Genetic ablation of CD38 protects against Western diet-induced exercise intolerance and metabolic inflexibility
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE69062 | GEO | 2015/05/20
SECONDARY ACCESSION(S): PRJNA284416
REPOSITORIES: GEO
Similar Datasets
Project description:Mammalian female reproductive lifespan is typically significantly shorter than life expectancy and is associated with a decrease in ovarian NAD levels. However, the mechanisms underlying this loss of ovarian NAD are unclear. Here, we show that CD38, a NAD consuming enzyme, is expressed in the ovarian extrafollicular space, primarily in immune cells, and its levels increase with reproductive age. Reproductively young mice lacking CD38 exhibit larger primordial follicle pools, elevated ovarian NAD levels, and increased fecundity relative to wild type controls. This larger ovarian reserve results from a prolonged window of follicle formation during early development. However, the beneficial effect of CD38 loss on reproductive function is not maintained at advanced age. Our results demonstrate a novel role of CD38 in regulating ovarian NAD metabolism and establishing the ovarian reserve, a critical process that dictates a female reproductive lifespan.
| MSV000092808 | MassIVE
Project description:Objectives: In gout, flares of severely painful inflammatory arthritis intersect with metabolism, circadian rhythm, and macrophage activation. NAD+ is a necessary cofactor and key metabolite in cellular bioenergy homeostasis, and NAD+ suppresses the NLRP3 inflammasome and inflammation. However, cellular NAD+ declines in inflammatory states, associated with increased activity of the leukocyte-expressed NADase CD38. Gouty arthritis is principally prevented and treated with nonselective and frequently toxic drugs (colchicine, NSAIDs, corticosteroids). Hence, we tested the potential role of therapeutically targeting CD38 and NAD+ in gout. Methods: We studied cultured mouse wild type and CD38 knockout (KO) murine bone marrow derived macrophages (BMDMs) stimulated by monosodium urate (MSU) crystals, and the air pouch gout synovitis model. Results: MSU crystals induced CD38 in BMDMs in vitro, associated with NAD+ depletion, and IL-1b and CXCL1 release, effects reversed by pharmacologic CD38 inhibitors (apigenin, 78c). Mouse air pouch inflammatory responses to MSU crystals were blunted by CD38 KO and apigenin. Pharmacologic CD38 inhibition suppressed MSU crystal-induced NLRP3 inflammasome activation and increased anti-inflammatory SIRT3-SOD2 in macrophages. BMDM RNA-seq analysis of 176 differentially expressed genes (DEGs) revealed CD38 control of multiple MSU crystal-modulated inflammation pathways. The top DEGs included the circadian rhythm modulator GRP176, and the metalloreductase STEAP4 that mediates iron homeostasis, and promotes oxidative stress and NF-kB activation when it is overexpressed. Conclusion: CD38 and NAD+ depletion are druggable targets controlling the MSU crystal- induced inflammation program. Targeting CD38 and NAD+ are potentially novel selective molecular approaches to limit gouty arthritis.
2024-05-08 | GSE214587 | GEO
Project description:Decline in tissue NAD levels during aging has been linked to aging-associated diseases, such as age-related metabolic disease, physical decline, and Alzheimers disease. However, the mechanism for aging-associated NAD decline remains unclear. Here we report that pro-inflammatory M1 macrophages, but not naive or M2 macrophages, highly express the NAD consuming enzyme CD38 and have enhanced CD38-dependent NADase activity. Furthermore, we show that aging is associated with enhanced inflammation due to increased senescent cells, and the accumulation of CD38 positive M1 macrophages in visceral white adipose tissue. We also find that inflammatory cytokines found in the supernatant from senescent cells (Senescence associated secretory proteins, SASP) induces macrophages to proliferate and express CD38. As senescent cells progressively accumulate in adipose tissue during aging, these results highlight a new causal link between visceral tissue senescence and tissue NAD decline during aging and may present a novel therapeutic opportunity to maintain NAD levels during aging.
2019-04-25 | MSV000083726 | MassIVE
Project description:Quiescence is a fundamental property that protects hematopoietic stem cells’ (HSCs) function throughout life. A subpopulation of deeply quiescent, so-called dormant HSCs (dHSCs) harbors the highest long-term blood repopulation capacity and resides at the top of the hematopoietic hierarchy. However, the mechanisms of HSC dormancy remain elusive, mainly due to the absence of surface markers for dHSCs’ prompt isolation. We identified CD38 nicotinamide adenine dinucleotide (NAD+) catabolic ecto-enzyme as a novel surface marker for murine dHSCs. The product of CD38 cyclase activity – cyclic adenosine diphosphate ribose (cADPR), regulates the expression of the transcription factor and cell cycle regulator c-Fos via an increase of cytoplasmic Ca2+ concentration. Strikingly, we uncovered that c-Fos drives HSCs quiescence through the induction of the cell cycle inhibitor p57Kip2 expression. Moreover, we found a similar CD38-dependent mechanism of quiescence regulation for human HSCs, which are CD38 negative. Specifically, we found that CD38 ecto-enzymatic activity at the neighboring CD38-positive cells promote human HSCs’ dormancy. Together, our work reveals how extracellular metabolic cues trigger a signaling cascade blocking HSC cell cycle entrance. Pharmacological manipulations of defined pathway will provide new strategies to modulate HSCs activation upon infections, blood loss or transplantation in clinical practice.
2022-02-18 | GSE196759 | GEO
Project description:The ecto-enzyme CD38 is a marker of unfavorable prognosis for chronic lymphocytic leukemia (CLL) patients and an indicator of activation and proliferation of leukemic cells. Here we show that CD38 is enzymatically active in primary CLL cells and that its forced expression increases disease aggressiveness in a xenograft model. The effect is completely lost when using an enzyme deficient version of CD38 with a single amino-acid mutation. Through the enzymatic conversion of NAD, CD38 increases cytoplasmic Ca2+ concentrations, positively influencing proliferation, chemotaxis, adhesion and matrix digestion. Inhibition of the enzymatic activities of CD38 using the flavonoid kuromanin blocks CLL homing. In a short-term xenograft model using primary cells, kuromanin treatment traps CLL cells in the blood, increasing responses to chemotherapy. Microarrays were performed comparing genetic signature derived from Mec-1 cell line variants, generated infecting cells by lentiviruses carrying the genetic material for a wild-type (CD38WT ) or an enzymatically-inactive form of CD38 (CD38M), grown in vitro and in vivo in NSG mice. GFP+ Mec-1 clones (Mec-1/GFP) were generated with the same protocol and used as control.
2014-04-01 | E-GEOD-56369 | biostudies-arrayexpress
Project description:Quiescence is a fundamental property that protects hematopoietic stem cells’ (HSCs) function throughout life. A subpopulation of deeply quiescent, so-called dormant HSCs (dHSCs) harbors the highest long-term blood repopulation capacity and resides at the top of the hematopoietic hierarchy. However, the mechanisms of HSC dormancy remain elusive, mainly due to the absence of surface markers for dHSCs’ prompt isolation. We identified CD38 nicotinamide adenine dinucleotide (NAD+) catabolic ecto-enzyme as a novel surface marker for murine dHSCs. The product of CD38 cyclase activity – cyclic adenosine diphosphate ribose (cADPR), regulates the expression of the transcription factor and cell cycle regulator c-Fos via an increase of cytoplasmic Ca2+ concentration. Strikingly, we uncovered that c-Fos drives HSCs quiescence through the induction of the cell cycle inhibitor p57Kip2 expression. Moreover, we found a similar CD38-dependent mechanism of quiescence regulation for human HSCs, which are CD38 negative. Specifically, we found that CD38 ecto-enzymatic activity at the neighboring CD38-positive cells promote human HSCs’ dormancy. Together, our work reveals how extracellular metabolic cues trigger a signaling cascade blocking HSC cell cycle entrance. Pharmacological manipulations of defined pathway will provide new strategies to modulate HSCs activation upon infections, blood loss or transplantation in clinical practice.
2022-02-18 | GSE196758 | GEO
Project description:Mammalian female reproductive lifespan is typically significantly shorter than life expectancy and is associated with a decrease in ovarian NAD levels. However, the mechanisms underlying this loss of ovarian NAD are unclear. Here, we show that CD38, a NAD consuming enzyme, is expressed in the ovarian extrafollicular space, primarily in immune cells, and its levels increase with reproductive age. Reproductively young mice lacking CD38 exhibit larger primordial follicle pools, elevated ovarian NAD levels, and increased fecundity relative to wild type controls. This larger ovarian reserve results from a prolonged window of follicle formation during early development. However, the beneficial effect of CD38 loss on reproductive function is not maintained at advanced age. Our results demonstrate a novel role of CD38 in regulating ovarian NAD metabolism and establishing the ovarian reserve, a critical process that dictates a female reproductive lifespan.
| MSV000092808 | GNPS
Project description:The ecto-enzyme CD38 is a marker of unfavorable prognosis for chronic lymphocytic leukemia (CLL) patients and an indicator of activation and proliferation of leukemic cells. Here we show that CD38 is enzymatically active in primary CLL cells and that its forced expression increases disease aggressiveness in a xenograft model. The effect is completely lost when using an enzyme deficient version of CD38 with a single amino-acid mutation. Through the enzymatic conversion of NAD, CD38 increases cytoplasmic Ca2+ concentrations, positively influencing proliferation, chemotaxis, adhesion and matrix digestion. Inhibition of the enzymatic activities of CD38 using the flavonoid kuromanin blocks CLL homing. In a short-term xenograft model using primary cells, kuromanin treatment traps CLL cells in the blood, increasing responses to chemotherapy.
2014-04-01 | GSE56369 | GEO
Project description:CD38 and CD49d are associated negative prognosticators in chronic lymphocytic leukemia (CLL). Despite evidence that both molecules are involved in interactions occurring between CLL and normal cells in the context of CLL-involved tissues, a functional link is still missing. Using gene expression profiles comparing CD38+CD49d+ vs. CD38-CD49d- CLL cells, we demonstrated overexpression of the CCL3 and CCL4 chemokines in cells from the former group. These chemokines were also upregulated by CD38 signals in CLL; moreover, CCL3 was expressed by CLL cells from bone marrow biopsies (BMB) of CD38+CD49d+ but not CD38-CD49d- cases. High levels of CCR1 and, to a lesser extent, CCR5, the receptors for CCL3 and CCL4, were found in CLL-derived monocyte-macrophages. Consistently, CCL3 increased monocyte migration, and CD68+ macrophage infiltration was particularly high in BMB from CD38+CD49d+ CLL. Conditioned media from CCL3-stimulated macrophages induced endothelial cells to express VCAM-1, the CD49d ligand, likely through TNFα over-production. These effects were apparent in BMB from CD38+CD49d+CLL, where lymphoid infiltrates were characterized by a prominent meshwork of VCAM-1+ stromal/endothelial cells. Lastly, CD49d engagement by VCAM-1-transfectants increased viability of CD38+CD49d+ CLL cells. Altogether, CD38 and CD49d can be thought of as a part of a consecutive chain of events ultimately leading to improved survival of CLL cells.
2009-03-03 | GSE14560 | GEO
Project description:Type 2 diabetes (T2D) has become an epidemic in our modern lifestyle, likely due to calorie-rich diets overwhelming our adaptive metabolic pathways. One such pathway is mediated by nicotinamide phosphoribosyltransferase (NAMPT), the rate-limiting enzyme in mammalian NAD+ biosynthesis, and the NAD+-dependent protein deacetylase SIRT1. Here we show that NAMPT-mediated NAD+ biosynthesis is severely compromised in metabolic organs by high-fat diet (HFD). Strikingly, nicotinamide mononucleotide (NMN), a product of the NAMPT reaction and a key NAD+ intermediate, ameliorates glucose intolerance by restoring NAD+ levels in HFD-induced T2D mice. NMN also enhances hepatic insulin sensitivity and restores gene expression related to oxidative stress, inflammatory response, and circadian rhythm, partly through SIRT1 activation. Furthermore, NAD+ and NAMPT levels show significant decreases in multiple organs during aging, and NMN improves glucose intolerance and lipid profiles in age-induced T2D mice. These findings provide critical insights into a novel intervention against diet- and age-induced T2D. 4 regular chow fed mice (RC1-4) vs 4 high-fat diet fed (HFD) (HFD1a-4a) mice were analyzed on one chip (Chip-A). 4 HFD mice (HFD1b-4b) vs 4 HFD-NMN treated mice (NMN1-4) were examined on the other chip (Chip-B).
2011-12-05 | E-GEOD-31647 | biostudies-arrayexpress