Whole-brain activation signatures of weight-lowering drugs
Henrik H Hansen1, Johanna Perens1, Urmas Roostalu1
1Gubra, Hørsholm, Denmark.
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.
Insights
This study mapped brain-wide neuronal activation from six anti-obesity drugs in mice. Key feeding and reward circuits were consistently targeted, identifying potential neuroanatomical targets for future weight-loss therapies.
Area of Science:
- Neuroscience
- Pharmacology
- Obesity Research
Background:
- Effective anti-obesity therapeutics require targeting brain mechanisms controlling body weight.
- Understanding neurocircuitry activated by weight-lowering drugs is crucial for therapeutic development.
Purpose of the Study:
- To determine whole-brain activation signatures of six different weight-lowering drug classes.
- To identify key neuroanatomical targets for future anti-obesity therapeutics.
Main Methods:
- Mice received acute treatment with lorcaserin, rimonabant, bromocriptine, sibutramine, semaglutide, or setmelanotide.
- Whole-brain neuronal activation was analyzed using c-Fos immunohistochemistry and 3D imaging.
- Data mining was facilitated by a web-based 3D imaging data viewer.
Main Results:
- All tested weight-lowering drugs induced widespread brain activation with similar c-Fos expression patterns.
- Consistent activation was observed in homeostatic and non-homeostatic feeding centers (dorsal vagal complex, hypothalamus).
- Limbic structures and the dopaminergic system also showed concurrent activation.
Conclusions:
- Whole-brain c-Fos signatures reveal discrete brain regions and neurocircuits targeted by weight-lowering drugs.
- These identified regions represent potential key neuroanatomical targets for novel anti-obesity therapies.
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