Biology subjects

Matveyenko, A. V.

Publications and source records attributed to Matveyenko, A. V..

3 recordsLinked to original sources

bioRxiv2026

Circadian feeding rhythm loss drives sex-specific β-cell dysfunction in diet-induced obesity

Diet-induced obesity (DIO), modeled by a high-fat diet (HFD), adversely affects circadian glucose homeostasis partly by dysregulating fasting/feeding cycles. However, its impact on circadian {beta}-cell function and relevant transcriptional programs remains unclear. To investigate this, we exposed male and female C57BL/6 mice to either chow or HFD for eight weeks and assessed behavioral (feeding/activity), physiological (glucose tolerance/insulin secretion), transcriptomic (RNA sequencing (RNA-seq)), and epigenomic (Assay for Transposase-Accessible Chromatin using Sequencing (ATAC-seq)) circadian rhythms. Additionally, we tested whether normalizing fasting/feeding cycles via time-restricted feeding (tRF) during the dark- or light-phase of the circadian cycle could mitigate DIO's deleterious effects. DIO disrupted circadian fasting/feeding rhythms, with greater disruption in males than females (p<0.05 vs. CHOW). In males, DIO abolished circadian regulation of glucose tolerance and in vivo glucose-stimulated insulin secretion (GSIS) (p<0.05 vs. chow), whereas female mice maintained circadian glucose homeostasis. RNA-seq analysis of male islets revealed a 42.1% reduction in circadian-regulated transcripts under DIO, with weakened rhythms in key {beta}-cell pathways such as insulin secretion. Moreover, ATAC-Seq analysis indicated reduced chromatin accessibility of genes/pathways related to insulin secretion and glucose hemostasis under DIO (p<0.05 vs. chow) during both dark- or light-phase of the circadian cycle. Notably, dark-phase time-restricted feeding (tRF) restored circadian glucose tolerance, GSIS, and islet gene expression, whereas light-phase tRF enhanced {beta}-cell function during the normally inactive/light phase of the circadian cycle, further suppressing circadian rhythmicity of the islet transcriptome. Motif analysis indicated that DIO suppressed the activity of D-box transcription factors (TFs) (DBP and TEF) while enhancing the activity of ETS family TFs (ELK1, ETS2, ELF2, and GABPA), which was partly mitigated by dark-phase tRF. Our study demonstrates that DIO disrupts circadian {beta}-cell function and gene expression by dysregulating fasting/feeding cycles in male mice and reveals significant sex differences in how DIO affects circadian glucose homeostasis and {beta}-cell function.

physiology↗

bioRxiv2024

Lipotoxicity Induces Beta Cell Small Extracellular Vesicle-mediated Beta Cell Dysfunction

Chronically elevated circulating excess free fatty acids (i.e. lipotoxicity) is a pathological process implicated in several metabolic disorders, including obesity-driven Type 2 diabetes (T2D). Lipotoxicity exerts detrimental effects on pancreatic islet {beta}-cells by reducing glucose-stimulated insulin secretion (GSIS), altering {beta}-cell transcriptional identity, and promoting apoptosis. While {beta}-cell-derived small extracellular vesicles (sEV) have been shown to contribute to {beta}-cell failure in T2D, their specific role in lipotoxicity-mediated {beta}-cell failure remains to be elucidated. In this work, we demonstrate that lipotoxicity enhances the release of sEVs from {beta}-cells, which exhibit altered proteomic and lipidomic profiles. These lipotoxic sEV induce {beta}-cell dysfunction in healthy mouse and human islets and trigger significant islet transcriptional changes, including the upregulation of genes associated with the TGF{beta}/Smad3 pathway, as noted by RNA sequencing. Importantly, pharmacological inhibition of the TGF{beta}I/II receptor improved lipotoxic sEV-induced {beta}-cell dysfunction, underscoring their involvement in activating the TGF{beta}/Smad3 pathway during this process. We have comprehensively characterized lipotoxic {beta}-cell sEVs and implicated their role in inducing {beta}-cell functional failure in T2D. These findings highlight potential avenues for therapeutic interventions targeting sEV-mediated pathways to preserve {beta}-cell health in metabolic disorders. Article HighlightsO_LIDiabetogenic lipotoxic conditions enhance {beta}-cell sEV release and induce alterations in both protein and lipid content. C_LIO_LIGlobal islet transcriptional changes and alterations in {beta}-cell function were noted upon exposure to lipotoxic sEV. C_LIO_LILipotoxic sEV were shown to activate the TGF{beta}/Smad3 pathway and blockade of this pathway improved {beta}-cell function. C_LI

molecular biology↗

bioRxiv2019

Pro-inflammatory cytokines disrupt β-cell circadian clocks in diabetes

Intrinsic {beta}-cell circadian clocks are a prerequisite for the control of glucose homeostasis through regulation of {beta}-cell function and turnover. However, little is known about the contributions of circadian clock disruption to the natural progression of {beta}-cell failure in diabetes. To address this, we examined the effects of cytokine-mediated inflammation, common to the pathophysiology of Type 1 and Type 2 diabetes, on the physiological, molecular, and epigenetic regulation of circadian clocks in {beta}-cells. Specifically, we provide evidence that the key diabetogenic cytokine IL-1{beta} disrupts functionality of the {beta}-cell circadian clock and circadian regulation of insulin secretion through impaired expression of the key transcription factor Bmal1, evident at the level of promoter activation, mRNA, and protein expression. Additionally, IL-1{beta}-mediated inflammation was shown to augment genome-wide DNA-binding patterns of Bmal1 (and its heterodimer, Clock) in {beta}-cells towards binding sites in the proximity of genes annotated to pathways regulating {beta}-cell apoptosis, inflammation, and dedifferentiation. Finally, we identified that the development of hyperglycemia in humans is associated with compromised {beta}-cell BMAL1 expression suggestive of a causative link between circadian clock disruption and {beta}-cell failure in diabetes.

cell biology↗