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Joseph Tam
Obesity and Metabolism Laboratory, Institute for Drug Research, School of Pharmacy, Faculty of Medicine, The Hebrew University, Jerusalem, Israel

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Research article
Published: 29 July 2021 in Science
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Aging is an established risk factor for vascular diseases, but vascular aging itself may contribute to the progressive deterioration of organ function. Here, we show in aged mice that vascular endothelial growth factor (VEGF) signaling insufficiency, which is caused by increased production of decoy receptors, may drive physiological aging across multiple organ systems. Increasing VEGF signaling prevented age-associated capillary loss, improved organ perfusion and function, and extended life span. Healthier aging was evidenced by favorable metabolism and body composition and amelioration of aging-associated pathologies including hepatic steatosis, sarcopenia, osteoporosis, “inflammaging” (age-related multiorgan chronic inflammation), and increased tumor burden. These results indicate that VEGF signaling insufficiency affects organ aging in mice and suggest that modulating this pathway may result in increased mammalian life span and improved overall health.

ACS Style

M. Grunewald; S. Kumar; H. Sharife; E. Volinsky; A. Gileles-Hillel; T. Licht; A. Permyakova; L. Hinden; S. Azar; Y. Friedmann; P. Kupetz; R. Tzuberi; A. Anisimov; K. Alitalo; M. Horwitz; S. Leebhoff; O. Z. Khoma; R. Hlushchuk; V. Djonov; R. Abramovitch; J. Tam; E. Keshet. Counteracting age-related VEGF signaling insufficiency promotes healthy aging and extends life span. Science 2021, 373, eabc8479 .

AMA Style

M. Grunewald, S. Kumar, H. Sharife, E. Volinsky, A. Gileles-Hillel, T. Licht, A. Permyakova, L. Hinden, S. Azar, Y. Friedmann, P. Kupetz, R. Tzuberi, A. Anisimov, K. Alitalo, M. Horwitz, S. Leebhoff, O. Z. Khoma, R. Hlushchuk, V. Djonov, R. Abramovitch, J. Tam, E. Keshet. Counteracting age-related VEGF signaling insufficiency promotes healthy aging and extends life span. Science. 2021; 373 (6554):eabc8479.

Chicago/Turabian Style

M. Grunewald; S. Kumar; H. Sharife; E. Volinsky; A. Gileles-Hillel; T. Licht; A. Permyakova; L. Hinden; S. Azar; Y. Friedmann; P. Kupetz; R. Tzuberi; A. Anisimov; K. Alitalo; M. Horwitz; S. Leebhoff; O. Z. Khoma; R. Hlushchuk; V. Djonov; R. Abramovitch; J. Tam; E. Keshet. 2021. "Counteracting age-related VEGF signaling insufficiency promotes healthy aging and extends life span." Science 373, no. 6554: eabc8479.

Review
Published: 25 February 2021 in The FEBS Journal
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Diabetes kidney disease (DKD) is a major healthcare problem associated with increased risk for developing end‐stage kidney disease and high mortality. It is widely accepted that DKD is primarily a glomerular disease. Recent findings however suggest that kidney proximal tubule cells (KPTCs) may play a central role in the pathophysiology of DKD. In diabetes and obesity, KPTCs are exposed to nutrient overload, including glucose, free‐fatty acids and amino acids, which dysregulate nutrient and energy sensing by mechanistic target of rapamycin complex 1 and AMP‐activated protein kinase, with subsequent induction of tubular injury, inflammation, and fibrosis. Pharmacological treatments that modulate nutrient sensing and signaling in KPTCs, including cannabinoid‐1 receptor antagonists and sodium glucose transporter 2 inhibitors, exert robust kidney protective effects. Shedding light on how nutrients are sensed and metabolized in KPTCs and in other kidney domains, and on their effects on signal transduction pathways that mediate kidney injury, is important for understanding the pathophysiology of DKD and for the development of novel therapeutic approaches in DKD and probably also in other forms of kidney disease.

ACS Style

Liad Hinden; Aviram Kogot‐Levin; Joseph Tam; Gil Leibowitz. Pathogenesis of diabesity‐induced kidney disease: role of kidney nutrient sensing. The FEBS Journal 2021, 1 .

AMA Style

Liad Hinden, Aviram Kogot‐Levin, Joseph Tam, Gil Leibowitz. Pathogenesis of diabesity‐induced kidney disease: role of kidney nutrient sensing. The FEBS Journal. 2021; ():1.

Chicago/Turabian Style

Liad Hinden; Aviram Kogot‐Levin; Joseph Tam; Gil Leibowitz. 2021. "Pathogenesis of diabesity‐induced kidney disease: role of kidney nutrient sensing." The FEBS Journal , no. : 1.

Journal article
Published: 17 February 2021 in Cells
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The renal proximal tubule cells (RPTCs), well-known for maintaining glucose and mineral homeostasis, play a critical role in the regulation of kidney function and bone remodeling. Deterioration in RPTC function may therefore lead to the development of diabetic kidney disease (DKD) and osteoporosis. Previously, we have shown that the cannabinoid-1 receptor (CB1R) modulates both kidney function as well as bone remodeling and mass via its direct role in RPTCs and bone cells, respectively. Here we employed genetic and pharmacological approaches that target CB1R, and found that its specific nullification in RPTCs preserves bone mass and remodeling both under normo- and hyper-glycemic conditions, and that its chronic blockade prevents the development of diabetes-induced bone loss. These protective effects of negatively targeting CB1R specifically in RPTCs were associated with its ability to modulate erythropoietin (EPO) synthesis, a hormone known to affect bone mass and remodeling. Our findings highlight a novel molecular mechanism by which CB1R in RPTCs remotely regulates skeletal homeostasis via a kidney-to-bone axis that involves EPO.

ACS Style

Saja Baraghithy; Yael Soae; Dekel Assaf; Liad Hinden; Shiran Udi; Adi Drori; Yankel Gabet; Joseph Tam. Renal Proximal Tubule Cell Cannabinoid-1 Receptor Regulates Bone Remodeling and Mass via a Kidney-to-Bone Axis. Cells 2021, 10, 414 .

AMA Style

Saja Baraghithy, Yael Soae, Dekel Assaf, Liad Hinden, Shiran Udi, Adi Drori, Yankel Gabet, Joseph Tam. Renal Proximal Tubule Cell Cannabinoid-1 Receptor Regulates Bone Remodeling and Mass via a Kidney-to-Bone Axis. Cells. 2021; 10 (2):414.

Chicago/Turabian Style

Saja Baraghithy; Yael Soae; Dekel Assaf; Liad Hinden; Shiran Udi; Adi Drori; Yankel Gabet; Joseph Tam. 2021. "Renal Proximal Tubule Cell Cannabinoid-1 Receptor Regulates Bone Remodeling and Mass via a Kidney-to-Bone Axis." Cells 10, no. 2: 414.

Journal article
Published: 19 November 2020 in eLife
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The soluble isoform of leptin receptor (sOb-R), secreted by the liver, regulates leptin bioavailability and bioactivity. Its reduced levels in diet-induced obesity (DIO) contribute to hyperleptinemia and leptin resistance, effects that are regulated by the endocannabinoid (eCB)/CB1R system. Here we show that pharmacological activation/blockade and genetic overexpression/deletion of hepatic CB1R modulates sOb-R levels and hepatic leptin resistance. Interestingly, peripheral CB1R blockade failed to reverse DIO-induced reduction of sOb-R levels, increased fat mass and dyslipidemia, and hepatic steatosis in mice lacking C/EBP homologous protein (CHOP), whereas direct activation of CB1R in wild-type hepatocytes reduced sOb-R levels in a CHOP-dependent manner. Moreover, CHOP stimulation increased sOb-R expression and release via a direct regulation of its promoter, while CHOP deletion reduced leptin sensitivity. Our findings highlight a novel molecular aspect by which the hepatic eCB/CB1R system is involved in the development of hepatic leptin resistance and in the regulation of sOb-R levels via CHOP.

ACS Style

Adi Drori; Asaad Gammal; Shahar Azar; Liad Hinden; Rivka Hadar; Daniel Wesley; Alina Nemirovski; Gergő Szanda; Maayan Salton; Boaz Tirosh; Joseph Tam. CB1R regulates soluble leptin receptor levels via CHOP, contributing to hepatic leptin resistance. eLife 2020, 9, 1 .

AMA Style

Adi Drori, Asaad Gammal, Shahar Azar, Liad Hinden, Rivka Hadar, Daniel Wesley, Alina Nemirovski, Gergő Szanda, Maayan Salton, Boaz Tirosh, Joseph Tam. CB1R regulates soluble leptin receptor levels via CHOP, contributing to hepatic leptin resistance. eLife. 2020; 9 ():1.

Chicago/Turabian Style

Adi Drori; Asaad Gammal; Shahar Azar; Liad Hinden; Rivka Hadar; Daniel Wesley; Alina Nemirovski; Gergő Szanda; Maayan Salton; Boaz Tirosh; Joseph Tam. 2020. "CB1R regulates soluble leptin receptor levels via CHOP, contributing to hepatic leptin resistance." eLife 9, no. : 1.

Journal article
Published: 26 September 2020 in Molecular Metabolism
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The endocannabinoid (eCB) system is increasingly recognized as being crucially important in obesity-related hepatic steatosis. By activating the hepatic cannabinoid-1 receptor (CB1R), eCBs modulate lipogenesis and fatty acid oxidation. However, the underlying molecular mechanisms are largely unknown. We combined unbiased bioinformatics techniques, mouse genetic manipulations, multiple pharmacological, molecular, and cellular biology approaches, and genomic sequencing to systematically decipher the role of the hepatic CB1R in modulating fat utilization in the liver and explored the downstream molecular mechanisms. Using an unbiased normalized phylogenetic profiling analysis, we found that the CB1R evolutionarily coevolves with peroxisome proliferator-activated receptor-alpha (PPARα), a key regulator of hepatic lipid metabolism. In diet-induced obese (DIO) mice, peripheral CB1R blockade (using AM6545) induced the reversal of hepatic steatosis and improved liver injury in WT, but not in PPARα−/− mice. The antisteatotic effect mediated by AM6545 in WT DIO mice was accompanied by increased hepatic expression and activity of PPARα as well as elevated hepatic levels of the PPARα-activating eCB-like molecules oleoylethanolamide and palmitoylethanolamide. Moreover, AM6545 was unable to rescue hepatic steatosis in DIO mice lacking liver sirtuin 1 (SIRT1), an upstream regulator of PPARα. Both of these signaling molecules were modulated by the CB1R as measured in hepatocytes exposed to lipotoxic conditions or treated with CB1R agonists in the absence/presence of AM6545. Furthermore, using microRNA transcriptomic profiling, we found that the CB1R regulated the hepatic expression, acetylation, and transcriptional activity of p53, resulting in the enhanced expression of miR-22, which was found to specifically target SIRT1 and PPARα. We provide strong evidence for a functional role of the p53/miR-22/SIRT1/PPARα signaling pathway in potentially mediating the antisteatotic effect of peripherally restricted CB1R blockade.

ACS Style

Shahar Azar; Shiran Udi; Adi Drori; Rivka Hadar; Alina Nemirovski; Kiran V. Vemuri; Maya Miller; Dana Sherill-Rofe; Yhara Arad; Devorah Gur-Wahnon; Xiaoling Li; Alexandros Makriyannis; Danny Ben-Zvi; Yuval Tabach; Iddo Z. Ben-Dov; Joseph Tam. Reversal of diet-induced hepatic steatosis by peripheral CB1 receptor blockade in mice is p53/miRNA-22/SIRT1/PPARα dependent. Molecular Metabolism 2020, 42, 101087 .

AMA Style

Shahar Azar, Shiran Udi, Adi Drori, Rivka Hadar, Alina Nemirovski, Kiran V. Vemuri, Maya Miller, Dana Sherill-Rofe, Yhara Arad, Devorah Gur-Wahnon, Xiaoling Li, Alexandros Makriyannis, Danny Ben-Zvi, Yuval Tabach, Iddo Z. Ben-Dov, Joseph Tam. Reversal of diet-induced hepatic steatosis by peripheral CB1 receptor blockade in mice is p53/miRNA-22/SIRT1/PPARα dependent. Molecular Metabolism. 2020; 42 ():101087.

Chicago/Turabian Style

Shahar Azar; Shiran Udi; Adi Drori; Rivka Hadar; Alina Nemirovski; Kiran V. Vemuri; Maya Miller; Dana Sherill-Rofe; Yhara Arad; Devorah Gur-Wahnon; Xiaoling Li; Alexandros Makriyannis; Danny Ben-Zvi; Yuval Tabach; Iddo Z. Ben-Dov; Joseph Tam. 2020. "Reversal of diet-induced hepatic steatosis by peripheral CB1 receptor blockade in mice is p53/miRNA-22/SIRT1/PPARα dependent." Molecular Metabolism 42, no. : 101087.

Preprint content
Published: 24 September 2020
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IL-6 signaling via its receptor (IL-6R) and co-receptor (gp130) performs multiple roles in regulating metabolic homeostasis. However, gp130 is also expressed systemically in a soluble form (sgp130), which limits soluble IL-6 receptor (sIL-6R)-mediated signaling - also called trans-signaling. Here we find that transgenic peripheral sgp130-mediated trans-signaling blockade induces mature-onset obesity, while differentially affecting age-dependent behavioral determinants of energy expenditure. In youth, trans-signaling blockade increases feeding associated with reduced leptin sensitivity but increases energy expenditure to maintain metabolic balance. In aging, reduced physical activity predisposes mice to adiposity, adipose tissue macrophage recruitment, hepatosteatosis, hyperglycemia, and insulin resistance. Mechanistically, trans-signaling blockade reduces hepatic Stat3 phosphorylation and suppresses PPARα, associated with miR-21 upregulation, while pharmacological activation of PPARα prevents obesity and hepatosteatosis, and rescues insulin sensitivity. Together these experiments reveal a role for peripheral IL-6 trans-signaling in metabolic homeostasis and provide clinical significance to elevated sgp130 levels found in some obese and diabetic patients.

ACS Style

Tali Lanton; Orr Levkovitch-Siany; Shiran Udi; Joseph Tam; Rinat Abramovich; Sharon Perles; Evan Williams; Jacob Rachmilewitz; Uria Mor; Eran Elinav; Dirk Schmidt-Arras; Ateequr Rehman; Philip Rosenstiel; Anastasios Giannou; Samuel Huber; Stefan Rose-John; Eithan Galun; Jonathan H. Axelrod. Peripheral sgp130-mediated trans-signaling blockade induces obesity and insulin resistance in mice via PPARα suppression. 2020, 1 .

AMA Style

Tali Lanton, Orr Levkovitch-Siany, Shiran Udi, Joseph Tam, Rinat Abramovich, Sharon Perles, Evan Williams, Jacob Rachmilewitz, Uria Mor, Eran Elinav, Dirk Schmidt-Arras, Ateequr Rehman, Philip Rosenstiel, Anastasios Giannou, Samuel Huber, Stefan Rose-John, Eithan Galun, Jonathan H. Axelrod. Peripheral sgp130-mediated trans-signaling blockade induces obesity and insulin resistance in mice via PPARα suppression. . 2020; ():1.

Chicago/Turabian Style

Tali Lanton; Orr Levkovitch-Siany; Shiran Udi; Joseph Tam; Rinat Abramovich; Sharon Perles; Evan Williams; Jacob Rachmilewitz; Uria Mor; Eran Elinav; Dirk Schmidt-Arras; Ateequr Rehman; Philip Rosenstiel; Anastasios Giannou; Samuel Huber; Stefan Rose-John; Eithan Galun; Jonathan H. Axelrod. 2020. "Peripheral sgp130-mediated trans-signaling blockade induces obesity and insulin resistance in mice via PPARα suppression." , no. : 1.

Journal article
Published: 01 September 2020 in Gastroenterology
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Background & Aims Development of nonalcoholic steatohepatitis (NASH) is associated with reductions in hepatic microRNA122 (MIR122); the RAR related orphan receptor A (RORA) promotes expression of MIR122. Increasing expression of RORA in livers of mice increases expression of MIR122 and reduces lipotoxicity. We investigated the effects of a RORA agonist in mouse models of NASH. Methods We screened a chemical library to identify agonists of RORA and tested their effects on a human hepatocellular carcinoma cell line (Huh7). C57BL/6 mice were fed a chow or high-fat diet (HFD) for 4 weeks to induce fatty liver. Mice were given hydrodynamic tail vein injections of a MIR122 antagonist (antagomiR-122) or a control antagomiR once each week for 3 weeks while still on the HFD or chow diet, or intraperitoneal injections of the RORA agonist RS-2982 or vehicle, twice each week for 3 weeks. Livers, gonad white adipose, and skeletal muscle were collected and analyzed by reverse-transcription polymerase chain reaction, histology, and immunohistochemistry. A separate group of mice were fed an atherogenic diet, with or without injections of RS-2982 for 3 weeks; livers were analyzed by immunohistochemistry, and plasma was analyzed for levels of aminotransferases. We analyzed data from liver tissues from patients with NASH included in the RNA-sequencing databases GSE33814 and GSE89632. Results Injection of mice with antagomiR-122 significantly reduced levels of MIR122 in plasma, liver, and white adipose tissue; in mice on an HFD, antagomiR-122 injections increased fat droplets and total triglyceride content in liver and reduced β-oxidation and energy expenditure, resulting in significantly more weight gain than in mice given the control microRNA. We identified RS-2982 as an agonist of RORA and found it to increase expression of MIR122 promoter activity in Huh7 cells. In mice fed an HFD or atherogenic diet, injections of RS-2982 increased hepatic levels of MIR122 precursors and reduced hepatic synthesis of triglycerides by reducing expression of biosynthesis enzymes. In these mice, RS-2982 significantly reduced hepatic lipotoxicity, reduced liver fibrosis, increased insulin resistance, and reduced body weight compared with mice injected with vehicle. Patients who underwent cardiovascular surgery had increased levels of plasma MIR122 compared to its levels before surgery; increased expression of plasma MIR122 was associated with increased levels of plasma free fatty acids and levels of RORA. Conclusions We identified the compound RS-2982 as an agonist of RORA that increases expression of MIR122 in cell lines and livers of mice. Mice fed an HFD or atherogenic diet given injections of RS-2982 had reduced hepatic lipotoxicity, liver fibrosis, and body weight compared with mice given the vehicle. Agonists of RORA might be developed for treatment of NASH.

ACS Style

Chofit Chai; Bryan Cox; Dayana Yaish; Devora Gross; Nofar Rosenberg; Franck Amblard; Zohar Shemuelian; Maytal Gefen; Amit Korach; Oren Tirosh; Tali Lanton; Henrike Link; Joseph Tam; Anna Permyakova; Gunes Ozhan; Jonathan Citrin; Haixing Liao; Mirna Tannous; Michal Hahn; Jonathan Axelrod; Enara Arretxe; Cristina Alonso; Ibon Martinez-Arranz; Pablo Ortiz Betés; Rifaat Safadi; Ahmad Salhab; Johnny Amer; Zahira Tber; Seema Mengshetti; Hilla Giladi; Raymond F. Schinazi; Eithan Galun. Agonist of RORA Attenuates Nonalcoholic Fatty Liver Progression in Mice via Up-regulation of MicroRNA 122. Gastroenterology 2020, 159, 999 -1014.e9.

AMA Style

Chofit Chai, Bryan Cox, Dayana Yaish, Devora Gross, Nofar Rosenberg, Franck Amblard, Zohar Shemuelian, Maytal Gefen, Amit Korach, Oren Tirosh, Tali Lanton, Henrike Link, Joseph Tam, Anna Permyakova, Gunes Ozhan, Jonathan Citrin, Haixing Liao, Mirna Tannous, Michal Hahn, Jonathan Axelrod, Enara Arretxe, Cristina Alonso, Ibon Martinez-Arranz, Pablo Ortiz Betés, Rifaat Safadi, Ahmad Salhab, Johnny Amer, Zahira Tber, Seema Mengshetti, Hilla Giladi, Raymond F. Schinazi, Eithan Galun. Agonist of RORA Attenuates Nonalcoholic Fatty Liver Progression in Mice via Up-regulation of MicroRNA 122. Gastroenterology. 2020; 159 (3):999-1014.e9.

Chicago/Turabian Style

Chofit Chai; Bryan Cox; Dayana Yaish; Devora Gross; Nofar Rosenberg; Franck Amblard; Zohar Shemuelian; Maytal Gefen; Amit Korach; Oren Tirosh; Tali Lanton; Henrike Link; Joseph Tam; Anna Permyakova; Gunes Ozhan; Jonathan Citrin; Haixing Liao; Mirna Tannous; Michal Hahn; Jonathan Axelrod; Enara Arretxe; Cristina Alonso; Ibon Martinez-Arranz; Pablo Ortiz Betés; Rifaat Safadi; Ahmad Salhab; Johnny Amer; Zahira Tber; Seema Mengshetti; Hilla Giladi; Raymond F. Schinazi; Eithan Galun. 2020. "Agonist of RORA Attenuates Nonalcoholic Fatty Liver Progression in Mice via Up-regulation of MicroRNA 122." Gastroenterology 159, no. 3: 999-1014.e9.

Preprint content
Published: 14 July 2020
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The soluble isoform of leptin receptor (sOb-R), secreted by the liver, regulates leptin bioavailability and bioactivity. Its reduced levels in diet-induced obesity (DIO) contributes to hyperleptinemia and leptin resistance, effects that are known to be regulated by the endocannabinoid (eCB)/CB1R system. Here we show that pharmacological activation/blockade as well as genetic overexpression/deletion of hepatic CB1R modulates sOb-R levels and consequently hepatic leptin resistance. Interestingly, peripheral CB1R blockade failed to reverse DIO-induced reduction of sOb-R levels, fat mass, dyslipidemia, and hepatic steatosis in mice lacking C/EBP homologous protein (CHOP), whereas direct activation of CB1R in hepatocytes reduced sOb-R levels in a CHOP-dependent manner. Moreover, CHOP stimulation increased sOb-R expression and release via a direct regulation of its promoter, while CHOP deletion reduced leptin sensitivity. Our findings highlight a novel molecular aspect by which the hepatic eCB/CB1R system involves in the development of hepatic leptin resistance by regulating sOb-R levels via CHOP.SummaryHere we describe a novel molecular aspect by which the hepatic endocannabinoid/CB1R system contributes to hepatic leptin resistance by regulating soluble leptin receptor levels via CHOP.

ACS Style

Adi Drori; Asaad Gammal; Shahar Azar; Liad Hinden; Rivka Hadar; Daniel Wesley; Alina Nemirovski; Gergő Szanda; Maayan Salton; Boaz Tirosh; Joseph Tam. CB1R Regulates Soluble Leptin Receptor Levels via CHOP, Contributing to Hepatic Leptin Resistance. 2020, 1 .

AMA Style

Adi Drori, Asaad Gammal, Shahar Azar, Liad Hinden, Rivka Hadar, Daniel Wesley, Alina Nemirovski, Gergő Szanda, Maayan Salton, Boaz Tirosh, Joseph Tam. CB1R Regulates Soluble Leptin Receptor Levels via CHOP, Contributing to Hepatic Leptin Resistance. . 2020; ():1.

Chicago/Turabian Style

Adi Drori; Asaad Gammal; Shahar Azar; Liad Hinden; Rivka Hadar; Daniel Wesley; Alina Nemirovski; Gergő Szanda; Maayan Salton; Boaz Tirosh; Joseph Tam. 2020. "CB1R Regulates Soluble Leptin Receptor Levels via CHOP, Contributing to Hepatic Leptin Resistance." , no. : 1.

Journal article
Published: 16 October 2019 in Molecules
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Oleoyl serine (OS), an endogenous fatty acyl amide (FAA) found in bone, has been shown to have an anti-osteoporotic effect. OS, being an amide, can be hydrolyzed in the body by amidases. Hindering its amide bond by introducing adjacent substituents has been demonstrated as a successful method for prolonging its skeletal activity. Here, we tested the therapeutic efficacy of two methylated OS derivatives, oleoyl α-methyl serine (HU-671) and 2-methyl-oleoyl serine (HU-681), in an ovariectomized mouse model for osteoporosis by utilizing combined micro-computed tomography, histomorphometry, and cell culture analyses. Our findings indicate that daily treatment for 6 weeks with OS or HU-671 completely rescues bone loss, whereas HU-681 has only a partial effect. The increased bone density was primarily due to enhanced trabecular thickness and number. Moreover, the most effective dose of HU-671 was 0.5 mg/kg/day, an order of magnitude lower than with OS. The reversal of bone loss resulted from increased bone formation and decreased bone resorption, as well as reversal of bone marrow adiposity. These results were further confirmed by determining the serum levels of osteocalcin and type 1 collagen C-terminal crosslinks, as well as demonstrating the enhanced antiadipogenic effect of HU-671. Taken together, these data suggest that methylation interferes with OS’s metabolism, thus enhancing its effects by extending its availability to its target cells.

ACS Style

Saja Baraghithy; Reem Smoum; Malka Attar-Namdar; Raphael Mechoulam; Itai Bab; Joseph Tam. HU-671, a Novel Oleoyl Serine Derivative, Exhibits Enhanced Efficacy in Reversing Ovariectomy-Induced Osteoporosis and Bone Marrow Adiposity. Molecules 2019, 24, 3719 .

AMA Style

Saja Baraghithy, Reem Smoum, Malka Attar-Namdar, Raphael Mechoulam, Itai Bab, Joseph Tam. HU-671, a Novel Oleoyl Serine Derivative, Exhibits Enhanced Efficacy in Reversing Ovariectomy-Induced Osteoporosis and Bone Marrow Adiposity. Molecules. 2019; 24 (20):3719.

Chicago/Turabian Style

Saja Baraghithy; Reem Smoum; Malka Attar-Namdar; Raphael Mechoulam; Itai Bab; Joseph Tam. 2019. "HU-671, a Novel Oleoyl Serine Derivative, Exhibits Enhanced Efficacy in Reversing Ovariectomy-Induced Osteoporosis and Bone Marrow Adiposity." Molecules 24, no. 20: 3719.

Research paper
Published: 23 August 2019 in British Journal of Pharmacology
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Background and Purpose Obesity, an important risk factor for developing chronic kidney disease (CKD), affects the kidneys by two main molecular signalling pathways: the endocannabinoid/CB1 receptor system, whose activation in obesity promotes renal inflammation, fibrosis, and injury, and the inducible NOS (iNOS), which generates ROS resulting in oxidative stress. Hence, a compound that inhibits both peripheral CB1 receptors and iNOS may serve as an effective therapeutic agent against obesity‐induced CKD. Experimental Approach Here, we describe the effect of a novel peripherally restricted, orally bioavailable dual CB1 receptor/iNOS antagonist, MRI‐1867 (3 mg·kg−1), in ameliorating obesity‐induced CKD, and compared its metabolic and renal efficacies to a stand‐alone peripheral CB1 receptor antagonist (JD5037; 3 mg·kg−1), iNOS antagonist (1400W; 10 mg·kg−1), and pair feeding. Mice with high‐fat diet‐induced obesity were treated orally with these compounds or vehicle (Veh) for 28 days. Standard diet‐fed mice treated with Veh served as controls. Key Results Enhanced expression of CB1 receptors and iNOS in renal tubules was found in human kidney patients with obesity and other CKDs. The hybrid inhibitor ameliorated obesity‐induced kidney morphological and functional changes via decreasing kidney inflammation, fibrosis, oxidative stress, and renal injury. Some of these features were independent of the improved metabolic profile mediated via inhibition of CB1 receptors. An additional interesting finding is that these beneficial effects on the kidney were partially associated with modulating renal adiponectin signalling. Conclusions and Implications Collectively, our results highlight the therapeutic relevance of blocking CB1 receptors and iNOS in ameliorating obesity‐induced CKD.

ACS Style

Shiran Udi; Liad Hinden; Majdoleen Ahmad; Adi Drori; Malliga R. Iyer; Resat Cinar; Michal Herman‐Edelstein; Joseph Tam. Dual inhibition of cannabinoid CB 1 receptor and inducible NOS attenuates obesity‐induced chronic kidney disease. British Journal of Pharmacology 2019, 177, 110 -127.

AMA Style

Shiran Udi, Liad Hinden, Majdoleen Ahmad, Adi Drori, Malliga R. Iyer, Resat Cinar, Michal Herman‐Edelstein, Joseph Tam. Dual inhibition of cannabinoid CB 1 receptor and inducible NOS attenuates obesity‐induced chronic kidney disease. British Journal of Pharmacology. 2019; 177 (1):110-127.

Chicago/Turabian Style

Shiran Udi; Liad Hinden; Majdoleen Ahmad; Adi Drori; Malliga R. Iyer; Resat Cinar; Michal Herman‐Edelstein; Joseph Tam. 2019. "Dual inhibition of cannabinoid CB 1 receptor and inducible NOS attenuates obesity‐induced chronic kidney disease." British Journal of Pharmacology 177, no. 1: 110-127.

Review
Published: 15 May 2019 in Toxins
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In this review, we discuss the role of the endocannabinoid (eCB) system in regulating energy and metabolic homeostasis. Endocannabinoids, via activating the cannabinoid type-1 receptor (CB1R), are commonly known as mediators of the thrifty phenotype hypothesis due to their activity in the central nervous system, which in turn regulates food intake and underlies the development of metabolic syndrome. Indeed, these findings led to the clinical testing of globally acting CB1R blockers for obesity and various metabolic complications. However, their therapeutic potential was halted due to centrally mediated adverse effects. Recent observations that highlighted the key role of the peripheral eCB system in metabolic regulation led to the preclinical development of various novel compounds that block CB1R only in peripheral organs with very limited brain penetration and without causing behavioral side effects. These unique molecules, which effectively ameliorate obesity, type II diabetes, fatty liver, insulin resistance, and chronic kidney disease in several animal models, are likely to be further developed in the clinic and may revive the therapeutic potential of blocking CB1R once again.

ACS Style

Shira Hirsch; Joseph Tam. Cannabis: From a Plant That Modulates Feeding Behaviors toward Developing Selective Inhibitors of the Peripheral Endocannabinoid System for the Treatment of Obesity and Metabolic Syndrome. Toxins 2019, 11, 275 .

AMA Style

Shira Hirsch, Joseph Tam. Cannabis: From a Plant That Modulates Feeding Behaviors toward Developing Selective Inhibitors of the Peripheral Endocannabinoid System for the Treatment of Obesity and Metabolic Syndrome. Toxins. 2019; 11 (5):275.

Chicago/Turabian Style

Shira Hirsch; Joseph Tam. 2019. "Cannabis: From a Plant That Modulates Feeding Behaviors toward Developing Selective Inhibitors of the Peripheral Endocannabinoid System for the Treatment of Obesity and Metabolic Syndrome." Toxins 11, no. 5: 275.

Short communication
Published: 31 January 2019 in Molecular Metabolism
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WWOX, a well-established tumor suppressor, is frequently lost in cancer and plays important roles in DNA damage response and cellular metabolism. We re-analyzed several genome-wide association studies (GWAS) using the Type 2 Diabetes Knowledge Portal website to uncover WWOX's association with metabolic syndrome (MetS). Using several engineered mouse models, we studied the effect of somatic WWOX loss on glucose homeostasis. Several WWOX variants were found to be strongly associated with MetS disorders. In mouse models, somatic ablation of Wwox in skeletal muscle (WwoxΔSKM) results in weight gain, glucose intolerance, and insulin resistance. Furthermore, WwoxΔSKM mice display reduced amounts of slow-twitch fibers, decreased mitochondrial quantity and activity, and lower glucose oxidation levels. Mechanistically, we found that WWOX physically interacts with the cellular energy sensor AMP-activated protein kinase (AMPK) and that its loss is associated with impaired activation of AMPK, and with significant accumulation of the hypoxia inducible factor 1 alpha (HIF1α) in SKM. Our studies uncover an unforeseen role of the tumor suppressor WWOX in whole-body glucose homeostasis and highlight the intimate relationship between cancer progression and metabolic disorders, particularly obesity and type-2 diabetes. Genetics, Metabolic Syndrome, Diabetes.

ACS Style

Muhannad Abu-Remaileh; Monther Abu-Remaileh; Rania Akkawi; Ibrahim Knani; Shiran Udi; Micheal E. Pacold; Joseph Tam; Rami I. Aqeilan. WWOX somatic ablation in skeletal muscles alters glucose metabolism. Molecular Metabolism 2019, 22, 132 -140.

AMA Style

Muhannad Abu-Remaileh, Monther Abu-Remaileh, Rania Akkawi, Ibrahim Knani, Shiran Udi, Micheal E. Pacold, Joseph Tam, Rami I. Aqeilan. WWOX somatic ablation in skeletal muscles alters glucose metabolism. Molecular Metabolism. 2019; 22 ():132-140.

Chicago/Turabian Style

Muhannad Abu-Remaileh; Monther Abu-Remaileh; Rania Akkawi; Ibrahim Knani; Shiran Udi; Micheal E. Pacold; Joseph Tam; Rami I. Aqeilan. 2019. "WWOX somatic ablation in skeletal muscles alters glucose metabolism." Molecular Metabolism 22, no. : 132-140.

Journal article
Published: 30 January 2019 in Molecular Autism
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The endocannabinoid system (ECS) is a major regulator of synaptic plasticity and neuromodulation. Alterations of the ECS have been demonstrated in several animal models of autism spectrum disorder (ASD). In some of these models, activating the ECS rescued the social deficits. Evidence for dysregulations of the ECS in human ASD are emerging, but comprehensive assessments and correlations with disease characteristics have not been reported yet. Serum levels of the main endocannabinoids, N-arachidonoylethanolamine (AEA or anandamide) and 2-arachidonoylglycerol (2-AG), and their related endogenous compounds, arachidonic acid (AA), N-palmitoylethanolamine (PEA), and N-oleoylethanolamine (OEA), were analyzed by liquid chromatography/tandem mass spectrometry in 93 children with ASD (age = 13.1 ± 4.1, range 6–21; 79% boys) and 93 age- and gender-matched neurotypical children (age = 11.8 ± 4.3, range 5.5–21; 79% boys). Results were associated with gender and use of medications, and were correlated with age, BMI, and adaptive functioning of ASD participants as reflected by scores of Autism Diagnostic Observation Schedule (ADOS-2), Vineland Adaptive Behavior Scale-II (VABS-II), and Social Responsiveness Scale-II (SRS-2). Children with ASD had lower levels (pmol/mL, mean ± SEM) of AEA (0.722 ± 0.045 vs. 1.252 ± 0.072, P < 0.0001, effect size 0.91), OEA (17.3 ± 0.80 vs. 27.8 ± 1.44, P < 0.0001, effect size 0.94), and PEA (4.93 ± 0.32 vs. 7.15 ± 0.37, P < 0.0001, effect size 0.65), but not AA and 2-AG. Serum levels of AEA, OEA, and PEA were not significantly associated or correlated with age, gender, BMI, medications, and adaptive functioning of ASD participants. In children with ASD, but not in the control group, younger age and lower BMI tended to correlate with lower AEA levels. However, these correlations were not statistically significant after a correction for multiple comparisons. We found lower serum levels of AEA, PEA, and OEA in children with ASD. Further studies are needed to determine whether circulating endocannabinoid levels can be used as stratification biomarkers that identify clinically significant subgroups within the autism spectrum and if they reflect lower endocannabinoid “tone” in the brain, as found in animal models of ASD.

ACS Style

Adi Aran; Maya Eylon; Moria Harel; Lola Polianski; Alina Nemirovski; Sigal Tepper; Aviad Schnapp; Hanoch Cassuto; Nadia Wattad; Joseph Tam. Lower circulating endocannabinoid levels in children with autism spectrum disorder. Molecular Autism 2019, 10, 1 -11.

AMA Style

Adi Aran, Maya Eylon, Moria Harel, Lola Polianski, Alina Nemirovski, Sigal Tepper, Aviad Schnapp, Hanoch Cassuto, Nadia Wattad, Joseph Tam. Lower circulating endocannabinoid levels in children with autism spectrum disorder. Molecular Autism. 2019; 10 (1):1-11.

Chicago/Turabian Style

Adi Aran; Maya Eylon; Moria Harel; Lola Polianski; Alina Nemirovski; Sigal Tepper; Aviad Schnapp; Hanoch Cassuto; Nadia Wattad; Joseph Tam. 2019. "Lower circulating endocannabinoid levels in children with autism spectrum disorder." Molecular Autism 10, no. 1: 1-11.

Full paper
Published: 19 October 2018 in ChemMedChem
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Due to the toxicity of platinum compounds used in the clinic as anticancer chemotherapies, the safe titanium serves as an attractive alternative. Lately, we introduced a new family of Ti complexes based on readily available phenolato ligands, demonstrating an incredibly high hydrolytic stability, with the lead compound phenolaTi demonstrating a wide cytotoxic activity towards the NCI‐60 panel of NIH human cancer cell lines, with an average GI50 of 4.7±2 µM. Herein, we evaluated in vivo: (a) the safety, and (b) the growth inhibitory (efficacy) of this compound. PhenolaTi was effective in vivo against colon (CT‐26) and lung (LLC‐1) murine cell lines in syngeneic hosts and towards a human colon cancer (HT‐29) cell line in immune deficient (Nude) mice, with an efficacy similar to that of known chemotherapy. Notably, no clinical signs of toxicity were observed in the treated mice; namely, no effect on body weight, spleen weight or kidney function, unlike observed with the positive control Pt drugs. Studies of combinations of PhenolaTi and Pt drugs evinced that similar efficacy with reduced toxicity may be achieved, which is highly valuable for medicinal applications.

ACS Style

Nitzan Ganot; Ori Briaitbard; Asaad Gammal; Joseph Tam; Jacob Hochman; Edit Y. Tshuva. In Vivo Anticancer Activity of a Nontoxic Inert Phenolato Titanium Complex: High Efficacy on Solid Tumors Alone and Combined with Platinum Drugs. ChemMedChem 2018, 13, 2290 -2296.

AMA Style

Nitzan Ganot, Ori Briaitbard, Asaad Gammal, Joseph Tam, Jacob Hochman, Edit Y. Tshuva. In Vivo Anticancer Activity of a Nontoxic Inert Phenolato Titanium Complex: High Efficacy on Solid Tumors Alone and Combined with Platinum Drugs. ChemMedChem. 2018; 13 (21):2290-2296.

Chicago/Turabian Style

Nitzan Ganot; Ori Briaitbard; Asaad Gammal; Joseph Tam; Jacob Hochman; Edit Y. Tshuva. 2018. "In Vivo Anticancer Activity of a Nontoxic Inert Phenolato Titanium Complex: High Efficacy on Solid Tumors Alone and Combined with Platinum Drugs." ChemMedChem 13, no. 21: 2290-2296.

Original contributions
Published: 22 September 2018 in Obesity Surgery
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The endocannabinoid (eCB) system plays a key role in the development of obesity and its comorbidities. Limited information exists on the changes in circulating eCBs following bariatric surgery. This study aims to (i) assess the circulating levels of eCBs and related molecules and (ii) examine the association between their levels and numerous clinical/metabolic features pre- and post-operatively. Sixty-five morbidly obese patients (age 42.78 ± 9.27 years; BMI 42.00 ± 5.01 kg/m2) underwent laparoscopic sleeve gastrectomy (LSG) surgery, and were followed up for 12 months. Data collected included anthropometrics and metabolic parameters. The serum levels of the eCBs, 2-arachidonoylglycerol (2-AG), anandamide (AEA); and their related molecules, arachidonic acid (AA) and oleoylethanolamine (OEA) were measured by liquid chromatography-mass spectrometry. Levels of 2-AG, AEA, and AA were reduced post operatively with no differences in serum OEA levels. The delta changes in eCB levels between pre- and post-operation were correlated with the delta of different metabolic parameters. Positive correlations were found between delta AA and waist circumference (WC) (r = 0.28, P < 0.05), free fat mass (r = 0.26, P < 0.05), SteatoTest score (r = 0.45, P < 0.05), and ALT (r = 0.32, P < 0.05). Delta AEA levels positively correlated with WC (r = 0.30, P < 0.05). Delta 2-AG levels positively correlated with total cholesterol (r = 0.27, P < 0.05), triglycerides (r = 0.55, P < 0.05), and SteatoTest score (r = 0.27, P < 0.05). Delta OEA levels negatively correlated with fasting glucose levels (r = − 0.27, P < 0.05). This study provides compelling evidence that LSG surgery induces reductions in the circulating 2-AG, AEA, and AA levels, and that these changes are associated with clinical benefits related to the surgery including reduced fat mass, hepatic steatosis, glucose, and improved lipid profile.

ACS Style

Shahar Azar; Shiri Sherf-Dagan; Alina Nemirovski; Muriel Webb; Asnat Raziel; Andrei Keidar; David Goitein; Nasser Sakran; Oren Shibolet; Joseph Tam; Shira Zelber-Sagi. Circulating Endocannabinoids Are Reduced Following Bariatric Surgery and Associated with Improved Metabolic Homeostasis in Humans. Obesity Surgery 2018, 29, 268 -276.

AMA Style

Shahar Azar, Shiri Sherf-Dagan, Alina Nemirovski, Muriel Webb, Asnat Raziel, Andrei Keidar, David Goitein, Nasser Sakran, Oren Shibolet, Joseph Tam, Shira Zelber-Sagi. Circulating Endocannabinoids Are Reduced Following Bariatric Surgery and Associated with Improved Metabolic Homeostasis in Humans. Obesity Surgery. 2018; 29 (1):268-276.

Chicago/Turabian Style

Shahar Azar; Shiri Sherf-Dagan; Alina Nemirovski; Muriel Webb; Asnat Raziel; Andrei Keidar; David Goitein; Nasser Sakran; Oren Shibolet; Joseph Tam; Shira Zelber-Sagi. 2018. "Circulating Endocannabinoids Are Reduced Following Bariatric Surgery and Associated with Improved Metabolic Homeostasis in Humans." Obesity Surgery 29, no. 1: 268-276.

Original article
Published: 09 August 2018 in Diabetes, Obesity and Metabolism
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Aims To evaluate the specific role of the endocannabinoid/CB1R system in modulating mitochondrial dynamics in the metabolically active renal proximal tubular cells (RPTCs). Materials and methods We utilized mitochondrialy‐targeted GFP in live cells (wild‐type and null for the CB1R), and electron microscopy in kidney sections of RPTC‐CB1R‐/‐ mice and their littermate controls. In both in vitro and in vivo conditions, we assessed the ability of CB1R agonism or fatty acid flux to modulate mitochondrial architecture and function. Results Direct stimulation of CB1R resulted in mitochondrial fragmentation in RPTCs. This process was mediated, at least in part, by modulating the phosphorylation levels of the canonical fission protein dynamin‐related protein 1 on both S637 and S616 residues. CB1R‐induced mitochondrial fission was associated with mitochondrial dysfunction, as documented by reduced oxygen consumption and ATP production, increased reactive oxygen species and cellular lactate levels, as well as a decline in mitochondrial biogenesis. Likewise, we documented that exposure of RPTCs to a fatty acid flux induced CB1R‐depended mitochondrial fission, lipotoxicity, and cellular dysfunction. Conclusions CB1R plays a key role in inducing mitochondrial fragmentation in RPTCs, leading to a decline in organelle’s function, and contributing to renal tubular injury associated with lipotoxicity and other metabolic diseases. This article is protected by copyright. All rights reserved.

ACS Style

Adi Drori; Anna Permyakova; Rivka Hadar; Shiran Udi; Alina Nemirovski; Joseph Tam. Cannabinoid-1 receptor regulates mitochondrial dynamics and function in renal proximal tubular cells. Diabetes, Obesity and Metabolism 2018, 21, 146 -159.

AMA Style

Adi Drori, Anna Permyakova, Rivka Hadar, Shiran Udi, Alina Nemirovski, Joseph Tam. Cannabinoid-1 receptor regulates mitochondrial dynamics and function in renal proximal tubular cells. Diabetes, Obesity and Metabolism. 2018; 21 (1):146-159.

Chicago/Turabian Style

Adi Drori; Anna Permyakova; Rivka Hadar; Shiran Udi; Alina Nemirovski; Joseph Tam. 2018. "Cannabinoid-1 receptor regulates mitochondrial dynamics and function in renal proximal tubular cells." Diabetes, Obesity and Metabolism 21, no. 1: 146-159.

Journal article
Published: 01 March 2018 in Bone
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The endocannabinoid (eCB) system, including its receptors, ligands, and their metabolizing enzymes, plays an important role in bone physiology. Skeletal cannabinoid type 1 (CB1) receptor signaling transmits retrograde signals that restrain norepinephrine (NE) release, thus transiently stimulating bone formation following an acute challenge, suggesting a feedback circuit between sympathetic nerve terminals and osteoblasts. To assess the effect of chronic in vivo occurrence of this circuit, we characterized the skeletal phenotype of mice with a conditional deletion of the CB1 receptor in adrenergic/noradrenergic cells, including sympathetic nerves. Whereas the deletion of the CB1 receptor did not affect bone mass accrual in the distal femoral metaphysis and in vertebral bodies of young, 12-week-old mice, it substantially increased bone mass in aged, 35-week-old mutant mice as compared to wild-type controls. Contrary to our expectations, specific deficiency of the CB1 receptor in sympathetic neurons led to a markedly increased bone mass phenotype, associated with an enhanced bone formation rate and reduced osteoclastogenesis. Mechanistically, the reduced skeletal eCB 'tone' in the null mice did not reflect in increased sympathetic tone and reduced bone formation, suggesting that constitutive genetic inactivation of sympathetic CB1 receptor disrupts the negative feedback loop between eCBs and NE signaling in bone.

ACS Style

Saif Deis; Raj Kamal Srivastava; Inigo Ruiz de Azua; Laura Bindila; Saja Baraghithy; Beat Lutz; Itai Bab; Joseph Tam. Age-related regulation of bone formation by the sympathetic cannabinoid CB1 receptor. Bone 2018, 108, 34 -42.

AMA Style

Saif Deis, Raj Kamal Srivastava, Inigo Ruiz de Azua, Laura Bindila, Saja Baraghithy, Beat Lutz, Itai Bab, Joseph Tam. Age-related regulation of bone formation by the sympathetic cannabinoid CB1 receptor. Bone. 2018; 108 ():34-42.

Chicago/Turabian Style

Saif Deis; Raj Kamal Srivastava; Inigo Ruiz de Azua; Laura Bindila; Saja Baraghithy; Beat Lutz; Itai Bab; Joseph Tam. 2018. "Age-related regulation of bone formation by the sympathetic cannabinoid CB1 receptor." Bone 108, no. : 34-42.

Review
Published: 11 January 2018 in European Journal of Internal Medicine
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Endocannabinoids (eCBs) are internal lipid mediators recognized by the cannabinoid-1 and -2 receptors (CB1R and CB2R, respectively), which also mediate the different physiological effects of marijuana. The endocannabinoid system, consisting of eCBs, their receptors, and the enzymes involved in their biosynthesis and degradation, is present in a vast number of peripheral organs. In this review we describe the role of the eCB/CB1R system in modulating the metabolism in several peripheral organs. We assess how eCBs, via activating the CB1R, contribute to obesity and regulate food intake. In addition, we describe their roles in modulating liver and kidney functions, as well as bone remodeling and mass. Special importance is given to emphasizing the efficacy of the recently developed peripherally restricted CB1R antagonists, which were pre-clinically tested in the management of energy homeostasis, and in ameliorating both obesity- and diabetes-induced metabolic complications.

ACS Style

Joseph Tam; Liad Hinden; Adi Drori; Shiran Udi; Shahar Azar; Saja Baraghithy. The therapeutic potential of targeting the peripheral endocannabinoid/CB 1 receptor system. European Journal of Internal Medicine 2018, 49, 23 -29.

AMA Style

Joseph Tam, Liad Hinden, Adi Drori, Shiran Udi, Shahar Azar, Saja Baraghithy. The therapeutic potential of targeting the peripheral endocannabinoid/CB 1 receptor system. European Journal of Internal Medicine. 2018; 49 ():23-29.

Chicago/Turabian Style

Joseph Tam; Liad Hinden; Adi Drori; Shiran Udi; Shahar Azar; Saja Baraghithy. 2018. "The therapeutic potential of targeting the peripheral endocannabinoid/CB 1 receptor system." European Journal of Internal Medicine 49, no. : 23-29.

Journal article
Published: 01 November 2017 in Gastroenterology
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In biochemical and histologic studies of plasma, liver, muscle, and adipose tissues from mice, we found that FFAs increase hepatic expression and secretion of MIR122, which regulates energy storage vs expenditure in liver and peripheral tissues. Strategies to reduce triglyceride levels, by increasing MIR122, might be developed for treatment of metabolic syndrome.

ACS Style

Chofit Chai; Mila Rivkin; Liav Berkovits; Alina Simerzin; Elina Zorde-Khvalevsky; Nofar Rosenberg; Shiri Klein; Dayana Yaish; Ronen Durst; Shoshana Shpitzen; Shiran Udi; Joseph Tam; Joerg Heeren; Anna Worthmann; Christoph Schramm; Johannes Kluwe; Revital Ravid; Eran Hornstein; Hilla Giladi; Eithan Galun. Metabolic Circuit Involving Free Fatty Acids, microRNA 122, and Triglyceride Synthesis in Liver and Muscle Tissues. Gastroenterology 2017, 153, 1404 -1415.

AMA Style

Chofit Chai, Mila Rivkin, Liav Berkovits, Alina Simerzin, Elina Zorde-Khvalevsky, Nofar Rosenberg, Shiri Klein, Dayana Yaish, Ronen Durst, Shoshana Shpitzen, Shiran Udi, Joseph Tam, Joerg Heeren, Anna Worthmann, Christoph Schramm, Johannes Kluwe, Revital Ravid, Eran Hornstein, Hilla Giladi, Eithan Galun. Metabolic Circuit Involving Free Fatty Acids, microRNA 122, and Triglyceride Synthesis in Liver and Muscle Tissues. Gastroenterology. 2017; 153 (5):1404-1415.

Chicago/Turabian Style

Chofit Chai; Mila Rivkin; Liav Berkovits; Alina Simerzin; Elina Zorde-Khvalevsky; Nofar Rosenberg; Shiri Klein; Dayana Yaish; Ronen Durst; Shoshana Shpitzen; Shiran Udi; Joseph Tam; Joerg Heeren; Anna Worthmann; Christoph Schramm; Johannes Kluwe; Revital Ravid; Eran Hornstein; Hilla Giladi; Eithan Galun. 2017. "Metabolic Circuit Involving Free Fatty Acids, microRNA 122, and Triglyceride Synthesis in Liver and Muscle Tissues." Gastroenterology 153, no. 5: 1404-1415.

Journal article
Published: 13 October 2017 in Journal of the American Society of Nephrology
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Altered glucose reabsorption via the facilitative glucose transporter 2 (GLUT2) during diabetes may lead to renal proximal tubule cell (RPTC) injury, inflammation, and interstitial fibrosis. These pathologies are also triggered by activating the cannabinoid-1 receptor (CB1R), which contributes to the development of diabetic nephropathy (DN). However, the link between CB1R and GLUT2 remains to be determined. Here, we show that chronic peripheral CB1R blockade or genetically inactivating CB1Rs in the RPTCs ameliorated diabetes-induced renal structural and functional changes, kidney inflammation, and tubulointerstitial fibrosis in mice. Inhibition of CB1R also downregulated GLUT2 expression, affected the dynamic translocation of GLUT2 to the brush border membrane of RPTCs, and reduced glucose reabsorption. Thus, targeting peripheral CB1R or inhibiting GLUT2 dynamics in RPTCs has the potential to treat and ameliorate DN. These findings may support the rationale for the clinical testing of peripherally restricted CB1R antagonists or the development of novel renal-specific GLUT2 inhibitors against DN.

ACS Style

Liad Hinden; Shiran Udi; Adi Drori; Asaad Gammal; Alina Nemirovski; Rivka Hadar; Saja Baraghithy; Anna Permyakova; Matan Geron; Merav Cohen; Sabina Tsytkin-Kirschenzweig; Yael Riahi; Gil Leibowitz; Yaakov Nahmias; Avi Priel; Joseph Tam. Modulation of Renal GLUT2 by the Cannabinoid-1 Receptor: Implications for the Treatment of Diabetic Nephropathy. Journal of the American Society of Nephrology 2017, 29, 434 -448.

AMA Style

Liad Hinden, Shiran Udi, Adi Drori, Asaad Gammal, Alina Nemirovski, Rivka Hadar, Saja Baraghithy, Anna Permyakova, Matan Geron, Merav Cohen, Sabina Tsytkin-Kirschenzweig, Yael Riahi, Gil Leibowitz, Yaakov Nahmias, Avi Priel, Joseph Tam. Modulation of Renal GLUT2 by the Cannabinoid-1 Receptor: Implications for the Treatment of Diabetic Nephropathy. Journal of the American Society of Nephrology. 2017; 29 (2):434-448.

Chicago/Turabian Style

Liad Hinden; Shiran Udi; Adi Drori; Asaad Gammal; Alina Nemirovski; Rivka Hadar; Saja Baraghithy; Anna Permyakova; Matan Geron; Merav Cohen; Sabina Tsytkin-Kirschenzweig; Yael Riahi; Gil Leibowitz; Yaakov Nahmias; Avi Priel; Joseph Tam. 2017. "Modulation of Renal GLUT2 by the Cannabinoid-1 Receptor: Implications for the Treatment of Diabetic Nephropathy." Journal of the American Society of Nephrology 29, no. 2: 434-448.