Biology subjects

Kahn, C. R.

Publications and source records attributed to Kahn, C. R..

7 recordsLinked to original sources

bioRxiv2026

Cold acclimation reprograms hepatic lipid composition toward n-3 HUFAs to uncouple adipose-derived lipid flux from steatosis

While cold exposure drives lipid flux from adipose tissue to the liver, this enhanced inter-organ crosstalk does not result in sustained hepatic steatosis during prolonged acclimation, indicating that factors beyond lipid flux shape metabolic outcome. To interrogate this adaptation, we performed integrated lipidomic and metabolic profiling across tissues and circulating lipoproteins over the course of cold acclimation. We showed that cold acclimation induces systemic reprogramming of lipid quality in mice, characterized by enrichment of n-3 highly unsaturated fatty acids (HUFAs) as a consequence of upregulation of fatty acid desaturases (FADS1 and 2) in the liver and white adipose tissue, thus increasing hepatic n-3/n-6 ratio. Cold-induced increase in n-3 HUFAs cause the suppression of SCD1-mediated desaturation, thus yielding a depletion of monounsaturated fatty acids (MUFAs) in the liver, along with the suppression of lipogenic markers. Notably, this high-HUFA/low-MUFA lipid signature is present in both hepatic free fatty acid and triglyceride pools, indicating that lipid remodeling occurs upstream of triglyceride synthesis. Lipidomic analysis revealed that the remodeled triglycerides are incorporated into very-low-density and intermediate density lipoproteins (VLDL and IDL), thereby propagating hepatic lipid reprogramming to the circulation. Thus, by selectively increasing endogenous n-3 HUFA availability, cold adaptation suppresses hepatic DNL and MUFA-driven triglyceride assembly, buffering lipid accumulation despite sustained fatty acid influx and reshaping systemic lipid distribution with potential cardiometabolic impact.

biochemistry↗

bioRxiv2025

Protein Kinase C δ: a critical hub regulating macrophage immunomodulatory functions during Mycobacterium tuberculosis infection

A host-modulating candidate gene involved in putative pathogen-killing pathways, with potential novel therapeutic intervention, Protein Kinase C - {delta} (PKC{delta}) has been recognized as a critical marker of inflammation with clinical and experimental evidence in recent years. Pulmonary microenvironment during Mtb infection is largely governed by lung resident macrophages, initiating innate and subsequent adaptive immune responses. We investigated the role of PKC{delta} in macrophages using a macrophage-specific PKC{delta} knockout mice model (LysMcrePKC{delta}flox/flox). PKC{delta} deficiency in macrophages triggers an early lymphocytic immune response, increases neutrophil recruitment, and reduces inflammatory macrophages in the lungs, leading to higher Mtb burden and exacerbated pathology. Experimental and omics analysis further revealed that dysregulation of antimicrobial effector functions is detrimental to macrophages ability to restrict bacterial growth in vitro. Importantly this defect was mitigated by exogenous GM-CSF supplementation and/or overexpressing PKC{delta} in macrophages. Thus, PKC{delta} plays a crucial role in immune modulation during Mtb infection with GM-CSF amongst several downstream pathways through which PKC{delta} exerts its regulatory effects. TeaserPKC{delta} is crucial for immune modulation during Mtb infection revealing macrophages as a potential axis of signaling.

immunology↗

bioRxiv2024

Loss of Insulin Signaling in Microglia Impairs Cellular Uptake of Aβ and Neuroinflammatory Response Exacerbating Alzheimer-like Neuropathology

Insulin receptors are present on cells throughout the body, including the brain. Dysregulation of insulin signaling in neurons and astrocytes has been implicated in altered mood, cognition, and the pathogenesis of Alzheimers disease (AD). To define the role of insulin signaling in microglia, the primary phagocytes in brain critical for maintenance and damage repair, we created mice with an inducible microglia-specific insulin receptor knockout (MG-IRKO). RiboTag profiling of microglial mRNAs revealed that loss of insulin signaling results in alterations of gene expression in pathways related to innate immunity and cellular metabolism. In vitro, loss of insulin signaling in microglia results in metabolic reprograming with an increase in glycolysis and impaired uptake of A{beta}. In vivo, MG-IRKO mice exhibit alterations in mood and social behavior, and when crossed with the 5xFAD mouse model of AD, the resultant mice exhibit increased levels of A{beta} plaque and elevated neuroinflammation. Thus, insulin signaling in microglia plays a key role in microglial cellular metabolism, neuroinflammation and the ability of the cells to take up A{beta}, such that reduced insulin signaling in microglia alters mood and social behavior and accelerates AD pathogenesis. Together these data indicate key roles of insulin action in microglia and the potential of targeting insulin signaling in microglia in treatment of AD.

neuroscience↗

bioRxiv2022

Modulation of the gut microbiome by novel synthetic glycans for the production of propionate and the reduction of cardiometabolic risk factors

BackgroundIncreasing evidence indicates that an altered gut microbiome participates in the development of cardiometabolic syndrome and associated risk factors, such as insulin resistance, dyslipidemia, and obesity, and that targeting the gut microbiome is a promising strategy to lower the risk for cardiometabolic diseases. Part of this reduction is mediated by specific metabolites generated by the gut microbiome. Propionate, a short-chain fatty acid (SCFA) produced from dietary glycans by certain gut microbes is known to exert multiple beneficial metabolic effects. Here, we identify KB39, a novel gut microbiome-targeting synthetic glycan selected for its strong propionate-producing capacity, and demonstrate its effects in vivo to reduce cardiometabolic disease using western diet-fed LDL receptor knock-out mice. MethodsEx vivo fermentation screening of a large library of synthetic glycan ensembles was performed using gut microbiome communities from healthy subjects and overweight patients with type 2 diabetes. A synthetic glycan identified for its high propionate-producing capacity (KB39) was then tested in vivo for effects on systemic, blood and cecal metabolic parameters in Ldlr-/- mice fed a western diet. ResultsEx vivo screening of ~600 synthetic glycans using human gut microbiota from healthy subjects and patients with type 2 diabetes identified a novel glycan (KB39) with high propionate-producing capacity that increased propionate contribution to total SCFA and propionate-producing bacterial taxa compared to negative control. In western diet-fed Ldlr-/- mice, KB39 treatment resulted in an enrichment in propiogenic bacteria and propionate biosynthetic genes in vivo and an increase in absolute and relative amounts of propionate in the cecum. This also resulted in significant decreases in serum total cholesterol, LDL-cholesterol, and insulin levels, as well as reduced hepatic triglycerides and cholesterol content compared to non-treated animals. Importantly, KB39 treatment significantly reduced atherosclerosis, liver steatosis and inflammation, upregulated hepatic expression of genes involved in fatty acid oxidation and downregulated transcriptional markers of inflammation, fibrosis and insulin resistance with only a mild lowering of body weight gain. ConclusionsOur data show that KB39, a novel synthetic glycan supporting a high propionate-producing microbiome, can reduce cardiometabolic risk factors and disease in mice and suggest this approach could be of benefit for the prevention or treatment of cardiometabolic diseases in humans. CLINICAL PERSPECTIVEWhat is new? O_LIA novel synthetic glycan, KB39, was selected from a library of compounds for its high propionate-producing capacity and beneficial effects on the human gut microbiome composition C_LIO_LIKB39 modulates the gut microbiome for high propionate production and significantly reduces cardiometabolic risk factors and disease in a murine model of cardiometabolic diseases C_LI What are the clinical implications? O_LIKB39, delivered orally, could be of benefit for the prevention or treatment of cardiometabolic diseases in humans C_LIO_LIThe efficacy of KB39 in mice compared to the clinical drug fenofibrate justifies further study in humans C_LI

microbiology↗

bioRxiv2020

Parabacteroides distasonis insulin B:9-23 epitope mimic stimulates insulin specific T-cells and enhances Type 1 Diabetes in NOD mice

Type 1 Diabetes (T1D) is an autoimmune disease characterized by the destruction of pancreatic {beta}-cells. One of the earliest aspects of this process is development of autoantibodies and T-cells directed at an epitope in the B-chain of insulin (insB:9-23). Analysis of microbial protein sequences with homology to insB:9-23 sequence revealed 17 peptides showing >50% identity to insB:9-23. Of these, one peptide, found in the normal human gut commensal Parabacteroides distasonis, activated both human T cell clones from T1D patients and T-cell hybridomas from non-obese diabetic (NOD) mice specific to insB:9-23. Immunization of NOD mice with P. distasonis insB:9-23 peptide mimic or insB:9-23 peptide verified immune cross-reactivity. Colonization of female NOD mice with P. distasonis accelerated the development of T1D, increasing macrophages, dendritic cells and destructive CD8+ T-cells, while decreasing FoxP3+ regulatory T-cells. Western blot analysis identified P. distasonis reacting antibodies in sera of NOD mice colonized with P. distasonis and human T1D patients. Furthermore, adoptive transfer of splenocytes from P. distasonis treated mice to NOD/SCID mice enhanced disease phenotype in the recipients. Finally, analysis of human infant gut microbiome data revealed that exposure of infants to P. distasonis may modulate disease pathogenesis. Taken together, these data demonstrate the potential role for an insB:9-23-mimimetic peptide from gut microbiota as a molecular trigger or modifier of T1D pathogenesis. SIGNIFICANCE STATEMENTIn Type 1 diabetes (T1D), immune cells destroy pancreatic {beta}-cells. The trigger of this response, however, is unknown. Some sequences (epitopes) in the insulin molecule form a major target for this autoimmune response. We have identified a sequence in a human gut bacterium that can mimetic this insulin epitope. Immune cells specific to insulin cross-react with this bacterial mimetic. Further, this bacterium can accelerate diabetes onset in a mouse model of T1D, inducing destructive and decreasing protective immune cells. We found this mimetic in the gut of children developing T1D. Furthermore, T1D patients have a stronger immune response to this bacterium compared to healthy individuals. Taken together, this bacterial mimetic in human gut has the potential to trigger/modify T1D onset.

immunology↗

bioRxiv2020

Characterization of Viral Insulins Reveals White Adipose Tissue Specific Effects in Mice

Members of the insulin/IGF superfamily are well conserved across the evolutionary tree. We recently showed that four viruses in the Iridoviridae family possess genes that encode proteins highly homologous to human insulin/IGF-1. Using chemically synthesized single chain (sc), i.e. IGF-1-like, forms of the viral insulin/IGF-1 like peptides (VILPs), we previously showed that they can stimulate human receptors. Because these peptides possess potential cleavage sites to form double chain (dc), i.e. more insulin-like, VILPs, in this study, we have characterized dc forms of VILPs for Grouper iridovirus (GIV), Singapore grouper iridovirus (SGIV) and Lymphocystis disease virus-1 (LCDV-1). GIV and SGIV dcVILPs bind to both isoforms of human insulin receptor (IR-A, IR-B) and to the IGF1R, and for the latter show higher affinity than human insulin. These dcVILPs stimulate IR and IGF1R phosphorylation and post-receptor signaling in vitro and in vivo. Both GIV and SGIV dcVILPs stimulate glucose uptake in mice. In vivo infusion experiments in awake mice revealed that while insulin (0.015 nmol/kg/min) and GIV dcVILP (0.75nmol/kg/min) stimulated a comparable glucose uptake in heart, skeletal muscle and brown adipose tissue, GIV dcVILP stimulated ~2 fold higher glucose uptake in white adipose tissue (WAT) compared to insulin. This was associated with increased Akt phosphorylation and glucose transporter type 4 (GLUT4) gene expression compared to insulin. Taken together, these results show that GIV and SGIV dcVILPs are active members of the insulin superfamily with unique characteristics. Elucidating the mechanism of tissue specificity for GIV dcVILP will help us to better understand insulin action, design new analogues that specifically target the tissues, and provide new insights into their potential role in disease.

cell biology↗

bioRxiv2018

Multi-Omic Profiling Reveals the Opposing Forces of Excess Dietary Sugar and Fat on Liver Mitochondria Protein Acetylation and Succinylation

Dietary macronutrient composition alters metabolism through several mechanisms, including post-translational modification (PTM) of proteins. To connect diet and molecular changes, here we performed short- and long-term feeding of mice with standard chow diet (SCD) and high-fat diet (HFD), with or without glucose or fructose supplementation, and quantified liver metabolites, 861 proteins, and 1,815 protein level-corrected mitochondrial acetylation and succinylation sites. Nearly half the acylation sites were altered by at least one diet; nutrient-specific changes in protein acylation sometimes encompass entire pathways. Although acetyl-CoA is an intermediate in both sugar and fat metabolism, acetyl-CoA had a dichotomous fate depending on its source; chronic feeding of dietary sugars induced protein hyperacetylation, whereas the same duration of HFD did not. Instead, HFD resulted in citrate accumulation, anaplerotic metabolism of amino acids, and protein hypo-succinylation. Together, our results demonstrate novel connections between dietary macronutrients, protein post-translational modifications, and regulation of fuel selection in liver.\n\nGraphical Abstract\n\nO_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=200 SRC=\"FIGDIR/small/263426_ufig1.gif\" ALT=\"Figure 1\">\nView larger version (53K):\norg.highwire.dtl.DTLVardef@1419c64org.highwire.dtl.DTLVardef@82a874org.highwire.dtl.DTLVardef@16023org.highwire.dtl.DTLVardef@4ed44e_HPS_FORMAT_FIGEXP M_FIG Graphical Abstract\n\nC_FIG

systems biology↗