Biology subjects

Annicotte, J.-S.

Publications and source records attributed to Annicotte, J.-S..

4 recordsLinked to original sources

bioRxiv2026

Fatty acids from adipocyte lipolysis stimulate insulin secretion

White adipose tissue and pancreatic islets play central roles in the regulation of metabolic homeostasis. Although ectopic lipid accumulation is established as a driver of impaired insulin secretion, the acute contribution of adipocyte lipolysis to islet function remains poorly documented. Here, we investigated a mouse model with inducible adipocyte-specific deletion of both adipose triglyceride lipase (ATGL) and hormone-sensitive lipase (HSL), which leads to defective adipocyte lipolysis. Despite preserved ex vivo islet function, these mice displayed a marked reduction in insulin secretion in response to stimulation of adipocyte {beta}3-adrenoceptors, as well as following glucose and arginine challenges. Mechanistically, we identified non-esterified fatty acids as critical mediators of lipolysis-driven insulin secretion, engaging pancreatic signaling of the free fatty acid receptors FFAR4 (a.k.a. GPR120) and FFAR1 (a.k.a. GPR40). The regulation of insulin secretion by adipocyte lipolysis was preserved in high-fat diet-induced obesity. These findings identify an underappreciated adipose-islet crosstalk that couples adipocyte lipolysis to insulin secretion and links lipid and glucose metabolism.

physiology↗

bioRxiv2025

Sex-dependent effects of maternal high-fat diet during lactation in adult THY-Tau22 mice offspring

The perinatal environment has been suggested to participate to the development of tauopathies and Alzheimers disease but the molecular and cellular mechanisms involved remain contradictory and under-investigated. Here, we evaluated the effects of a maternal high-fat diet (HFD) during lactation on the development of tauopathy in the THY-Tau22 mouse strain, a model of progressive tau pathology associated with cognitive decline. During lactation, dams were fed either a chow diet (13.6% of fat) or a HFD (58% of fat). At weaning, offspring was fed a chow diet until sacrifice at 4 months of age (the onset of tau pathology) or 7 months of age (the onset of cognitive impairment). During lactation, maternal HFD increased body weight gain in offspring. At 3 months of age, maternal HFD led to a mild glucose intolerance only in male offspring. Moreover, it impaired spatial memory in both male and female 6-month-old offspring, with males being more impacted. These cognitive deficits were associated with increased phosphorylation of hippocampal tau protein-observed at 4 months in males and at 7 months in females, highlighting a sex-specific temporal shift. Additionally, maternal HFD modified adult hippocampal neurogenesis (AHN), leading to an increase of mature neuronal cells number in females and of dendritic arborization length in males. Synaptic analysis further revealed that maternal HFD led to synaptic loss only in males. Finally, multi-omics approaches showed that maternal HFD has long-term consequences on both transcriptome, proteome and regulome, this effect being also sex-dependent with mitochondrial pathways, ribosomal activity, cilium and the extracellular matrix predominantly impacted in males, while gliogenesis, myelination and synaptic plasticity were primarily affected in females. Regulome analysis suggested that this sex-dependent phenotype was more related to a temporal shift rather than distinct sex-specific alterations. Collectively, our data suggest that maternal malnutrition accelerates the development of tauopathy in THY-Tau22 offspring, with sex-dependent effects, males being impacted earlier than females. These findings highlight the critical role of the perinatal environment as a key window of opportunity for interventions aimed at preventing the development of neurodegenerative diseases.

neuroscience↗

bioRxiv2023

High-throughput quantitative screening of glucose-stimulated insulin secretion and insulin content using automated MAL-DI-TOF mass spectrometry

Type 2 diabetes (T2D) is a metabolic disorder characterized by loss of pancreatic {beta}- cell function, decreased insulin secretion and increased insulin resistance, that affects more than 400 million people worldwide. Although several treatments are proposed to patients suffering from T2D, long-term control of glycemia remains a challenge. Therefore, identifying new potential drugs and targets that positively affect {beta}-cell function and insulin secretion remains crucial. Here, we developed an automated approach to allow the identification of new compounds or genes potentially involved in {beta}-cell function in a 384-well plate format, using the murine {beta}-cell model Min6. Using MALDI-TOF mass spectrometry, we have implemented a high-throughput screening (HTS) strategy based on the automation of a cellular assay allowing to detect insulin secretion in response to glucose, quantitative detection of insulin, in a miniaturized system. As a proof of concept, we screened siRNA targeting well-know {beta}-cell genes and 1600 chemical compounds and identified several molecules as potential regulators of insulin secretion and/or synthesis, demonstrating that our approach allows HTS of insulin secretion in vitro.

physiology↗

bioRxiv2021

A crosstalk between E2F1 and GLP-1 signaling pathways modulates insulin secretion

Compromised {beta}-cell function contributes to type 2 diabetes (T2D) development. The glucagon like peptide 1 (Glp-1) has emerged as a hormone with broad pharmacological potential toward T2D treatment, notably by improving {beta}-cell functions. Recent data have shown that the transcription factor E2f1, besides its role as a cell cycle regulator, is involved in glucose homeostasis by modulating {beta}-cell mass, function and identity. Here, we demonstrate a crosstalk between the E2F1, phosphorylation of retinoblastoma protein (pRb) and Glp-1 signaling pathways. We found that {beta}-cell specific E2f1 deficient mice (E2f1{beta}-/-) presented with impaired glucose homeostasis and decreased glucose stimulated-insulin secretion mediated by exendin 4 (i.e., GLP1R agonist), which were associated with decreased expression of Glp1r encoding Glp-1 receptor (GLP1R) in E2f1{beta}-/- pancreatic islets. Decreasing E2F1 transcriptional activity with an E2F inhibitor in islets from nondiabetic humans decreased GLP1R levels and blunted the incretin effect of exendin 4 on insulin secretion. Conversely, overexpressing E2f1 in pancreatic {beta} cells increased Glp1r expression associated with enhanced insulin secretion mediated by GLP1R agonist. Interestingly, kinome analysis of mouse islets demonstrated that an acute treatment with exendin 4 increased pRb phosphorylation and subsequent E2f1 transcriptional activity. This study suggests a molecular crosstalk between the E2F1/pRb and GLP1R signaling pathways that modulates insulin secretion and glucose homeostasis.

physiology↗