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Behavioural and neurochemical mechanisms underpinning the synergistic feeding-suppressive effect of GLP-1/CCK combinatorial therapy

ABSTRACT: Behavioural and neurochemical mechanisms underpinning the synergistic feeding-suppressive effect of GLP-1/CCK combinatorial therapy

PROVIDER: PRJNA560362 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR9972540_1.fastq.gz	Fastqsanger.gz
	SRR9972540_2.fastq.gz	Fastqsanger.gz
	SRR9972550_1.fastq.gz	Fastqsanger.gz
	SRR9972550_2.fastq.gz	Fastqsanger.gz
	SRR9972560_1.fastq.gz	Fastqsanger.gz

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Behavioural and neurochemical mechanisms underpinning the synergistic feeding-suppressive effect of GLP-1/CCK combinatorial therapy

Project description: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.

2019-08-16 | GSE135862 | GEO

Behavioural and neurochemical mechanisms underpinning the feeding-suppressive effect of GLP-1/CCK combinatorial therapy.

Project description:ObjectivesCombinatorial therapies are under intense investigation to develop more efficient anti-obesity drugs; however, little is known about how they act in the brain to produce enhanced anorexia and weight loss. The goal of this study was to identify the brain sites and neuronal populations engaged during the co-administration of GLP-1R and CCK1R agonists, an efficient combination therapy in obese rodents.MethodsWe measured acute and long-term feeding and body weight responses and neuronal activation patterns throughout the neuraxis and in specific neuronal subsets in response to GLP-1R and CCK1R agonists administered alone or in combination in lean and high-fat diet fed mice. We used PhosphoTRAP to obtain unbiased molecular markers for neuronal populations selectively activated by the combination of the two agonists.ResultsThe initial anorectic response to GLP-1R and CCK1R co-agonism was mediated by a reduction in meal size, but over a few hours, a reduction in meal number accounted for the sustained feeding suppressive effects. The nucleus of the solitary tract (NTS) is one of the few brain sites where GLP-1R and CCK1R signalling interact to produce enhanced neuronal activation. None of the previously categorised NTS neuronal subpopulations relevant to feeding behaviour were implicated in this increased activation. However, we identified NTS/AP Calcrl+ neurons as treatment targets.ConclusionsCollectively, these studies indicated that circuit-level integration of GLP-1R and CCK1R co-agonism in discrete brain nuclei including the NTS produces enhanced rapid and sustained appetite suppression and weight loss.

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