Biology subjects

Palaniyandi, J.

Publications and source records attributed to Palaniyandi, J..

4 recordsLinked to original sources

bioRxiv2026

β-cell-specific Ahr expression is critical to high-fat diet-induced hyperinsulinemia

ObjectiveThe aryl hydrocarbon receptor (AhR) pathway primarily mediates pollutant responses by activating xenobiotic metabolism enzymes like cytochrome P450 1A1 and 1A2 (CYP1A). Although AhR has also been implicated in systemic metabolic dysfunction and is inducible in pancreatic islets, its role in islet physiology remains unclear. MethodsWe analyzed a publicly available bulk human islet transcriptomic dataset to identify pathways associated with CYP1A1 expression. We also assessed islet responses to the pollutant 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and glucolipotoxicity (GLT) in vitro using two mouse models: a global Cyp1a1/1a2 double knockout (CypKO) model, which disrupts canonical AhR-CYP1A signaling in whole islets, and a {beta}-cell-specific Ahr knockout ({beta}AhrKO) model, which abolishes AhR signaling selectively in {beta}-cells. We then examined the role of {beta}-cell Ahr in early adaptation to high-fat diet (HFD) feeding in vivo. ResultsXenobiotic and nutrient metabolism pathways were enriched in donors with high CYP1A1 expression. Global Cyp1a1/1a2 deletion increased susceptibility of female mouse islets to TCDD-induced impairments in insulin secretion but had minimal effects on GLT responses in either sex. In contrast, {beta}-cell Ahr deletion did not affect islet responses to TCDD, but exacerbated GLT-induced islet dysfunction in male islets and increased baseline insulin secretion in both vehicle- and GLT-exposed female islets in vitro. Lastly, {beta}-cell Ahr deletion prevented adaptive HFD-induced hyperinsulinemia in both sexes in vivo. ConclusionIslet AhR signaling shapes responses to chemical and nutrient stressors in a context- and sex-dependent manner. While the canonical AhR-CYP1A axis supports female islet resilience to TCDD, {beta}-cell AhR signaling more broadly regulates nutrient stress responses in both sexes.

physiology↗

bioRxiv2026

Cisplatin exposure alters long-term metabolic phenotype of male, but not female, high-fat diet-fed mice.

Cancer survivors face an increased risk of metabolic complications compared to the general population. Our group demonstrated that cisplatin, a platinum-based chemotherapeutic agent, robustly disrupts insulin secretion in vitro in mouse and human islets, and reduces plasma insulin levels in mice 2 weeks post-in vivo exposure. The long-term effects of in vivo cisplatin exposure alongside a pre-existing metabolic stressor, such as high-fat diet (HFD) feeding, have not been characterized. In the present study, male and female mice fed either a standard rodent chow or a 45 kcal% HFD were exposed to vehicle or 2 mg/kg cisplatin every other day for 2 weeks and then tracked for 18 weeks. Cisplatin exposure substantially influenced the metabolic phenotype of HFD-fed males but had limited impact on female HFD-fed mice. Vehicle-HFD and cisplatin-HFD male mice were both glucose intolerant compared to chow-fed controls yet, cisplatin-HFD male mice were lean, lacked a compensatory hyperinsulinemia response, and displayed increased insulin sensitivity compared to vehicle-HFD and vehicle-chow male controls. Additionally, transcriptional changes in islets isolated at 18-weeks post-exposure were largely cisplatin-driven in male mice, but diet-driven in female mice. Our study demonstrates that HFD-fed male mice exposed to cisplatin display persistent and exacerbated metabolic dysregulation relative to controls. ARTICLE HIGHLIGHTSO_ST_ABSWhy did we undertake this study?C_ST_ABSWe previously characterized the short-term metabolic effects of cisplatin exposure in vivo, but the long-term metabolic effects of cisplatin remained unknown. What is the specific question(s) we wanted to answer?How does cisplatin treatment impact long-term metabolic health outcomes in mice and do outcomes differ in the presence of a metabolic stressor? What did we find?Cisplatin significantly alters the metabolic phenotype of high-fat diet-fed male mice. What are the implications of our findings?Understanding how cisplatin exposure and metabolic stress interact is critical to mitigate long-term metabolic dysregulation in cancer survivors.

physiology↗

bioRxiv2025

Acute PFOS exposure consistently dysregulates glucose-stimulated insulin secretion across model systems

Aims/hypothesisPoly- and perfluoroalkyl substances (PFAS) are fluorinated chemicals widely used in consumer and industrial products. Serum PFAS concentrations have been linked to increased type 2 diabetes risk, but whether this is caused by direct effects of PFAS on the endocrine pancreas remains unclear. This study expands on previous biodistribution data to better characterize PFAS accumulation in human pancreas. We also assessed the effects of perfluorooctane sulfonic acid (PFOS) on pancreatic beta cell function using various model systems. MethodsWe measured concentrations of three legacy PFAS (PFOS, PFOA, PFHxS) in plasma and pancreas from 88 human donors. We also modeled PFOS and PFOA exposure in mice to confirm our human biodistribution data. We next exposed immortalized INS-1 cells, primary human donor islets, and primary mouse islets to DMSO (vehicle) or PFOS (1, 10 or 100 M) either acutely during a glucose-stimulated insulin secretion (GSIS) assay or for 48h (prolonged) and GSIS was subsequently measured. We also assessed whether the acute effects of PFOS on GSIS in mouse islets were mediated by G-protein coupled receptor-40 (GPR40) and/or glucagon-like peptide-1 receptor (GLP-1R). Lastly, we exposed female mice to DMSO or 10 mg/kg PFOS with or without a 2 g/kg glucose bolus to assess the acute effects of PFOS on glucose homeostasis in vivo. ResultsPFOS was detected at higher concentrations in both plasma and pancreas compared to PFOA and PFHxS in our human donor population. Similarly, PFOS accumulated in pancreas at concentrations 2x higher than PFOA in our mouse model. We provide compelling evidence that PFOS exposure dysregulates insulin secretion in various model systems. Prolonged PFOS exposure suppressed GSIS in INS-1 832/3 cells and mouse islets, whereas acute PFOS exposure stimulated GSIS in mouse islets and in a subset of our human donor islets. We also show that the acute effects of PFOS on GSIS in mouse islets were partly mediated by GLP-1R. Importantly, acute PFOS exposure increased plasma insulin levels in female mice in vivo, but only when PFOS exposure was concurrent with a glucose bolus. ConclusionsLegacy PFAS chemicals are consistently detected in human pancreas tissue. We clearly show that PFOS exposure dysregulates insulin secretion in various model systems, although effects varied based on the model and duration of exposure. Collectively, our findings support emerging evidence that PFOS contribute to beta cell dysfunction and points to the importance of model selection when assessing toxicological effects of PFAS on islet function.

molecular biology↗

bioRxiv2023

The aryl hydrocarbon receptor in beta-cells mediates the effects of TCDD on glucose homeostasis in mice

Chronic exposure to persistent organic pollutants (POPs) is associated with increased incidence of type 2 diabetes, hyperglycemia, and poor insulin secretion in humans. Dioxins and dioxin-like compounds are a broad class of POPs that exert cellular toxicity through activation of the aryl hydrocarbon receptor (AhR). We previously showed that a single high-dose injection of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD, aka dioxin; 20 {micro}g/kg) in vivo reduced fasting and glucose-stimulated plasma insulin levels for up to 6 weeks in male and female mice. TCDD-exposed male mice were also modestly hypoglycemic and had increased insulin sensitivity, whereas TCDD-exposed females were transiently glucose intolerant; whether these effects are driven by AhR activation in {beta}-cells requires investigation. Here we exposed female and male {beta}-cell specific AhR knockout ({beta}AhrKO) mice and littermate Ins1-Cre genotype controls ({beta}AhrWT) to a single high dose of 20 {micro}g/kg TCDD and tracked the mice for 6 weeks. We found that deleting AhR from {beta}-cells increased insulin secretion ex vivo in female mouse islets and promoted modest weight gain in male mice under baseline conditions. Importantly, high-dose TCDD exposure impaired glucose homeostasis and {beta}-cell function in {beta}AhrWT mice, but these phenotypes were largely abolished in TCDD-exposed {beta}AhrKO mice. Our study demonstrates that AhR signaling in {beta}-cell is important for regulating baseline {beta}-cell function in female mice and energy homeostasis in male mice. We also show that {beta}-cell AhR signaling largely mediates the effects of TCDD on glucose homeostasis in both female and male mice, suggesting that the effects of TCDD on {beta}-cell function/health are driving metabolic phenotypes in peripheral tissues.

molecular biology↗