2-Aminoadipic acid protects against obesity and diabetes

Xu, Wangyang; Shen, Yan; Zhu, Houbao; Gao, Junhui; Zhang, Chen; Tang, Lian; Shen, Lu; Shen, Chunling; Zhang, Hongxin; Li, Ziwei; Meng, Peng; Wan, Ying-Han; Fei, Jian; Wang, Zhugang

doi:10.1530/joe-19-0157

Cited by 35 publications

(24 citation statements)

References 37 publications

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“…In another study, Wang et al showed that treatment of diet-induced obesity with pipecolic acid significantly reduced body weight, fat accumulation, and lowered fasting glucose. Pipecolate regulating glycolipid metabolism is independent of diet and exercise, implying that improving its level can be a mean to treat diabetes (Xu et al, 2019). Our observations of a decrease in the levels of pipecolate in established T2DM cases are consistent with the previous findings and a possible explanation could be that pipecolate contribution to maintaining glucose homeostasis is overcome in established diabetes.…”

Section: Figure 5 | (A)supporting

confidence: 91%

Distinctive Metabolomics Patterns Associated With Insulin Resistance and Type 2 Diabetes Mellitus

Dubayee

Alshahrani

et al. 2020

Front. Mol. Biosci.

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Obesity is associated with an increased risk of insulin resistance (IR) and type 2 diabetes mellitus (T2DM) which is a multi-factorial disease associated with a dysregulated metabolism and can be prevented in pre-diabetic individuals with impaired glucose tolerance. A metabolomic approach emphasizing metabolic pathways is critical to our understanding of this heterogeneous disease. This study aimed to characterize the serum metabolomic fingerprint and multi-metabolite signatures associated with IR and T2DM. Here, we have used untargeted high-performance chemical isotope labeling (CIL) liquid chromatography-mass spectrometry (LC-MS) to identify candidate biomarkers of IR and T2DM in sera from 30 adults of normal weight, 26 obese adults, and 16 adults newly diagnosed with T2DM. Among the 3633 peak pairs detected, 62% were either identified or matched. A group of 78 metabolites were up-regulated and 111 metabolites were down-regulated comparing obese to lean group while 459 metabolites were up-regulated and 166 metabolites were down-regulated comparing T2DM to obese groups. Several metabolites were identified as IR potential biomarkers, including amino acids (Asn, Gln, and His), methionine (Met) sulfoxide, 2-methyl-3-hydroxy-5-formylpyridine-4-carboxylate, serotonin, L-2-amino-3-oxobutanoic acid, and 4,6-dihydroxyquinoline. T2DM was associated with dysregulation of 42 metabolites, including amino acids, amino acids metabolites, and dipeptides. In conclusion, these pilot data have identified IR and T2DM metabolomics panels as potential novel biomarkers of IR and identified metabolites associated with T2DM, with possible diagnostic and therapeutic applications. Further studies to confirm these associations in prospective cohorts are warranted.

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Section: Figure 5 | (A)supporting

confidence: 91%

Distinctive Metabolomics Patterns Associated With Insulin Resistance and Type 2 Diabetes Mellitus

Dubayee

Alshahrani

et al. 2020

Front. Mol. Biosci.

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“…For instance, several types of tumors, including lymphomas and malignant brain tumors, overexpress the DHTKD1-encoded OADH (Kiełbus et al, 2015;Papatheodorou et al, 2018), and inhibition of OADH in such tumors by AP may be a plausible therapeutic strategy. The DHTKD1 expression is known to be changed in the ageand metabolic-syndrome-related pathologies, such as obesity, diabetes, neurodegenerations, and inflammatory disorders (Xu et al, 2012(Xu et al, , 2018(Xu et al, , 2019Lim et al, 2014;Wu et al, 2014;Kiełbus et al, 2015;Plubell et al, 2018;Sherrill et al, 2018;Timmons et al, 2018;Luan et al, 2020). However, the exact molecular mechanisms underlying the relation between these disorders and OADH function are unknown.…”

Section: Discussionmentioning

confidence: 99%

Selective Inhibition of 2-Oxoglutarate and 2-Oxoadipate Dehydrogenases by the Phosphonate Analogs of Their 2-Oxo Acid Substrates

et al. 2021

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Phosphonate analogs of pyruvate and 2-oxoglutarate are established specific inhibitors of cognate 2-oxo acid dehydrogenases. The present work develops application of this class of compounds to specific in vivo inhibition of 2-oxoglutarate dehydrogenase (OGDH) and its isoenzyme, 2-oxoadipate dehydrogenase (OADH). The isoenzymes-enriched preparations from the rat tissues with different expression of OADH and OGDH are used to characterize their interaction with 2-oxoglutarate (OG), 2-oxoadipate (OA) and the phosphonate analogs. Despite a 100-fold difference in the isoenzymes ratio in the heart and liver, similar Michaelis saturations by OG are inherent in the enzyme preparations from these tissues (KmOG = 0.45 ± 0.06 and 0.27 ± 0.026 mM, respectively), indicating no significant contribution of OADH to the OGDH reaction, or similar affinities of the isoenzymes to OG. However, the preparations differ in the catalysis of OADH reaction. The heart preparation, where OADH/OGDH ratio is ≈ 0.01, possesses low-affinity sites to OA (KmOA = 0.55 ± 0.07 mM). The liver preparation, where OADH/OGDH ratio is ≈ 1.6, demonstrates a biphasic saturation with OA: the low-affinity sites (Km,2OA = 0.45 ± 0.12 mM) are similar to those of the heart preparation; the high-affinity sites (Km,1OA = 0.008 ± 0.001 mM), revealed in the liver preparation only, are attributed to OADH. Phosphonate analogs of C5-C7 dicarboxylic 2-oxo acids inhibit OGDH and OADH competitively to 2-oxo substrates in all sites. The high-affinity sites for OA are affected the least by the C5 analog (succinyl phosphonate) and the most by the C7 one (adipoyl phosphonate). The opposite reactivity is inherent in both the low-affinity OA-binding sites and OG-binding sites. The C6 analog (glutaryl phosphonate) does not exhibit a significant preference to either OADH or OGDH. Structural analysis of the phosphonates binding to OADH and OGDH reveals the substitution of a tyrosine residue in OGDH for a serine residue in OADH among structural determinants of the preferential binding of the bulkier ligands to OADH. The consistent kinetic and structural results expose adipoyl phosphonate as a valuable pharmacological tool for specific in vivo inhibition of the DHTKD1-encoded OADH, a new member of mammalian family of 2-oxo acid dehydrogenases, up-regulated in some cancers and associated with diabetes and obesity.

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“…As shown in Table 1, decreased Monoolein, a kind of glycerides of unsaturated fatty acids, may be caused by oxidative damage. Aminoadipic acid (2-AAA), an intermediate metabolite of lysine metabolism, could modulate insulin secretion 31 .…”

Section: Discussionmentioning

confidence: 99%

Toxicology of tramadol following chronic exposure based on metabolomics of the cerebrum in mice

Xia

Liu

Shao

et al. 2020

Sci Rep

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tramadol is an opioid used as an analgesic for treating moderate or severe pain. the long-term use of tramadol can induce several adverse effects. The toxicological mechanism of tramadol abuse is unclear. Metabolomics is a very useful method for investigating the toxicology of drug abuse. We investigated the impact of chronic tramadol administration on the cerebrum of mice, focusing on the metabolites after tramadol administration. The mice received 20 or 50 mg/kg body weight tramadol dissolved in physiological saline daily for 5 weeks via oral gavage. Compared with the control group, the low dose tramadol group showed seven potential biomarkers, including gamma-hydroxybutyric acid, succinate semialdehyde, and methylmalonic acid, which were either up-or down-regulated. Compared with the control group, the high dose tramadol group showed ten potential biomarkers, including gamma-hydroxybutyric acid, glutamine, and O-phosphorylethanolamine, which were either up-or down-regulated. the up-regulated gamma-hydroxybutyric acid and the downregulated succinate semialdehyde revealed that the neurotransmitter system was disrupted after tramadol abuse. Compared with the low dose tramadol group, there were twenty-nine potential biomarkers in the high dose tramadol group, mainly related to the pentose phosphate pathway and glycerophospholipid metabolism. In conclusion, metabolomics in the tramadol abuse group demonstrated that long-term tramadol abuse can result in oxidative damage, inflammation, and disruption of the GABA neurotransmitter system, which will help to elucidate the toxicology of tramadol abuse. Tramadol is an effective analgesic agent for the treatment of moderately severe pain 1. Tramadol is considered to exert analgesic effects by binding the μ-opioid receptors and modulating the noradrenergic, GABAergic and serotonergic systems 2, 3 , or by acting as a serotonin-norepinephrine (NE) reuptake inhibitor 4. Tramadol in clinical not only can be used in general surgery, obstetrics, pediatrics and the treatment of oral surgery, as well as a variety of acute postoperative pain, is also used to relieve chronic pain, such as cancer 5. Because its analgesic action time is longer;its analgesia intensity decreased slowly, it is a relatively ideal drug for chronic pain medication.Most common side effects of tramadol include nausea, vomiting, sweating, fatigue, sedation 6, 7 , and dry mouth 8. More severe side effects include angioedema, increased effect of anticoagulants, hypoglycemia 7, 9 and serotonin toxicity 8 .Tramadol was identified as a controlled substance in the USA and UK (schedule IV drug) in 2014 10, 11 , and is also a controlled psychotropic substance in China, as more young people are abusing it to obtain psychological satisfaction. Having a lower affinity for the μ-opioid receptor, Tramadol has shown to have a lower risk for addiction with chronic use when compared with other opiates e.g. morphine and oxycodone 9, 12. Thus, many studies on the risks of opioid abuse have excluded tramadol 12-14. Mohamed HM 4 ...

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2-Aminoadipic acid protects against obesity and diabetes

Cited by 35 publications

References 37 publications

Distinctive Metabolomics Patterns Associated With Insulin Resistance and Type 2 Diabetes Mellitus

Distinctive Metabolomics Patterns Associated With Insulin Resistance and Type 2 Diabetes Mellitus

Selective Inhibition of 2-Oxoglutarate and 2-Oxoadipate Dehydrogenases by the Phosphonate Analogs of Their 2-Oxo Acid Substrates

Toxicology of tramadol following chronic exposure based on metabolomics of the cerebrum in mice

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