The human batokine EPDR1 regulates β-cell metabolism and function

Cataldo, Luis Rodrigo; Gao, Qian; Argemi-Muntadas, Lidia; Hodek, Ondřej; Cowan, Elaine; Hladkou, Sergey; Gheibi, Sevda; Sartipy, Peter; Prasad, Rashmi; Eliasson, Lena; Schéele, Camilla; Fex, Malin; Mulder, Hindrik; Moritz, Thomas

doi:10.1016/j.molmet.2022.101629

Cited by 11 publications

(5 citation statements)

References 54 publications

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“…Additionally, taking advantage of a recently developed genetically encoded ratiometric fluorescent reporter, Perceval HR, 137 we and others have observed glucose responsiveness of the cytosolic pool of ATP/ADP ratio in the rat INS1 832/13 19,106,134,138 and human EndoC-βH1 139 βcell lines and mouse islets. 75 Consistently, stimulation of clonal β cells as well as rodent and human islets with glucose increases mitochondrial OCR 1.5 to 3 times 19,131,134,140 and from oligomycinsensitive (ATP-coupled) respiration in INS1E cells it has been calculated that glucose raises the ATP supply up to six times. 129 The special metabolic characteristics that β cells exhibit to maintain their glucose sensor function does not, however, imply that bioenergetic principles are broken.…”

Section: Energy Supply-versus Energy-demand-driven Metabolismmentioning

confidence: 94%

“…This notwithstanding, growing evidence supports an energy supply-driven metabolism in β cells as several studies have demonstrated a glucose-dependent rise ATP/ADP ratio in various βcell models, 76,131 rodent and human islets 136 by use of direct (luminometric and mass-spectrometry) and indirect (creatine/phosphocreatine pools 129 ) methods. Additionally, taking advantage of a recently developed genetically encoded ratiometric fluorescent reporter, Perceval HR, 137 we and others have observed glucose responsiveness of the cytosolic pool of ATP/ADP ratio in the rat INS1 832/13 19,106,134,138 and human EndoC-βH1 139 βcell lines and mouse islets.…”

Section: Energy Supply-versus Energy-demand-driven Metabolismmentioning

confidence: 97%

“…In contrast, β cells possess a unique glucose-sensing mechanism as a result of adapted, not well understood, bioenergetic properties. 71,129 In β cells, the ATP/ADP ratio is flexible and instead responds to energy substrate supply by elevating mitochondrial OCR, OXPHOS and ATP production 19,71,[130][131][132][133][134] (Figure 2). Thus, β cells detect changes in substrate availability by adjusting the cytosolic ATP/ ADP ratio (Figure 2).…”

Section: Energy Supply-versus Energy-demand-driven Metabolismmentioning

confidence: 99%

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Unique features of β‐cell metabolism are lost in type 2 diabetes

Muñoz,

Fex,

Moritz

et al. 2024

Acta Physiologica

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Pancreatic β cells play an essential role in the control of systemic glucose homeostasis as they sense blood glucose levels and respond by secreting insulin. Upon stimulating glucose uptake in insulin‐sensitive tissues post‐prandially, this anabolic hormone restores blood glucose levels to pre‐prandial levels. Maintaining physiological glucose levels thus relies on proper β‐cell function. To fulfill this highly specialized nutrient sensor role, β cells have evolved a unique genetic program that shapes its distinct cellular metabolism. In this review, the unique genetic and metabolic features of β cells will be outlined, including their alterations in type 2 diabetes (T2D). β cells selectively express a set of genes in a cell type‐specific manner; for instance, the glucose activating hexokinase IV enzyme or Glucokinase (GCK), whereas other genes are selectively “disallowed”, including lactate dehydrogenase A (LDHA) and monocarboxylate transporter 1 (MCT1). This selective gene program equips β cells with a unique metabolic apparatus to ensure that nutrient metabolism is coupled to appropriate insulin secretion, thereby avoiding hyperglycemia, as well as life‐threatening hypoglycemia. Unlike most cell types, β cells exhibit specialized bioenergetic features, including supply‐driven rather than demand‐driven metabolism and a high basal mitochondrial proton leak respiration. The understanding of these unique genetically programmed metabolic features and their alterations that lead to β‐cell dysfunction is crucial for a comprehensive understanding of T2D pathophysiology and the development of innovative therapeutic approaches for T2D patients.

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Section: Energy Supply-versus Energy-demand-driven Metabolismmentioning

confidence: 94%

Section: Energy Supply-versus Energy-demand-driven Metabolismmentioning

confidence: 97%

Section: Energy Supply-versus Energy-demand-driven Metabolismmentioning

confidence: 99%

See 1 more Smart Citation

Unique features of β‐cell metabolism are lost in type 2 diabetes

Muñoz,

Fex,

Moritz

et al. 2024

Acta Physiologica

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“…In addition, the novel batokine ependymin-related protein 1 (EPDR1) has been detected in human plasma and implicated in the regulating mitochondrial respiration linked to BAT thermogenesis [120]. Moreover, EPDR1 is proposed to be a key regulator to maintain glucose homeostasis in obese people, due to the upregulation of EPDR1 that could improve β-cell function by promoting glycolysis and the TCA cycle [120,121]. In addition, active BAT is a source of C-X-C motif chemokine ligand-14 (CXCL14), which concertedly promotes adaptive thermogenesis via M2 macrophage recruitment, BAT activation, and the browning of WAT [119].…”

Section: Therapeutic Strategies For Obesitymentioning

confidence: 99%

New Mediators in the Crosstalk between Different Adipose Tissues

Gómez-Hernández,

de las Heras,

Gálvez

et al. 2024

IJMS

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Adipose tissue is a multifunctional organ that regulates many physiological processes such as energy homeostasis, nutrition, the regulation of insulin sensitivity, body temperature, and immune response. In this review, we highlight the relevance of the different mediators that control adipose tissue activity through a systematic review of the main players present in white and brown adipose tissues. Among them, inflammatory mediators secreted by the adipose tissue, such as classical adipokines and more recent ones, elements of the immune system infiltrated into the adipose tissue (certain cell types and interleukins), as well as the role of intestinal microbiota and derived metabolites, have been reviewed. Furthermore, anti-obesity mediators that promote the activation of beige adipose tissue, e.g., myokines, thyroid hormones, amino acids, and both long and micro RNAs, are exhaustively examined. Finally, we also analyze therapeutic strategies based on those mediators that have been described to date. In conclusion, novel regulators of obesity, such as microRNAs or microbiota, are being characterized and are promising tools to treat obesity in the future.

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“…Calcium-induced conformational changes in ependymin have been reported to be important for its interaction with the extracellular matrix, particularly with collagen [ 17 , 18 ]. Recent studies have shown that EPDR1 expression in beta cells is increased under metabolic overload (obesity) and directs glycolysis-derived pyruvate to the mitochondrial TCA cycle, thus enhancing stimulated secretory coupling and increasing insulin secretion [ 19 ]. Interestingly, through this mechanism, EPDR1 may reflect compensatory mitochondrial biosynthesis that replaces defective mitochondria, suggesting that its expression increased as a result of age-related cell organ dysfunction [ 20 ].…”

Section: Introductionmentioning

confidence: 99%

Aging Fibroblasts Adversely Affect Extracellular Matrix Formation via the Senescent Humoral Factor Ependymin-Related Protein 1

Takaya

Asou

Kishi

2022

Cells

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Skin senescence is characterized by a decrease in extracellular matrix and the accumulation of senescent fibroblasts in the dermis, and their secretion of humoral factors. Ependymin-related protein 1 (EPDR1) is involved in abnormal fibroblast metabolism and collagen deposition, however, its relation to skin aging is unclear. We investigated whether and how EPDR1 is involved in age-related dermal deterioration. When young dermal fibroblasts and senescent cells were co-cultured in a semipermeable membrane separation system, the young fibroblasts showed decreased gene expression of collagen type I α1 chain (COL1A1) and elastin, and increased expression of matrix metalloproteinase (MMP)1 and MMP3. Senescence marker expression and EPDR1 production were increased in the culture medium of senescent cells. Treatment of young fibroblasts with recombinant EPDR1, enhanced matrix-related gene expression and suppressed COL1A1 expression, whereas EPDR1 knockdown had the opposite effects. EPDR1 gene and protein expression were increased in aged skin, compared to young skin. These results suggest that senescent cells affect nearby fibroblasts, in part through EPDR1 secretion, and exert negative effects on matrix production in the dermis. These results may lead to the discovery of potential candidate targets in the development of skin anti-aging therapies.

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The human batokine EPDR1 regulates β-cell metabolism and function

Cited by 11 publications

References 54 publications

Unique features of β‐cell metabolism are lost in type 2 diabetes

Unique features of β‐cell metabolism are lost in type 2 diabetes

New Mediators in the Crosstalk between Different Adipose Tissues

Aging Fibroblasts Adversely Affect Extracellular Matrix Formation via the Senescent Humoral Factor Ependymin-Related Protein 1

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