Whole-brain activation signatures of weight-lowering drugs

Abstract

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.

Anorectic and aversive effects of GLP-1 receptor agonism are mediated by brainstem cholecystokinin neurons, and modulated by GIP receptor activation

“…Since the AP and the NTS are readily accessible to GLP-1R ligands when administered systemically [ 4 , 19 , 28 , 29 ], we asked whether CCK AP/NTS neurons express GLP-1R. We performed dual-label fluorescence in situ hybridization histology (FISH) in wild-type mice and found co-expression of Cck and Glp1r mRNAs within both the AP and the NTS ( Figure 1 E).…”

“…As this and other evidence point to the caudal brainstem as an important central hub mediating the anorectic effects of GLP-1R activation [ 4 , 6 , [18] , [19] , [20] ], here we identify the neurons involved. We and others have previously described a population of dorsal vagal complex neurons defined by the expression of cholecystokinin (CCK) [ [23] , [24] , [25] ].…”

“…In addition to improving glucose metabolism, GLP-1RAs potently suppress appetite and body weight. These anorectic and body weight-lowering effects are thought to be mediated by central mechanisms [ [3] , [4] , [5] , [6] , [7] , [8] ], as indicated also by human studies [ [9] , [10] , [11] , [12] ]. However, the neuronal substrates that mediate these effects are still poorly understood.…”

“…GLP-1R is distributed across several brain regions [ 12 , [15] , [16] , [17] ] and among these, the brainstem (which includes the dorsal vagal complex and the parabrachial nucleus) has long been considered an important site of action for GLP-1RAs [ 4 , 6 , [18] , [19] , [20] ]. The caudal brainstem has been shown to be sufficient for mediating anorexia elicited by GLP-1RAs in decerebrated rats [ 6 ].…”

Dissecting a disynaptic central amygdala-parasubthalamic nucleus neural circuit that mediates cholecystokinin-induced eating suppression

“…Although neurons in the LHA have been widely described in the regulation of eating [ 61 , [65] , [66] , [67] , [68] , [69] ], the role of PSTh neurons in eating is still relatively understudied [ 56 ]. Neurons in the PSTh are activated by CCK, refeeding after fasting, and weight-lowering drugs [ 37 , 51 , 70 , 71 ]. Unlike CEA PKC-δ+ neurons, PSTh neurons are not activated by bitter taste [ 72 ], suggesting PSTh neurons might have a more specific function in eating than CEA PKC-δ+ neurons and explaining why the approach combining CEA PKC-δ+ neurons with CCK circuit mapping is important in determining the neurons with more specific functions.…”