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BAT Transcriptomics in DIO Vehicle or Cotadutide Mice

ABSTRACT: BAT Transcriptomics in DIO Vehicle or Cotadutide Mice

PROVIDER: PRJNA1198044 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR31709505.fastq.gz	Fastqsanger.gz
	SRR31709505_1.fastq.gz	Fastqsanger.gz
	SRR31709505_2.fastq.gz	Fastqsanger.gz
	SRR31709506.fastq.gz	Fastqsanger.gz
	SRR31709506_1.fastq.gz	Fastqsanger.gz

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BAT Transcriptomics in DIO Vehicle or Cotadutide Mice

Project description:Early drivers of Type 2 diabetes mellitus (T2D) include ectopic fat accumulation, especially in the liver, that significantly impairs insulin sensitivity. In a T2D setting, GLP-1R/GCGR dual agonists have been shown to reduce glycaemia, body weight and hepatic steatosis. We utilized cotadutide, a well characterized GLP-1R/GCGR dual-agonist, to demonstrate improved insulin sensitivity during hyperinsulinemic euglycemic clamp following sub-chronic dosing in male, diet-induced obese mice. Cotadutide or GCGR monoagonist treatment resulted in specific increased brown adipose tissue (BAT) insulin-stimulated glucose uptake, while GLP-1R monoagonist only showed a weak effect. BAT from cotadutide treated mice had induction of UCP-1 protein, increased mitochondrial area and a transcriptomic profile of increased fat oxidation and mitochondrial activity. Thus, GLP-1R/GCGR dual agonism provides multimodal efficacy to decrease hepatic steatosis and consequently improve insulin sensitivity, in concert with recovery of endogenous β-cell function and reduced insulin demand. This substantiates GLP-1R/GCGR dual-agonism as a novel and effective T2D treatment.

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Project description:Bats have adapted to pathogens through diverse mechanisms, including increased resistance - rapid pathogen elimination, and tolerance - limiting tissue damage following infection. In the Egyptian fruit bat (an important model in comparative immunology) several mechanisms conferring disease tolerance were discovered, but mechanisms underpinning resistance remain poorly understood. Previous studies on other species suggested that elevated basal expression of innate immune genes may lead to increased resistance to infection. Here, we test whether such transcriptional patterns occur in Egyptian fruit bat tissues through single-cell and spatial transcriptomics of gut, lung and blood cells, comparing gene expression between bat, mouse and human. Despite numerous recent loss and expansion events of interferons in the bat genome, interferon expression and induction are remarkably similar to that of mouse. In contrast, central complement system genes are highly and uniquely expressed in key regions in bat lung and gut epithelium, unlike in human and mouse. These genes also evolve rapidly in their coding sequence across the bat lineage. Finally, the bat complement system displays strong hemolytic and inhibitory activities. Together, these results indicate a distinctive transcriptional divergence of the complement system, which may be linked to bat resistance, and highlight the intricate evolutionary landscape of bat immunity.

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