GSE135862
Behavioural and neurochemical mechanisms underpinning the synergistic feeding-suppressive effect of GLP-1/CCK combinatorial therapy
Combinatorial therapies are under intense investigation for the development of more efficient anti-obesity drugs, however little is known about how they act in brain to produce enhanced satiety and weight loss. Here we used a multidisciplinary strategy to decipher the central mechanisms engaged downstream from the co-administration of GLP-1R and CCK1R agonists, an efficient combination therapy in obese rodents. The nucleus of the solitary tract (NTS) contained one of the few neuronal populations synergistically activated in response to GLP-1R and CCK1R co-agonism. None of the previously categorized NTS neuronal subpopulations relevant to feeding behaviour were synergistically activated. However, using PhosphoTRAP, we obtained the molecular signature of NTS and ARH neurons synergistically regulated by the GLP-1R and CCK1R co-agonism and identified NTS/AP Calcrl+ neurons and ARH Adcyap1r1+ neurons as targets of this treatment. Collectively these studies advance our understanding of the central mechanisms involved in the synergistic appetite- and weight-suppressive effect of a combinatorial therapy. Overall design: 24 samples were analyzed , 3 for each groups and sample type (total RNA input and ipRNA)