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Qiu S, Wu Q, Wang H, Liu D, Chen C, Zhu Z, Zheng H, Yang G, Li L, Yang M. AZGP1 in POMC neurons modulates energy homeostasis and metabolism through leptin-mediated STAT3 phosphorylation. Nat Commun 2024; 15:3377. [PMID: 38643150 PMCID: PMC11032411 DOI: 10.1038/s41467-024-47684-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2023] [Accepted: 04/10/2024] [Indexed: 04/22/2024] Open
Abstract
Zinc-alpha2-glycoprotein (AZGP1) has been implicated in peripheral metabolism; however, its role in regulating energy metabolism in the brain, particularly in POMC neurons, remains unknown. Here, we show that AZGP1 in POMC neurons plays a crucial role in controlling whole-body metabolism. POMC neuron-specific overexpression of Azgp1 under high-fat diet conditions reduces energy intake, raises energy expenditure, elevates peripheral tissue leptin and insulin sensitivity, alleviates liver steatosis, and promotes adipose tissue browning. Conversely, mice with inducible deletion of Azgp1 in POMC neurons exhibit the opposite metabolic phenotypes, showing increased susceptibility to diet-induced obesity. Notably, an increase in AZGP1 signaling in the hypothalamus elevates STAT3 phosphorylation and increases POMC neuron excitability. Mechanistically, AZGP1 enhances leptin-JAK2-STAT3 signaling by interacting with acylglycerol kinase (AGK) to block its ubiquitination degradation. Collectively, these results suggest that AZGP1 plays a crucial role in regulating energy homeostasis and glucose/lipid metabolism by acting on hypothalamic POMC neurons.
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Affiliation(s)
- Sheng Qiu
- Department of Endocrinology, the Second Affiliated Hospital, Chongqing Medical University, Chongqing, 400010, China
- Key Laboratory of Medical Diagnostics of Ministry of Education, Department of Laboratory Medicine, Chongqing Medical University, Chongqing, 400016, China
| | - Qinan Wu
- Department of Endocrinology, The Affiliated Dazu Hospital of Chongqing Medical University, Chongqing, 402360, China
| | - Hao Wang
- Department of Endocrinology, the Second Affiliated Hospital, Chongqing Medical University, Chongqing, 400010, China
| | - Dongfang Liu
- Department of Endocrinology, the Second Affiliated Hospital, Chongqing Medical University, Chongqing, 400010, China
| | - Chen Chen
- Endocrinology, SBMS, Faculty of Medicine, University of Queensland, Brisbane, QLD, 4072, Australia
| | - Zhiming Zhu
- Department of Hypertension and Endocrinology, Daping Hospital, Third Military Medical University, Chongqing, 400042, China
| | - Hongting Zheng
- Department of Endocrinology, Xinqiao Hospital, Third Military Medical University, Chongqing, 400037, China
| | - Gangyi Yang
- Department of Endocrinology, the Second Affiliated Hospital, Chongqing Medical University, Chongqing, 400010, China.
| | - Ling Li
- Department of Endocrinology, the Second Affiliated Hospital, Chongqing Medical University, Chongqing, 400010, China.
- Key Laboratory of Medical Diagnostics of Ministry of Education, Department of Laboratory Medicine, Chongqing Medical University, Chongqing, 400016, China.
| | - Mengliu Yang
- Department of Endocrinology, the Second Affiliated Hospital, Chongqing Medical University, Chongqing, 400010, China.
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Wang Q, Su Y, Sun R, Xiong X, Guo K, Wei M, Yang G, Ru Y, Zhang Z, Li J, Zhang J, Qiao Q, Li X. MIIP downregulation drives colorectal cancer progression through inducing peri-cancerous adipose tissue browning. Cell Biosci 2024; 14:12. [PMID: 38245780 PMCID: PMC10800076 DOI: 10.1186/s13578-023-01179-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2023] [Accepted: 12/05/2023] [Indexed: 01/22/2024] Open
Abstract
BACKGROUND The enrichment of peri-cancerous adipose tissue is a distinctive feature of colorectal cancer (CRC), accelerating disease progression and worsening prognosis. The communication between tumor cells and adjacent adipocytes plays a crucial role in CRC advancement. However, the precise regulatory mechanisms are largely unknown. This study aims to explore the mechanism of migration and invasion inhibitory protein (MIIP) downregulation in the remodeling of tumor cell-adipocyte communication and its role in promoting CRC. RESULTS MIIP expression was found to be decreased in CRC tissues and closely associated with adjacent adipocyte browning. In an in vitro co-culture model, adipocytes treated with MIIP-downregulated tumor supernatant exhibited aggravated browning and lipolysis. This finding was further confirmed in subcutaneously allografted mice co-injected with adipocytes and MIIP-downregulated murine CRC cells. Mechanistically, MIIP interacted with the critical lipid mobilization factor AZGP1 and regulated AZGP1's glycosylation status by interfering with its association with STT3A. MIIP downregulation promoted N-glycosylation and over-secretion of AZGP1 in tumor cells. Subsequently, AZGP1 induced adipocyte browning and lipolysis through the cAMP-PKA pathway, releasing free fatty acids (FFAs) into the microenvironment. These FFAs served as the primary energy source, promoting CRC cell proliferation, invasion, and apoptosis resistance, accompanied by metabolic reprogramming. In a tumor-bearing mouse model, inhibition of β-adrenergic receptor or FFA uptake, combined with oxaliplatin, significantly improved therapeutic efficacy in CRC with abnormal MIIP expression. CONCLUSIONS Our data demonstrate that MIIP plays a regulatory role in the communication between CRC and neighboring adipose tissue by regulating AZGP1 N-glycosylation and secretion. MIIP reduction leads to AZGP1 oversecretion, resulting in adipose browning-induced CRC rapid progression and poor prognosis. Inhibition of β-adrenergic receptor or FFA uptake, combined with oxaliplatin, may represent a promising therapeutic strategy for CRC with aberrant MIIP expression.
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Affiliation(s)
- Qinhao Wang
- State Key Laboratory of Cancer Biology, Department of Biochemistry and Molecular Biology, Fourth Military Medical University, Xi'an, 710032, Shaanxi, China.
| | - Yuanyuan Su
- State Key Laboratory of Cancer Biology, Department of Biochemistry and Molecular Biology, Fourth Military Medical University, Xi'an, 710032, Shaanxi, China
- Department of Pharmacology, Medical College, Yan'an University, Yan'an, 716000, Shaanxi, China
| | - Ruiqi Sun
- State Key Laboratory of Cancer Biology, Department of Biochemistry and Molecular Biology, Fourth Military Medical University, Xi'an, 710032, Shaanxi, China
- Key Laboratory of Resource Biology and Biotechnology in Western China, Ministry of Education, College of Life Sciences, Northwest University, Xi'an, 710069, Shaanxi, China
| | - Xin Xiong
- State Key Laboratory of Cancer Biology, Department of Biochemistry and Molecular Biology, Fourth Military Medical University, Xi'an, 710032, Shaanxi, China
| | - Kai Guo
- Department of Burns and Cutaneous Surgery, Xijing Hospital, Fourth Military Medical University, Xi'an, 710032, Shaanxi, China
| | - Mengying Wei
- State Key Laboratory of Cancer Biology, Department of Biochemistry and Molecular Biology, Fourth Military Medical University, Xi'an, 710032, Shaanxi, China
| | - Guodong Yang
- State Key Laboratory of Cancer Biology, Department of Biochemistry and Molecular Biology, Fourth Military Medical University, Xi'an, 710032, Shaanxi, China
| | - Yi Ru
- State Key Laboratory of Cancer Biology, Department of Biochemistry and Molecular Biology, Fourth Military Medical University, Xi'an, 710032, Shaanxi, China
| | - Zhengxiang Zhang
- Department of Pharmacology, Medical College, Yan'an University, Yan'an, 716000, Shaanxi, China
| | - Jing Li
- Department of Orthopedics, Xijing Hospital, Fourth Military Medical University, Xi'an, 710032, Shaanxi, China
| | - Jing Zhang
- Key Laboratory of Resource Biology and Biotechnology in Western China, Ministry of Education. School of Medicine, Northwest University, Xi'an, 710069, Shaanxi, China
| | - Qing Qiao
- Department of General Surgery, Tangdu Hospital, Fourth Military Medical University, No. 569 Xinsi Road, Xi'an, 710038, Shaanxi, China.
| | - Xia Li
- State Key Laboratory of Cancer Biology, Department of Biochemistry and Molecular Biology, Fourth Military Medical University, Xi'an, 710032, Shaanxi, China.
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Liang Y, Zhao L, Dai C, Liu G, Zhong Y, Liu H, Mo L, Tan C, Liu X, Chen L. Epileptiform Discharges Reduce Neuronal ATP Production by Inhibiting F0F1-ATP Synthase Activity via A Zinc-α2-Glycoprotein-Dependent Mechanism. Mol Neurobiol 2023; 60:6627-6641. [PMID: 37468739 DOI: 10.1007/s12035-023-03508-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2023] [Accepted: 07/12/2023] [Indexed: 07/21/2023]
Abstract
Neuronal energy metabolism dysfunction, especially adenosine triphosphate (ATP) supply decrease, is observed in epilepsy and associated with epileptogenesis and prognosis. Zinc-α2-glycoprotein (ZAG) is known as an important modulator of energy metabolism and involved in neuronal glucose metabolism, fatty acid metabolism, and ketogenesis impairment in seizures, but its effect on neuronal ATP synthesis in seizures and the specific mechanism are unclear. In this study, we verified the localization of ZAG in primary cultured neuronal mitochondria by using double-labeling immunofluorescence, immune electron microscopy, and western blot. ZAG level in neuronal mitochondria was modulated by lentiviruses and detected by western blot. The F0F1-ATP synthase activity, ATP level, and acetyl-CoA level were measured. The binding between ZAG and F0F1-ATP synthase was determined by coimmunoprecipitation. We found that both ZAG and F0F1-ATP synthase existed in neuronal mitochondria, and there was mutual binding between them. Epileptiform discharge-induced decrease of mitochondrial ZAG level was reversed by ZAG overexpression. Epileptiform discharge or ZAG knockdown decreased F0F1-ATP synthase activity and ATP level in neurons, which were reversed by ZAG overexpression, while overexpression of ZAG along only increased F0F1-ATP synthase activity but not increased ATP level. Meanwhile, neither epileptiform discharges nor changes of ZAG level can alter the acetyl-CoA level. Moreover, epileptiform discharge did not alter F0F1-ATP synthase level. In conclusion, epileptiform discharge-induced ZAG decrease in neuronal mitochondria is correlated to F0F1-ATP synthase activity inhibition, which may possibly lead to ATP supply impairments. ZAG may be a potential therapeutic target for treating neuronal energy metabolism dysfunction in seizures with further researches.
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Affiliation(s)
- Yi Liang
- Department of Neurology, The Second Affiliated Hospital of Chongqing Medical University, 74 Linjiang Road, Yuzhong District, Chongqing, 400010, China
| | - Lili Zhao
- Department of Neurology, The Second Affiliated Hospital of Chongqing Medical University, 74 Linjiang Road, Yuzhong District, Chongqing, 400010, China
| | - Chengcheng Dai
- Department of Neurology, The Second Affiliated Hospital of Chongqing Medical University, 74 Linjiang Road, Yuzhong District, Chongqing, 400010, China
| | - Guohui Liu
- Department of Neurology, The Second Affiliated Hospital of Chongqing Medical University, 74 Linjiang Road, Yuzhong District, Chongqing, 400010, China
| | - Yuke Zhong
- Department of Neurology, The Second Affiliated Hospital of Chongqing Medical University, 74 Linjiang Road, Yuzhong District, Chongqing, 400010, China
| | - Hang Liu
- Department of Neurology, The Second Affiliated Hospital of Chongqing Medical University, 74 Linjiang Road, Yuzhong District, Chongqing, 400010, China
| | - Lijuan Mo
- Department of Neurology, The Second Affiliated Hospital of Chongqing Medical University, 74 Linjiang Road, Yuzhong District, Chongqing, 400010, China
| | - Changhong Tan
- Department of Neurology, The Second Affiliated Hospital of Chongqing Medical University, 74 Linjiang Road, Yuzhong District, Chongqing, 400010, China
| | - Xi Liu
- Department of Neurology, The Second Affiliated Hospital of Chongqing Medical University, 74 Linjiang Road, Yuzhong District, Chongqing, 400010, China.
| | - Lifen Chen
- Department of Neurology, The Second Affiliated Hospital of Chongqing Medical University, 74 Linjiang Road, Yuzhong District, Chongqing, 400010, China.
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Carpéné C, Stiliyanov Atanasov K, Les F, Mercader Barcelo J. Hyperglycemia and reduced adiposity of streptozotocin-induced diabetic mice are not alleviated by oral benzylamine supplementation. World J Diabetes 2022; 13:752-764. [PMID: 36188146 PMCID: PMC9521444 DOI: 10.4239/wjd.v13.i9.752] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/11/2022] [Revised: 05/13/2022] [Accepted: 08/22/2022] [Indexed: 02/05/2023] Open
Abstract
BACKGROUND Benzylamine (Bza) oral administration delays the onset of hyperglycemia in insulin-resistant db-/- mice; a genetic model of obesity and type 2 diabetes.
AIM To extend the antihyperglycemic properties of oral benzylamine to a model of insulin-deficient type 1 diabetes.
METHODS Male Swiss mice were rendered diabetic by streptozotocin treatment (STZ) and divided in two groups: one received 0.5% Bza as drinking solution for 24 d (STZ Bza-drinking) while the other was drinking water ad libitum. Similar groups were constituted in age-matched, nondiabetic mice. Food intake, liquid intake, body weight gain and nonfasting blood glucose levels were followed during treatment. At the end of treatment, fasted glycemia, liver and white adipose tissue (WAT) mass were measured, while glucose uptake assays were performed in adipocytes.
RESULTS STZ diabetic mice presented typical features of insulin-deficient diabetes: reduced body mass and increased blood glucose levels. These altered parameters were not normalized in the Bza-drinking group in spite of restored food and water intake. Bza consumption could not reverse the severe fat depot atrophy of STZ diabetic mice. In the nondiabetic mice, no difference was found between control and Bza-drinking mice for any parameter. In isolated adipocytes, hexose uptake was partially activated by 0.1 mmol/L Bza in a manner that was obliterated in vitro by the amine oxidase inhibitor phenelzine and that remained unchanged after Bza supplementation. Oxidation of 0.1 mmol/L Bza in WAT was lower in STZ diabetic than in normoglycemic mice.
CONCLUSION Bza supplementation could not normalize the altered glucose handling of STZ diabetic mice with severe WAT atrophy. Consequently, its antidiabetic potential in obese and diabetic rodents does not apply to lipoatrophic type 1 diabetic mice.
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Affiliation(s)
- Christian Carpéné
- Institut des Maladies Métaboliques et Cardiovasculaires, INSERM UMR 1297, Toulouse 31432, France
| | - Kristiyan Stiliyanov Atanasov
- Molecular Biology and One Health research group, Department of Fundamental Biology and Health Sciences, University of the Balearic Islands, Palma 07122, Spain
| | - Francisco Les
- Department of Pharmacy, Faculty of Health Sciences, Universidad San Jorge, Villanueva de Gállego, Zaragoza 50830, Spain
| | - Josep Mercader Barcelo
- Molecular Biology and One Health research group, Department of Fundamental Biology and Health Sciences, University of the Balearic Islands, Palma 07122, Spain
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5
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Carpéné C, Marti L, Morin N. Increased monoamine oxidase activity and imidazoline binding sites in insulin-resistant adipocytes from obese Zucker rats. World J Biol Chem 2022; 13:15-34. [PMID: 35126867 PMCID: PMC8790288 DOI: 10.4331/wjbc.v13.i1.15] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/26/2021] [Revised: 07/09/2021] [Accepted: 01/14/2022] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Despite overt insulin resistance, adipocytes of genetically obese Zucker rats accumulate the excess of calorie intake in the form of lipids.
AIM To investigate whether factors can replace or reinforce insulin lipogenic action by exploring glucose uptake activation by hydrogen peroxide, since it is produced by monoamine oxidase (MAO) and semicarbazide-sensitive amine oxidase (SSAO) in adipocytes.
METHODS 3H-2-deoxyglucose uptake (2-DG) was determined in adipocytes from obese and lean rats in response to insulin or MAO and SSAO substrates such as tyramine and benzylamine. 14C-tyramine oxidation and binding of imidazolinic radioligands [3H-Idazoxan, 3H-(2-benzofuranyl)-2-imidazoline] were studied in adipocytes, the liver, and muscle. The influence of in vivo administration of tyramine + vanadium on glucose handling was assessed in lean and obese rats.
RESULTS 2-DG uptake and lipogenesis stimulation by insulin were dampened in adipocytes from obese rats, when compared to their lean littermates. Tyramine and benzylamine activation of hexose uptake was vanadate-dependent and was also limited, while MAO was increased and SSAO decreased. These changes were adipocyte-specific and accompanied by a greater number of imidazoline I2 binding sites in the obese rat, when compared to the lean. In vitro, tyramine precluded the binding to I2 sites, while in vivo, its administration together with vanadium lowered fasting plasma levels of glucose and triacylglycerols in obese rats.
CONCLUSION The adipocytes from obese Zucker rats exhibit increased MAO activity and imidazoline binding site number. However, probably as a consequence of SSAO down-regulation, the glucose transport stimulation by tyramine is decreased as much as that of insulin in these insulin-resistant adipocytes. The adipocyte amine oxidases deserve more studies with respect to their putative contribution to the management of glucose and lipid handling.
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Affiliation(s)
- Christian Carpéné
- Institut des Maladies Métaboliques et Cardiovasculaires, INSERM, Toulouse 31342, France
| | - Luc Marti
- Institut des Maladies Métaboliques et Cardiovasculaires, INSERM, Toulouse 31342, France
| | - Nathalie Morin
- Institut des Maladies Métaboliques et Cardiovasculaires, INSERM, Toulouse 31342, France
- Faculté de Pharmacie de Paris, Paris University, Paris 75270, France
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6
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Carpéné C, Boulet N, Grolleau JL, Morin N. High doses of catecholamines activate glucose transport in human adipocytes independently from adrenoceptor stimulation or vanadium addition. World J Diabetes 2022; 13:37-53. [PMID: 35070058 PMCID: PMC8771263 DOI: 10.4239/wjd.v13.i1.37] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/18/2021] [Revised: 04/26/2021] [Accepted: 12/28/2021] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND When combined with vanadium salts, catecholamines strongly activate glucose uptake in rat and mouse adipocytes.
AIM To test whether catecholamines activate glucose transport in human adipocytes.
METHODS The uptake of 2-deoxyglucose (2-DG) was measured in adipocytes isolated from pieces of abdominal subcutaneous tissue removed from women undergoing reconstructive surgery. Pharmacological approaches with amine oxidase inhibitors, adrenoreceptor agonists and antioxidants were performed to unravel the mechanisms of action of noradrenaline or adrenaline (also named epinephrine).
RESULTS In human adipocytes, 45-min incubation with 100 µmol/L adrenaline or noradrenaline activated 2-DG uptake up to more than one-third of the maximal response to insulin. This stimulation was not reproduced with millimolar doses of dopamine or serotonin and was not enhanced by addition of vanadate to the incubation medium. Among various natural amines and adrenergic agonists tested, no other molecule was more efficient than adrenaline and noradrenaline in stimulating 2-DG uptake. The effect of the catecholamines was not impaired by pargyline and semicarbazide, contrarily to that of benzylamine or methylamine, which are recognized substrates of semicarbazide-sensitive amine oxidase. Hydrogen peroxide at 1 mmol/L activated hexose uptake but not pyrocatechol or benzoquinone, and only the former was potentiated by vanadate. Catalase and the phosphoinositide 3-kinase inhibitor wortmannin inhibited adrenaline-induced activation of 2-DG uptake.
CONCLUSION High doses of catecholamines exert insulin-like actions on glucose transport in human adipocytes. At submillimolar doses, vanadium did not enhance this catecholamine activation of glucose transport. Consequently, this dismantles our previous suggestion to combine the metal ion with catecholamines to improve the benefit/risk ratio of vanadium-based antidiabetic approaches.
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Affiliation(s)
- Christian Carpéné
- Institut des Maladies Métaboliques et Cardiovasculaires, INSERM UMR1297, Toulouse 31432, France
| | - Nathalie Boulet
- Team Dinamix, Institute of Metabolic and Cardiovascular Diseases (I2MC), Paul Sabatier University, Toulouse 31432, France
| | | | - Nathalie Morin
- Faculté de Pharmacie de Paris, Université de Paris, INSERM UMR-S 1139, 3PHM, Paris 75006, France
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7
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Zahid H, Lau AM, Kelly SM, Karu K, Gor J, Perkins SJ, McDermott LC. Identification of diverse lipid-binding modes in the groove of zinc α 2 glycoprotein reveals its functional versatility. FEBS J 2021; 289:1876-1896. [PMID: 34817923 DOI: 10.1111/febs.16293] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2021] [Revised: 11/03/2021] [Accepted: 11/22/2021] [Indexed: 11/28/2022]
Abstract
ZAG is a multifunctional glycoprotein with a class I MHC-like protein fold and an α1-α2 lipid-binding groove. The intrinsic ZAG ligand is unknown. Our previous studies showed that ZAG binds the dansylated C11 fatty acid, DAUDA, differently to the boron dipyrromethane C16 fatty acid, C16 -BODIPY. Here, the molecular basis for this difference was elucidated. Multi-wavelength analytical ultracentrifugation confirmed that DAUDA and C16 -BODIPY individually bind to ZAG and compete for the same binding site. Molecular docking of lipid-binding in the structurally related Cluster of differentiation 1 proteins predicted nine conserved ligand contact residues in ZAG. Twelve mutants were accordingly created by alanine scanning site directed mutagenesis for characterisation. Mutation of Y12 caused ZAG to misfold. Mutation of K147, R157 and A158 abrogated C16 -BODIPY but not DAUDA binding. L69 and T169 increased the fluorescence emission intensity of C16 -BODIPY but not of DAUDA compared to wild-type ZAG and showed that C16 -BODIPY binds close to T169 and L69. Distance measurements of the crystal structure revealed K147 forms a salt bridge with D83. A range of bioactive bulky lipids including phospholipids and sphingolipids displaced DAUDA from the ZAG binding site but unexpectedly did not displace C16 -BODIPY. We conclude that the ZAG α1-α2 groove contains separate but overlapping sites for DAUDA and C16 -BODIPY and is involved in binding to a bulkier and wider repertoire of lipids than previously reported. This work suggested that the in vivo activity of ZAG may be dictated by its lipid ligand.
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Affiliation(s)
- Henna Zahid
- Department of Structural and Molecular Biology, University College London, UK
| | - Andy M Lau
- Department of Structural and Molecular Biology, University College London, UK
| | - Sharon M Kelly
- Institute of Molecular, Cell and Systems Biology, College of Medical, Veterinary and Life Sciences, University of Glasgow, UK
| | - Kersti Karu
- Department of Chemistry, University College London, UK
| | - Jayesh Gor
- Department of Structural and Molecular Biology, University College London, UK
| | - Stephen J Perkins
- Department of Structural and Molecular Biology, University College London, UK
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Jargaud V, Bour S, Tercé F, Collet X, Valet P, Bouloumié A, Guillemot JC, Mauriège P, Jalkanen S, Stolen C, Salmi M, Smith DJ, Carpéné C. Obesity of mice lacking VAP-1/SSAO by Aoc3 gene deletion is reproduced in mice expressing a mutated vascular adhesion protein-1 (VAP-1) devoid of amine oxidase activity. J Physiol Biochem 2020; 77:141-154. [PMID: 32712883 DOI: 10.1007/s13105-020-00756-y] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2019] [Accepted: 06/29/2020] [Indexed: 12/18/2022]
Abstract
The product of Aoc3 gene is known as vascular adhesion protein-1 (VAP-1), a glycoprotein contributing to leukocyte extravasation and exhibiting semicarbazide-sensitive amine oxidase activity (SSAO). Regarding the immune functions of VAP-1/SSAO, it is known that mice bearing Aoc3 gene knock-out (AOC3KO) exhibit defects in leukocyte migration similar to those of mice expressing a mutated VAP-1 lacking functional SSAO activity (knock-in, AOC3KI). However, it has not been reported whether these models differ regarding other disturbances. Thus, we further compared endocrine-metabolic phenotypes of AOC3KO and AOC3KI mice to their respective control. Special attention was paid on adiposity, glucose and lipid handling, since VAP-1/SSAO is highly expressed in adipose tissue (AT). In both mouse lines, no tissue SSAO activity was found, while Aoc3 mRNA was absent in AOC3KO only. Although food consumption was unchanged, both AOC3KO and AOC3KI mice were heavier and fatter than their respective controls. Other alterations commonly found in adipocytes from both lines were loss of benzylamine insulin-like action with unchanged insulin lipogenic responsiveness and adiponectin expression. A similar downregulation of inflammatory markers (CD45, IL6) was found in AT. Glucose handling and liver mass remained unchanged, while circulating lipid profile was distinctly altered, with increased cholesterol in AOC3KO only. These results suggest that the lack of oxidase activity found in AOC3KI is sufficient to reproduce the metabolic disturbances observed in AOC3KO mice, save those related with cholesterol transport. Modulation of SSAO activity therefore constitutes a potential target for the treatment of cardiometabolic diseases, especially obesity when complicated by low-grade inflammation.
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Affiliation(s)
- Valentin Jargaud
- Institute of Metabolic and Cardiovascular Diseases, INSERM, UMR1048, Toulouse, France.,University of Toulouse, UMR1048, Paul Sabatier University, Toulouse, France.,Sanofi, Translational Sciences Unit, Chilly-Mazarin, France
| | - Sandy Bour
- Institute of Metabolic and Cardiovascular Diseases, INSERM, UMR1048, Toulouse, France.,University of Toulouse, UMR1048, Paul Sabatier University, Toulouse, France
| | - François Tercé
- Institute of Metabolic and Cardiovascular Diseases, INSERM, UMR1048, Toulouse, France.,University of Toulouse, UMR1048, Paul Sabatier University, Toulouse, France
| | - Xavier Collet
- Institute of Metabolic and Cardiovascular Diseases, INSERM, UMR1048, Toulouse, France.,University of Toulouse, UMR1048, Paul Sabatier University, Toulouse, France
| | - Philippe Valet
- Institute of Metabolic and Cardiovascular Diseases, INSERM, UMR1048, Toulouse, France.,University of Toulouse, UMR1048, Paul Sabatier University, Toulouse, France
| | - Anne Bouloumié
- Institute of Metabolic and Cardiovascular Diseases, INSERM, UMR1048, Toulouse, France.,University of Toulouse, UMR1048, Paul Sabatier University, Toulouse, France
| | | | - Pascale Mauriège
- Dept. of Kinesiology, Fac. of Medicine and PEPS, Laval University, Québec, Canada
| | - Sirpa Jalkanen
- MediCity and Institute of Biomedicine, University of Turku, Turku, Finland
| | - Craig Stolen
- MediCity and Biotie Therapies Plc, Turku, Finland
| | - Marko Salmi
- MediCity and Institute of Biomedicine, University of Turku, Turku, Finland
| | | | - Christian Carpéné
- Institute of Metabolic and Cardiovascular Diseases, INSERM, UMR1048, Toulouse, France. .,University of Toulouse, UMR1048, Paul Sabatier University, Toulouse, France.
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9
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Papukashvili D, Rcheulishvili N, Deng Y. Beneficial Impact of Semicarbazide-Sensitive Amine Oxidase Inhibition on the Potential Cytotoxicity of Creatine Supplementation in Type 2 Diabetes Mellitus. Molecules 2020; 25:molecules25092029. [PMID: 32349282 PMCID: PMC7248702 DOI: 10.3390/molecules25092029] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2020] [Revised: 04/16/2020] [Accepted: 04/24/2020] [Indexed: 02/06/2023] Open
Abstract
Creatine supplementation of the population with type 2 diabetes mellitus (T2DM) combined with an exercise program is known to be a possible therapy adjuvant with hypoglycemic effects. However, excessive administration of creatine leads to the production of methylamine which is deaminated by the enzyme semicarbazide-sensitive amine oxidase (SSAO) and as a result, cytotoxic compounds are produced. SSAO activity and reaction products are increased in the serum of T2DM patients. Creatine supplementation by diabetics will further augment the activity of SSAO. The current review aims to find a feasible way to ameliorate T2DM for patients who exercise and desire to consume creatine. Several natural agents present in food which are involved in the regulation of SSAO activity directly or indirectly are reviewed. Particularly, zinc-α2-glycoprotein (ZAG), zinc (Zn), copper (Cu), histamine/histidine, caffeine, iron (Fe), and vitamin D are discussed. Inhibiting SSAO activity by natural agents might reduce the potential adverse effects of creatine metabolism in population of T2DM.
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Affiliation(s)
- Dimitri Papukashvili
- School of Life Science, Beijing Institute of Technology, Beijing 100081, China; (D.P.); (N.R.)
| | - Nino Rcheulishvili
- School of Life Science, Beijing Institute of Technology, Beijing 100081, China; (D.P.); (N.R.)
| | - Yulin Deng
- School of Life Science, Beijing Institute of Technology, Beijing 100081, China; (D.P.); (N.R.)
- Beijing Key Laboratory for Separation and Analysis in Biomedicine and Pharmaceuticals, Beijing 100081, China
- Correspondence: ; Tel./Fax: +86-10-68914907
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