Whole-brain activation signatures of weight-lowering drugs

作者：Henrik H. Hansen, Johanna Perens, Urmas Roostalu, Jacob Lercke Skytte, Casper G. Salinas, Pernille Barkholt, Ditte Dencker Thorbek, Kristoffer T.G. Rigbolt, Niels Vrang, Jacob Jelsing, Jacob Hecksher‐Sørensen · 发表于：Molecular Metabolism · 年份：2021 · DOI：10.1016/j.molmet.2021.101171 · 被引用次数：71 · 研究领域：Regulation of Appetite and Obesity、Pharmacology and Obesity Treatment、Neurotransmitter Receptor Influence on Behavior

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 ...