Biology subjects

Pydi, S. P.

Publications and source records attributed to Pydi, S. P..

8 recordsLinked to original sources

bioRxiv2026

THE BILE ACID RECEPTOR TGR5 MODULATES HIPPOCAMPAL NEURAL STEM CELL STATE AND AGEING

Ageing locks hippocampal neural stem cells (NSCs) into deeper quiescence and inflammation-driven senescence, which are also associated with impaired cognition. The bile-acid receptor TGR5, a member class I G-protein coupled receptors (GPCRs), is expressed in cultured hippocampal NSCs and in SOX2-positive cells of the adult sub granular zone, yet its role in NSC homeostasis is unknown. In this study we show that TGR5 selective agonist, TC-G 1005, expanded the NSC pool without forcing neuronal differentiation. Primary NSCs treatment with TC-G 1005 increased BrdU incorporation and PCNA in a concentration-dependent manner, and both responses were lost after TGR5 knockdown. TGR5 agonism in differentiating cultures increased nestin, left doublecortin (DCX) unchanged and suppressed MAP2 expression, preserving stemness rather than neuronal commitment. The agonist also released BMP4-imposed quiescence, lowering FOXO3a and restoring phospho-EGFR and ASCL1, and reopened autophagic flux, with less p62 and LC3-II, fewer LAMP2 puncta and more Beclin-1. Furthermore, activation of TGR5 suppressed IL-6 induced p53 and p16 expression, restored proliferation and contracted the inflammatory transcriptome by more than 90%, including Cdkn2a, Cdkn2b and Cdk6. In 18-month-old mice, brain-penetrant TC-G 1005 (5 mg/kg, subcutaneously, twice daily for 28 days) expanded SOX2-positive and proliferating NSCs, reduced p16, recovered ASCL1 and improved spatial memory, without changing locomotion or generating DCX-positive neurons. Dentate gyrus-restricted TGR5 knockdown abolished these cellular effects and the rescue of spatial and social discrimination. Hippocampal proteomic analysis revealed that TC-G 1005 treated aged mice occupied an intermediate, partially rejuvenated position between young and aged proteomes, with 86 proteins shared between ageing- and treatment-responsive sets, and mitochondrial and complement C1q modules shifted toward youthful levels. TGR5 activation therefore relieves both quiescence and senescence in the aged neurogenic niche without driving neuronal differentiation. Collectively, these results suggest that TGR5 could be targeted to preserve cognition in ageing by rejuvenating the hippocampal stem-cell niche.

neuroscience↗

bioRxiv2026

Myeloid Gi signaling acts as a weight-independent immunometabolic switch controlling systemic insulin sensitivity

Metabolic dysfunction does not necessarily correlate with adiposity. Metabolically healthy obese individuals and insulin-resistant lean individuals represent a fundamental paradox that implicates immune cell intrinsic mechanisms in the pathogenesis of type 2 diabetes. Here, we identify myeloid Gi signaling as a previously unrecognized determinant of whole-body glucose homeostasis. Single-cell transcriptomic analysis of adipose tissue macrophages from obese mice and humans reveals marked alteration in Gnai isoform, suggesting that myeloid Gi signaling is functionally engaged during metabolic disease. Using complementary myeloid-specific rodent models of Gi inhibition (pertussis toxin) and chemogenetic Gi activation (DREADD), we demonstrate that inhibition of Gi signaling improves glucose tolerance and enhances insulin sensitivity under both regular chow and high-fat diet conditions, independent of body weight and energy expenditure. Whereas acute Gi activation in lean mice modestly enhances glucose disposal, the same intervention during diet-induced obesity markedly impairs systemic glucose homeostasis, revealing context-dependent pathway function. Mechanistically, Gi inhibition amplifies macrophage cAMP-CREB signaling to drive IL-6 production, engaging STAT3- and AMPK-dependent pathways in adipose tissue and skeletal muscle to support insulin action. Conversely, Gi activation engages a previously uncharacterized G{beta}{gamma}-mTOR/AKT-JNK cascade, driving IL-1{beta} secretion that directly impairs insulin signaling in adipocytes and myotubes. Pharmacological IL-6 receptor blockade abolishes the metabolic benefits of Gi inhibition, whereas IL-1 receptor antagonism fully rescues Gi activation-induced metabolic dysfunction, establishing these cytokines as obligate downstream effectors. This signaling architecture is conserved in human macrophages, and ATAC-seq profiling reveals chromatin remodeling at cAMP-CREB and IL-6 regulatory pathway loci, consistent with the observed transcriptional reprogramming. Together, these findings establish myeloid Gi signaling as a weight-independent immunometabolic switch that couples opposing cytokine programs to systemic insulin sensitivity and identify this pathway as a therapeutic target in obesity-associated metabolic disease. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=141 SRC="FIGDIR/small/713834v1_ufig1.gif" ALT="Figure 1"> View larger version (56K): org.highwire.dtl.DTLVardef@15e4576org.highwire.dtl.DTLVardef@224cd5org.highwire.dtl.DTLVardef@1e24888org.highwire.dtl.DTLVardef@1080bf3_HPS_FORMAT_FIGEXP M_FIG Graphical Abstract C_FIG

physiology↗

bioRxiv2025

Acute activation of Gq-signaling in islet macrophages inhibits β-cell insulin secretion through AMPK-sphingolipid axis

Obesity-associated inflammation disrupts pancreatic {beta}-cell function, but the immune-derived signals that directly regulate insulin secretion remain incompletely defined. Here, we identify myeloid Gq signaling as a critical immunometabolic node that links macrophage activation to {beta}-cell dysfunction. For the first time, we employed a chemogenetic approach (DREADDs) to selectively and temporally activate Gq-coupled GPCR signaling in myeloid cells to examine its effect on islet function. Our findings reveal that acute Gq activation in islet-resident macrophages impaired glucose-stimulated insulin secretion, uncovering a previously unrecognized immune-endocrine axis. Conversely, myeloid-specific Gq deletion improves systemic glucose homeostasis, underscoring the physiological relevance of this pathway. Mechanistic analysis revealed that Gq activation in macrophages stimulates AMPK signaling and drives the secretion of sphingolipids. These lipids suppress insulin secretion and introduce a new mechanism for immune-islet communication, extending beyond traditional cytokine-based models. We further identify the lipid-sensing receptor GPR18 as an upstream activator of the Gq-AMPK pathway in macrophages. GPR18 stimulation recapitulated the Gq-dependent sphingolipid secretion and {beta}-cell inhibitory phenotype, which was abolished in myeloid Gq-deficient mice. Collectively, these findings establish a mechanistic framework whereby macrophage Gq signaling integrates lipid sensing and metabolic stress to modulate {beta}-cell function. This work reveals a previously unrecognized macrophage-{beta}-cell communication axis with therapeutic potential for restoring insulin secretion in metabolic diseases such as obesity and type 2 diabetes. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=109 SRC="FIGDIR/small/680858v1_ufig1.gif" ALT="Figure 1"> View larger version (44K): org.highwire.dtl.DTLVardef@790c4dorg.highwire.dtl.DTLVardef@116cceborg.highwire.dtl.DTLVardef@1e76631org.highwire.dtl.DTLVardef@e65770_HPS_FORMAT_FIGEXP M_FIG C_FIG

physiology↗

bioRxiv2025

A Temporal Single-Cell Multi-Omics Atlas of Murine Pancreatic Islet Remodeling During Hyperglycaemia Progression

Pancreatic islets undergo coordinated cellular remodeling during obesity-induced insulin resistance (IR). However, the associated molecular changes across endocrine and non-endocrine compartments remain largely unexplored. Here, using longitudinal single-cell RNA sequencing (scRNA-seq) and single-cell ATAC sequencing (scATAC-seq) on islets from C57BL/6 mice subjected to high-fat diet (HFD) feeding for 8, 16, and 24 weeks, along with age-matched controls on regular chow, we mapped dynamic changes in islet cell composition and transcriptional states. Beta cells demonstrated pronounced stress-induced reprogramming, with the emergence of proliferative and dysfunctional subsets. Alpha and delta cell fractions declined under HFD, despite increased polyhormonal biosynthesis, suggesting functional rather than numerical adaptation. Immune profiling showed robust expansion of proinflammatory M1 macrophages and upregulation of NF-{kappa}B and chemotaxis pathways, particularly at 16 weeks. Notably, cell-cell communication analyses revealed diet-specific disruption in signaling networks. Under HFD conditions, intercellular communication among beta cells, macrophages, and delta cells was markedly altered, leading to the disruption of key signaling pathways such as the gastric inhibitory polypeptide receptor (GIPR) and major histocompatibility complex-I (MHC-I). Notably, C-C motif chemokine ligand 27A (Ccl27a) expression and chromatin accessibility were significantly altered in a distinct subpopulation of beta cells under HFD condition, indicative of a niche-specific regulatory mechanism. Integration with human islet datasets from obese and type 2 diabetes (T2D) donors confirmed conserved shifts in beta cell identity and immune activation. This study presents a comprehensive high-resolution atlas of islet remodeling under metabolic stress, identifying key communication nodes and transcriptional programs pertinent to T2D pathogenesis. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=141 SRC="FIGDIR/small/656754v1_ufig1.gif" ALT="Figure 1"> View larger version (52K): org.highwire.dtl.DTLVardef@64aee0org.highwire.dtl.DTLVardef@150beborg.highwire.dtl.DTLVardef@1c19c6dorg.highwire.dtl.DTLVardef@4d1a0_HPS_FORMAT_FIGEXP M_FIG C_FIG

genomics↗

bioRxiv2024

SARS-CoV-2 protein ORF3a induces Atg8ylation of lysosomal membranes

Atg8ylation is an autophagy associated response to membrane damage that recruits mammalian ATG8 proteins (mATG8s) to damaged membranes to promote their repair or removal. Here, we show that the SARS-CoV-2 protein ORF3a induces lysosomal membrane atg8ylation and that this response protects cells from death. mATG8s interact with ORF3a and are required for lysosomal damage induced by ORF3a. ORF3a targets mTOR in an Atg8ylation dependent manner and promotes lysophagy through mATG8 mediated coordination of TRIM16 and Galectin-3. ORF3a triggers apoptosis, necroptosis, and pyroptosis, whereas atg8ylation limits ORF3a- induced cell death. Together, our findings identify mATG8s and the autophagy conjugation machinery as key regulators of lysosomal atg8ylation and lysophagy in response to the SARS-CoV-2 virulence factor ORF3a.

cell biology↗

bioRxiv2024

Faster amylin aggregation on fibrillar collagen hastens diabetic progression through β cell death and loss of function

Amyloid deposition of the neuroendocrine peptide amylin in islet tissues is a hallmark of type 2 diabetes (T2DM), leading to {beta}-cell toxicity through nutrient deprivation, membrane rupture and apoptosis. Though accumulation of toxic amylin aggregates in islet matrices is well documented, the role of the islet extracellular matrix in mediating amylin aggregation and its pathological consequences remains elusive. Here, we address this question by probing amylin interaction with collagen I (Col I)--whose expression in the islet tissue increases during diabetes progression. By combining multiple biophysical techniques, we show that hydrophobic, hydrophilic & cation-{pi} interactions regulate amylin binding to Col I, with fibrillar collagen driving faster amylin aggregation. Amylin-entangled Col I matrices containing high amounts of amylin induce death and loss of function of INS1E {beta}-cells. Together, our results illustrate how amylin incorporation in islet matrices through amylin-Col interactions drives T2DM progression by impacting {beta}-cell viability and insulin secretion.

biophysics↗

bioRxiv2023

Thrombospondin 2 is a key determinant of fibrogenesis in NAFLD

Hepatic overexpression of the thrombospondin 2 gene (THBS2) and elevated levels of circulating thrombospondin 2 (TSP2) have been observed in patients with chronic liver disease. The current study aimed to identify the specific cells expressing THBS2/TSP2 in non-alcoholic fatty liver disease (NAFLD) and investigate the underlying mechanism behind THBS2/TSP2 up-regulation. Comprehensive NAFLD liver gene datasets, including single-cell RNA sequencing (scRNA-seq), in-house NAFLD liver tissue, and LX-2 cells derived from human hepatic stellate cells (HSCs), were analyzed using a combination of computational biology, genetic, immunological, and pharmacological approaches. Analysis of the genetic dataset revealed the presence of 1433 variable genes in patients with advanced fibrosis NAFLD, with THBS2 ranked among the top 2 genes. Quantitative polymerase chain reaction examination of NAFLD livers showed a significant correlation between THBS2 expression and fibrosis stage (r=0.349, p<0.001). In support of this, scRNA-seq data and in situ hybridization demonstrated that the THBS2 gene was highly expressed in HSCs of NAFLD patients with advanced fibrosis. Pathway analysis of the gene dataset revealed THBS2 expression to be associated with the transforming growth factor beta (TGF{beta}) pathway and collagen gene activation. Moreover, the activation of LX-2 cells with TGF{beta} increased THBS2/TSP2 and collagen expression independently of the TGF{beta}-SMAD2/3 pathway. THBS2 gene knockdown significantly decreased collagen expression in LX-2 cells. In conclusion, THBS2/TSP2 is highly expressed in HSCs and plays a role in regulating fibrogenesis in NAFLD patients. THBS2/TSP2 may therefore represent a potential target for anti-fibrotic therapy in NAFLD. (241 words) One-sentence summariesThrombospondin 2 represent a potential target for anti-fibrotic therapy in NAFLD.

molecular biology↗

bioRxiv2020

Lack of Adipocyte Purinergic P2Y6 Receptor Greatly Improves Whole Body Glucose Homeostasis

Uridine diphosphate (UDP)-activated purinergic receptor P2Y6 (P2Y6R) plays a crucial role in controlling energy balance through central mechanisms. However, P2Y6Rs roles in peripheral tissues regulating energy and glucose homeostasis remain unexplored. Here, we report the surprising novel finding that adipocyte-specific deletion of P2Y6R protects mice from diet-induced obesity, improving glucose tolerance and insulin sensitivity with reduced systemic inflammation. These changes were associated with reduced JNK signaling, and enhanced expression and activity of PPAR affecting downstream PGC1 levels leading to beiging of white fat. In contrast, P2Y6R deletion in skeletal muscle reduced glucose uptake resulting in impaired glucose homeostasis. Interestingly, whole body P2Y6R KO mice showed metabolic improvements similar to those observed with mice lacking P2Y6R only in adipocytes. Our findings provide compelling evidence that P2Y6R antagonists may prove useful for the treatment of obesity and type 2 diabetes.

physiology↗