Global deletion of NTPDase3 protects against diet-induced obesity by increasing basal energy metabolism

Sandhu, Bynvant; Pérez-Matos, Maria Camila; Tran, Stephanie; Singhal, Garima; Syed, Ismail; Feldbrügge, Linda; Mitsuhashi, Shuji; Pelletier, Julie; Huang, Jinhe; Yalcin, Yusuf; Csizmadia, Eva; Tiwari‐Heckler, Shilpa; Enjyoji, Keiichi; Sévigny, Jean; Maratos–Flier, Eleftheria; Robson, Simon C.; Jiang, Zhigang

doi:10.1016/j.metabol.2021.154731

Cited by 6 publications

(2 citation statements)

References 28 publications

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“…The literature is relatively scarce concerning NTPDase3 expression and function in other tissues. NTPDase3 is relatively abundant in pancreatic β-cells where it may function as a regulator of glucose-induced insulin secretion [ 70 , 71 ]. It was also found in hypocretin-1/orexin-A positive axon terminals of hypothalamic regions controlling feeding, circadian rhythm and reproduction behaviour [ 72 , 73 ].…”

Section: Discussionmentioning

confidence: 99%

Silencing NTPDase3 activity rehabilitates the osteogenic commitment of post-menopausal stem cell bone progenitors

et al. 2023

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Background Endogenously released adenine and uracil nucleotides favour the osteogenic commitment of bone marrow-derived mesenchymal stromal cells (BM-MSCs) through the activation of ATP-sensitive P2X7 and UDP-sensitive P2Y6 receptors. Yet, these nucleotides have their osteogenic potential compromised in post-menopausal (Pm) women due to overexpression of nucleotide metabolizing enzymes, namely NTPDase3. This prompted us to investigate whether NTPDase3 gene silencing or inhibition of its enzymatic activity could rehabilitate the osteogenic potential of Pm BM-MSCs. Methods MSCs were harvested from the bone marrow of Pm women (69 ± 2 years old) and younger female controls (22 ± 4 years old). The cells were allowed to grow for 35 days in an osteogenic-inducing medium in either the absence or the presence of NTPDase3 inhibitors (PSB 06126 and hN3-B3s antibody); pre-treatment with a lentiviral short hairpin RNA (Lenti-shRNA) was used to silence the NTPDase3 gene expression. Immunofluorescence confocal microscopy was used to monitor protein cell densities. The osteogenic commitment of BM-MSCs was assessed by increases in the alkaline phosphatase (ALP) activity. The amount of the osteogenic transcription factor Osterix and the alizarin red-stained bone nodule formation. ATP was measured with the luciferin-luciferase bioluminescence assay. The kinetics of the extracellular ATP (100 µM) and UDP (100 µM) catabolism was assessed by HPLC Results The extracellular catabolism of ATP and UDP was faster in BM-MSCs from Pm women compared to younger females. The immunoreactivity against NTPDase3 increased 5.6-fold in BM-MSCs from Pm women vs. younger females. Selective inhibition or transient NTPDase3 gene silencing increased the extracellular accumulation of adenine and uracil nucleotides in cultured Pm BM-MSCs. Downregulation of NTPDase3 expression or activity rehabilitated the osteogenic commitment of Pm BM-MSCs measured as increases in ALP activity, Osterix protein cellular content and bone nodule formation; blockage of P2X7 and P2Y6 purinoceptors prevented this effect. Conclusions Data suggest that NTPDase3 overexpression in BM-MSCs may be a clinical surrogate of the osteogenic differentiation impairment in Pm women. Thus, besides P2X7 and P2Y6 receptors activation, targeting NTPDase3 may represent a novel therapeutic strategy to increase bone mass and reduce the osteoporotic risk of fractures in Pm women.

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Section: Discussionmentioning

confidence: 99%

Silencing NTPDase3 activity rehabilitates the osteogenic commitment of post-menopausal stem cell bone progenitors

et al. 2023

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“…This phenotype was associated with higher uncoupling protein 1 (UCP-1) in brown adipose tissue. Studies on Entpd3 flox/flox;InsCre mice show a similar phenotype indicating Entpd3 in β cells is not protective against diet-induced obesity and insulin resistance ( Sandhu et al, 2021 ). The potential role of purinergic and adenosine signaling in pancreatogenic diabetes has a number of therapeutic implications and should be further explored.…”

Section: Inflammatory Pancreatic Diseasesmentioning

confidence: 99%

Purinergic and Adenosinergic Signaling in Pancreatobiliary Diseases

Faraoni

Robson

et al. 2022

Front. Physiol.

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Adenosine 5'-triphosphate (ATP), other nucleotides, and the nucleoside analogue, adenosine, all have the capacity to modulate cellular signaling pathways. The cellular processes linked to extracellular purinergic signaling are crucial in the initiation, evolution, and resolution of inflammation. Injured or dying cells in the pancreatobiliary tract secrete or release ATP, which results in sustained purinergic signaling mediated through ATP type-2 purinergic receptors (P2R). This process can result in chronic inflammation, fibrosis, and tumor development. In contrast, signaling via the extracellular nucleoside derivative adenosine via type-1 purinergic receptors (P1R) is largely anti-inflammatory, promoting healing. Failure to resolve inflammation, as in the context of primary sclerosing cholangitis or chronic pancreatitis, is a risk factor for parenchymal and end-organ scarring with the associated risk of pancreatobiliary malignancies. Emerging immunotherapeutic strategies suggest that targeting purinergic and adenosinergic signaling can impact the growth and invasive properties of cancer cells, potentiate anti-tumor immunity, and also block angiogenesis. In this review, we dissect out implications of disordered purinergic responses in scar formation, end-organ injury, and in tumor development. We conclude by addressing promising opportunities for modulation of purinergic/adenosinergic signaling in the prevention and treatment of pancreatobiliary diseases, inclusive of cancer.

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Understanding the Roles of Selenium on Thyroid Hormone-Induced Thermogenesis in Adipose Tissue

Ruswandi,

Lesmana,

Rosdianto

et al. 2023

Biol Trace Elem Res

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Global deletion of NTPDase3 protects against diet-induced obesity by increasing basal energy metabolism

Cited by 6 publications

References 28 publications

Silencing NTPDase3 activity rehabilitates the osteogenic commitment of post-menopausal stem cell bone progenitors

Silencing NTPDase3 activity rehabilitates the osteogenic commitment of post-menopausal stem cell bone progenitors

Purinergic and Adenosinergic Signaling in Pancreatobiliary Diseases

Understanding the Roles of Selenium on Thyroid Hormone-Induced Thermogenesis in Adipose Tissue

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