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Genetic ablation of CD38 protects against Western diet-induced exercise intolerance and metabolic inflexibility

ABSTRACT: CD38, a multi-functional membrane receptor and enzyme, consumes NAD+ to generate products such as cyclic-ADP-ribose. CD38 knockout mice show elevated tissue and blood NAD+ level. Chronic feeding of high-fat, high-sucrose diet to wild type mice leads to exercise intolerance and reduced metabolic flexibility. Loss of CD38 by genetic mutation protects mice from diet-induced metabolic deficit. These animal model results suggest that elevation of tissue NAD+ through genetic ablation of CD38 can profoundly alter energy homeostasis in animals that are maintained on a calorically-excessive Western diet.

ORGANISM(S): Mus musculus

PROVIDER: GSE69062 | GEO | 2015/05/20

SECONDARY ACCESSION(S): PRJNA284416

REPOSITORIES: GEO

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Genetic Ablation of CD38 Protects against Western Diet-Induced Exercise Intolerance and Metabolic Inflexibility.

Project description:Nicotinamide adenine dinucleotide (NAD+) is a key cofactor required for essential metabolic oxidation-reduction reactions. It also regulates various cellular activities, including gene expression, signaling, DNA repair and calcium homeostasis. Intracellular NAD+ levels are tightly regulated and often respond rapidly to nutritional and environmental changes. Numerous studies indicate that elevating NAD+ may be therapeutically beneficial in the context of numerous diseases. However, the role of NAD+ on skeletal muscle exercise performance is poorly understood. CD38, a multi-functional membrane receptor and enzyme, consumes NAD+ to generate products such as cyclic-ADP-ribose. CD38 knockout mice show elevated tissue and blood NAD+ level. Chronic feeding of high-fat, high-sucrose diet to wild type mice leads to exercise intolerance and reduced metabolic flexibility. Loss of CD38 by genetic mutation protects mice from diet-induced metabolic deficit. These animal model results suggest that elevation of tissue NAD+ through genetic ablation of CD38 can profoundly alter energy homeostasis in animals that are maintained on a calorically-excessive Western diet.

| S-EPMC4546114 | biostudies-literature

CD38 regulates ovarian function and fecundity via NAD metabolism

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.

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The NADase CD38 is a central regulator in gouty inflammation and a novel druggable therapeutic target

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.

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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.

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The enzymatic activities of CD38 enhance CLL growth and trafficking: implications for therapeutic targeting

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