A cross-species atlas of the dorsal vagal complex reveals neural mediators of the effects of cagrilintide on energy balance.

Cross-species transcriptomics atlas and functional validation study

“To understand mediators of cagrilintide action, we generated a transcriptomics atlas of over 530,000 cells comprising 80 neuronal cell populations across rat, mouse and macaque caudal brainstem, with spatial profiling to map distribution in the rat dorsal vagal complex (DVC).”

Diet-induced obese mice, diet-induced obese rats, lean rats, and rhesus macaques

“To identify species-specific transcriptional response to cagrilintide signalling in the DVC, we treated 30 diet-induced obese (DIO) mice and 42 DIO rats with either a single dose or seven daily doses of cagrilintide or vehicle (subcutaneous or s.c.).”

Over 530,000 cells analyzed across species

“To understand DVC conservation and function and the mechanisms of action for amylin analogues, we generated a comprehensive transcriptional atlas of the caudal brainstem comprising >530,400 cells across 90 cell populations from lean and obese mice and rats, and lean rhesus macaques.”

Acute (4 hours) and subchronic (7 days) treatment periods

“To identify cellular mediators of cagrilintide action, we used expression of the immediate early gene Fos and its downstream target genes (the Fos regulon) as a transcriptional proxy for neuronal activation.”

Cagrilintide regulates two conserved Calcr-expressing neuronal populations in the dorsal vagal complex

“Here we show that cagrilintide regulates two conserved Calcr-expressing DVC neuronal populations.”

Long-term cagrilintide treatment upregulates Prlh expression in NTS Calcr/Prlh cells in rats

“In contrast, long-term cagrilintide treatment in rats upregulates prolactin-releasing hormone (Prlh) expression in nucleus of the solitary tract Calcr/Prlh cells that are conserved across rodents, macaques and humans.”

Knockdown of DVC Prlh abrogates cagrilintide effects but not semaglutide effects

“Knocking down DVC Prlh abrogates the effects of cagrilintide but not semaglutide in rats.”

Silencing of NTS Calcr neurons in rats resulted in lethality, preventing broad manipulation of these neurons

“While these rats recovered normally over the week following surgery, all animals receiving intra-NTS AAV-DIO-TetTox-GFP died over the subsequent 2–3 weeks.”