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Role of CB2 in adipose tissue ILC2s

ABSTRACT: Development of type 2 diabetes mellitus (T2DM) is associated low-grade chronic type 2 inflammation and disturbance of glucose homeostasis. Group 2 innate lymphoid cells (ILC2s) play a critical role in maintaining adipose homeostasis via production of type 2 cytokines. Here, we demonstrate that CB2, a G-protein coupled receptor (GPCR) and member of endocannabinoid system, is expressed on both visceral adipose tissue (VAT)-derived murine and human ILC2s. Moreover, we utilize a combination of ex vivo and in vivo approaches to explore the functional and therapeutic impacts of CB2 engagement on VAT ILC2s in T2DM model. Our results show CB2 stimulation of ILC2s protects against insulin-resistance onset, ameliorates glucose tolerance, and reverses established insulin-resistance. Our mechanistic studies reveal that the therapeutic effects of CB2 are mediated through activation of AKT, ERK1/2 and CREB pathways on ILC2s. The results reveal that CB2 agonist can serve as candidate for prevention and treatment of T2DM.

ORGANISM(S): Mus musculus

PROVIDER: GSE268067 | GEO | 2024/08/16

REPOSITORIES: GEO

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Project description:Development of insulin resistance is a key pathogenic component underlying metabolic syndrome and Type 2 diabetes (T2DM). Despite its importance, the molecular mechanisms underlying insulin resistance are poorly understood. Genome-wide association studies for T2DM and other metabolic traits have led to the identification of many candidate SNPs, but the majority of these SNPs are noncoding and determination of associated causal genes and/or specific tissue sites of action have been difficult. Adipocytes are critical regulators of mammalian metabolic homeostasis, with important effects on appetite, satiety, glucose and lipid homeostasis, energy expenditure, blood pressure, and immune function. Although insulin resistance (IR) in skeletal muscle, the major source of glucose disposal, is responsible for the bulk of the hyperglycemia observed in T2DM, muscle IR KO mice are generally healthy, IR also occurs in adipocytes, and inflammation within adipose tissue has been proposed as a primary mediator of IR, resulting in excess release of free fatty acids as well as alterations in adipokine release. Absence of adipose tissue, as observed in various lipodystrophies, or adipocyte-specific knockout of genes such as GLUT4 or insulin receptor, also alter systemic IR and T2DM risk. Transcriptional changes in adipocytes associated with metabolic disease. Despite the importance of adipocytes to metabolic disease, we have a poor understanding of how the adipocyte transcriptome changes in the disease state. Studies investigating transcriptional changes in whole adipose tissue have shown decreases in genes involved in adipogenesis, as well as alterations in inflammation, mitochondrial metabolism, lipid metabolism, detoxification, and insulin signaling. However, the vast majority of these studies use total adipose tissue samples, which does not allow for the exclusive evaluation of gene expression in mature adipocytes due to the substantial number of nonadipocyte cells (immune cells, fibroblasts, endothelial cells, pre-adipocytes, and mesenchymal cells) that also reside in adipose tissue. This is particularly relevant when studying metabolic disorders related to obesity-associated insulin resistance because these conditions are characterized by an increased influx of inflammatory cells into the adipose tissue.

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Role of CB2 in adipose tissue ILC2s

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