, a web-based 3D imaging data viewer was developed. All weight-lowering drugs demonstrated brain-wide responses with notable similarities in c-Fos expression signatures. Overlapping c-Fos responses were detected in discrete homeostatic and non-homeostatic feeding centres located in the dorsal vagal complex and hypothalamus with concurrent activation of several limbic structures as well as the dopaminergic system. Conclusions: Whole-brain c-Fos expression signatures of various weight-lowering drug classes point to a discrete set of brain regions and neurocircuits which could represent key neuroanatomical targets for future anti-obesity therapeutics.

【 授权许可】

Unknown