Biology subjects

Castell, A.-L.

Publications and source records attributed to Castell, A.-L..

3 recordsLinked to original sources

bioRxiv2022

Beta-cell mass expansion during puberty involves serotonin signaling and determines glucose homeostasis in adulthood

Puberty is associated with transient insulin resistance that normally recedes at the end of puberty; however, in overweight children insulin resistance persists leading to an increased risk of type 2 diabetes. The mechanisms whereby pancreatic {beta} cells adapt to pubertal insulin resistance, and how they are affected by the metabolic status, have not been investigated. Here we show that puberty is associated with a transient increase in {beta}-cell proliferation in rats and humans of both sexes. In rats, {beta}-cell proliferation correlated with a rise in growth hormone (GH) levels. Serum from pubertal rats and humans promoted {beta}-cell proliferation, suggesting the implication of a circulating factor. In pubertal rat islets, expression of genes of the GH/serotonin (5-HT) pathway underwent changes consistent with proliferative effect. Inhibition of the pro-proliferative 5-HT receptor isoform HTR2b blocked the increase in {beta}-cell proliferation in pubertal islets ex vivo and in vivo. Peri-pubertal metabolic stress blunted {beta}-cell proliferation during puberty and led to altered glucose homeostasis later in life. This study identifies a role of GH/GHR/5-HT/HTR2b signaling in the control of {beta}-cell mass expansion during puberty and a mechanistic link between pubertal obesity and the risk of developing type 2 diabetes.

physiology↗

bioRxiv2021

Single-cell RNA sequencing reveals a role for reactive oxygen species and peroxiredoxins in fatty-acid-induced rat β-cell proliferation

The functional mass of insulin-secreting pancreatic {beta} cells expands to maintain glucose homeostasis in the face of nutrient excess, in part via replication of existing {beta} cells. To decipher the underlying molecular mechanisms, we assessed {beta}-cell proliferation in isolated rat islets exposed to glucose and oleate or palmitate for 48 h and analyzed the transcriptional response by single-cell RNA sequencing. Unsupervised clustering of pooled {beta} cells identified subpopulations, including proliferating {beta} cells. {beta}-cell proliferation increased in response to oleate but not palmitate. Both fatty acids enhanced the expression of genes involved energy metabolism and mitochondrial activity. Comparison of proliferating vs. non-proliferating {beta} cells and pseudotime ordering suggested the involvement of reactive oxygen species (ROS) and peroxiredoxin signaling. Accordingly, the antioxidant N-acetyl cysteine and the peroxiredoxin inhibitor Conoidin A both blocked oleate-induced {beta}-cell proliferation. Our data reveal a key role for ROS signaling in {beta}-cell proliferation in response to nutrients.

cell biology↗

bioRxiv2021

Very Long-Chain Unsaturated Sphingolipids Mediate Oleate-Induced Rat β-Cell Proliferation

Fatty-acid (FA) signaling contributes to {beta}-cell mass expansion in the face of nutrient excess, but the underlying mechanisms are poorly understood. Here we tested the hypothesis that sphingolipids, generated by the intracellular metabolism of FA, are implicated in the {beta}-cell proliferative response to FA. Isolated rat islets were exposed to individual FA in the presence of 16.7 mM glucose for 48 h and the contribution of the de novo sphingolipid synthesis pathway was tested using the serine palmitoyltransferase inhibitor myriocin, the sphingosine kinase (SphK) inhibitor SKI II, or adenovirus-mediated knockdown of SphK, fatty-acid-elongase-1 (ELOVL1) and acyl-CoA-binding protein (ACBP). Wistar rat were infused with glucose and the lipid emulsion ClinOleic and received SKI II by gavage. B-cell proliferation was assessed by immunochemistry or flow cytometry. Sphingolipidomic analyses were performed by LC-MS/MS. Amongst the various FA tested, only oleate increased {beta}-cell proliferation. Myriocin, SKI II, and SphK knockdown all decreased oleate-induced {beta}-cell proliferation. Oleate exposure did not increase the total amount of sphingolipids but led to a specific rise in 24:1 species. Knockdown of ACBP or ELOVL1 inhibited oleate-induced {beta}-cell proliferation. We conclude that unsaturated very long-chain sphingolipids produced from the available pool of C24:1 acyl-CoA mediate oleate-induced {beta}-cell proliferation in rats.

cell biology↗