Dataset Information

Systemic metabolic alterations correlate with islet-level prostaglandin E2 production and signaling mechanisms that predict beta-cell dysfunction in a mouse model of type 2 diabetes

ABSTRACT: The transition from β-cell compensation to β-cell failure is not well understood. Previous works by our group and others have demonstrated a role for Prostaglandin EP3 receptor (EP3), encoded by the Ptger3 gene, in the loss of functional β-cell mass in T2D. The primary endogenous EP3 ligand is the arachidonic acid metabolite, prostaglandin E2 (PGE2). Pancreatic islet EP3 expression, expression of PGE2 synthetic enzymes, and/or PGE2 excretion itself have all been shown as up-regulated in primary mouse and human islets isolated from animals or human organ donors with established T2D as compared to non-diabetic controls. In this study, we took advantage of a rare and fleeting phenotype in which a subset of Black and Tan BRachyury (BTBR) mice homozygous for the Leptinob/ob mutation—a strong genetic model of T2D—were entirely protected from fasting hyperglycemia even with equal obesity and insulin resistance as their hyperglycemic littermates. Utilizing this model, we found numerous alterations in full-body metabolic parameters in T2D-protected mice (e.g., gut microbiome composition, circulating pancreatic and incretin hormones, and markers of systemic inflammation) that correlate with improvements in EP3-mediated β-cell dysfunction.

INSTRUMENT(S): Bruker Daltonics solarix series

ORGANISM(S): Mus Musculus (mouse)

TISSUE(S): Blood Plasma

DISEASE(S): Type 2 Diabetes Mellitus

SUBMITTER: Yanlong Zhu

LAB HEAD: Ying Ge

PROVIDER: PXD022624 | Pride | 2021-09-09

REPOSITORIES: Pride

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Dataset's files

Source:

			Action	DRS
	Blank1Neg5ul_03_2059.baf	Other
	Blank1Neg5ul_03_2059.mzML	Mzml
	Blank1Pos5ul_01_1939.baf	Other
	Blank1Pos5ul_01_1939.mzML	Mzml
	Blank2Neg5ul_04_2060.baf	Other

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Publications

Systemic Metabolic Alterations Correlate with Islet-Level Prostaglandin E2 Production and Signaling Mechanisms That Predict β-Cell Dysfunction in a Mouse Model of Type 2 Diabetes.

Schaid Michael D MD Zhu Yanlong Y Richardson Nicole E NE Patibandla Chinmai C Ong Irene M IM Fenske Rachel J RJ Neuman Joshua C JC Guthery Erin E Reuter Austin A Sandhu Harpreet K HK Fuller Miles H MH Cox Elizabeth D ED Davis Dawn B DB Layden Brian T BT Brasier Allan R AR Lamming Dudley W DW Ge Ying Y Kimple Michelle E ME

Metabolites 20210116 1

The transition from β-cell compensation to β-cell failure is not well understood. Previous works by our group and others have demonstrated a role for Prostaglandin EP3 receptor (EP3), encoded by the Ptger3 gene, in the loss of functional β-cell mass in Type 2 diabetes (T2D). The primary endogenous EP3 ligand is the arachidonic acid metabolite prostaglandin E2 (PGE2). Expression of the pancreatic islet EP3 and PGE2 synthetic enzymes and/or PGE2 e ...[more]

PMID: 33467110

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Project description:Recognition of foreign antigens by B cell receptor (BCR) on mature B cells leads to their clonal expansion, which is critically important for the effective host defence of the organism. However, excessive antigenic responses or reaction of B cells against bodyâs own components frequently lead to diverse immune diseases, such as B-cell lymphoma or autoimmunity, that often affect humans. Identification of genes that restrain uncontrolled proliferation of B cells is therefore an important goal towards understanding the origin of such diseases. Here we identify Ptger4 as a negative feedback regulator of B-cell proliferation in response to BCR triggering, and show that its encoded EP4 receptor is a principal molecule conveying the growth-suppressive effect of prostaglandin E2 (PGE2). In controlled in vitro assays, Ptger4-/- B cells showed augmented proliferative response and increased expression of activating genes upon BCR stimulation. Stable knock-down of Ptger4 in B-cell lymphoma markedly accelerated tumour spread in mice, while Ptger4 overexpression yielded significant protection. Lack of Ptger4 rendered mouse B cells completely resistant to proliferation arrest signalled by PGE2, and we find by transcriptional profiling that intrinsic activity of Ptger4 and PGE2-EP4 signalling target a similar set of activating genes. We further show that Ptger4 inhibits mouse B-cell activation in vivo and find it significantly downregulated in human B-cell lymphoma. Our results demonstrate that Ptger4 functions in B cells as a candidate tumour suppressor whose activity is regulated by the presence of PGE2 in the microenvironment. These findings suggest that targeting EP4 receptor for prostaglandin may present a novel strategy for treatment of B-cell diseases. Keywords: time course, cell type comparison, compound treatment design, microarray experiment record B cells were extracted from spleen of Ptger4+/+ and Ptger4-/- mice, and incubated in vitro for the indicated period with or without anti-IgM (Fab')2 antibody fragments and co-treated with or without PGE2. Total RNA was extracted, amplified, labelled with Cy3 or Cy5, and hybridized to mouse 24k oligo-arrays using a dye-swap strategy.

Dataset Information

Systemic metabolic alterations correlate with islet-level prostaglandin E2 production and signaling mechanisms that predict beta-cell dysfunction in a mouse model of type 2 diabetes

Dataset's files

Publications

Systemic Metabolic Alterations Correlate with Islet-Level Prostaglandin E<sub>2</sub> Production and Signaling Mechanisms That Predict β-Cell Dysfunction in a Mouse Model of Type 2 Diabetes.

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