Radiometric assay of ghrelin hydrolase activity and 3H-ghrelin distribution into mouse tissues

Chen, Vicky Ping; Gao, Yang; Geng, Lihua; Brimijoin, Stephen

doi:10.1016/j.bcp.2015.10.016

Cited by 8 publications

(7 citation statements)

References 44 publications

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“…Similar results were obtained by quantitative mass spectrometry in collaboration with Schopfer et al, [12], and again with a new assay developed to track 3 H-ghrelin deacylation by quantitative transfer of free octanoic acid from aqueous media into toluene [13]. Although BChE hydrolyzes ghrelin less efficiently than smaller substrates, with a K m of 3.6 ± 0.3 μM and k cat of 2.2 ± 0.1 min −1 it can exert a strong influence on circulating levels of ghrelin.…”

Section: Introductionsupporting

confidence: 72%

Physiological roles for butyrylcholinesterase: A BChE-ghrelin axis

Brimijoin

Chen

Pang

et al. 2016

Chemico-Biological Interactions

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Butyrylcholinesterase (BChE) has long been regarded as an “orphan enzyme” with no specific physiological role other than to metabolize exogenous bioactive esters in the diet or in medicines. Human beings with genetic mutations that eliminate all BChE activity appear completely normal, and BChE-knockout mice have been described as “lacking a phenotype” except for faster weight gain on high-fat diets. However, our recent studies with viral gene transfer of BChE in mice reveal that BChE hydrolyses the so-called “hunger hormone,” ghrelin, at a rate which strongly affects the circulating levels of this peptide hormone. This action has important consequences for weight gain and fat metabolism. Surprisingly, it also impacts emotional behaviors such as aggression. Overexpression of BChE leads to low ghrelin levels in the blood stream and reduces aggression and social stress in mice. Under certain circumstances these combined effects contribute to increased life-span in group-housed animals. These findings may generalize to humans, as recent clinical studies by multiple investigators indicate that, among patients with severe cardiovascular disease, longevity correlates with increasing levels of plasma BChE activity.

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Section: Introductionsupporting

confidence: 72%

Physiological roles for butyrylcholinesterase: A BChE-ghrelin axis

Brimijoin

Chen

Pang

et al. 2016

Chemico-Biological Interactions

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“…Ghrelin is an acylated peptide released mostly by the stomach, but it crosses the blood brain barrier to communicate with central rewarding systems 5 . BChE modulates ghrelin's biological functions by cleaving the peptide's n-octanoyl group, leaving an inactive desacyl peptide 6-8 . Thus, BChE orchestrates many physiological pathways involving ghrelin.…”

Section: Introductionmentioning

confidence: 99%

Butyrylcholinesterase regulates central ghrelin signaling and has an impact on food intake and glucose homeostasis

et al. 2017

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Background Ghrelin is the only orexigenic hormone known to stimulate food intake and promote obesity and insulin resistance. We recently showed that plasma ghrelin is controlled by butyrylcholinesterase (BChE), which has a strong impact on feeding and weight gain. BChE knockout (KO) mice are prone to obesity on high-fat diet but hepatic BChE gene transfer rescues normal food intake and obesity resistance. However, these mice lack brain BChE and still develop hyperinsulinemia and insulin resistance, suggesting essential interactions between BChE and ghrelin within the brain. Methods To test the hypothesis we used four experimental groups: 1) untreated wild-type mice, 2) BChE KO mice with luciferase delivered by adeno-associated vector (AAV) in combined intravenous (i.v.) and intracerebral (i.c.) injections, 3) KO mice given AAV for mouse BChE (i.v. only), and 4) KO mice given the same vector both i.v. and i.c. All mice ate a 45% calorie high-fat diet from age 1-month. Body weight, body composition, daily caloric intake, and serum parameters were monitored throughout, and glucose tolerance and insulin tolerance tests were performed at intervals. Results Circulating ghrelin levels dropped substantially in the KO mice after i.v. AAV-BChE delivery, which led to normal food intake and healthy body weight. BChE KO mice that received AAV-BChE through i.v. and i.c. combined treatments not only resisted weight gain on high-fat diet but also retained normal glucose and insulin tolerance. Conclusions These data indicate a central role for BChE in regulating both insulin and glucose homeostasis. BChE gene transfer could be a useful therapy for complications linked to diet-induced obesity and insulin resistance.

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“…were designed in our lab to improve the catalytic efficiency of human BChE against cocaine for treatment of cocaine addiction and overdose [23, 26–32], and were not expected to improve the catalytic efficiency against ghrelin. Hence, it is not surprizing to know that CocH3 has a moderate catalytic efficiency ( k cat / K m = 4.8 × 10 5 min −1 M −1 ) against ghrelin compared to that ( k cat / K m = 6.1 × 10 5 min −1 M −1 ) of wild-type human BChE, and that CocH2 has a slightly lower catalytic efficiency ( k cat / K m = 2.2 × 10 5 min −1 M −1 ) against ghrelin [33]. All of the data imply that these CocHs, particularly CocH3, might be valuable for treatment of both cocaine abuse and obesity.…”

Section: Introductionmentioning

confidence: 99%

“…Further, based on the promising preclinical data for cocaine abuse treatment [36] and the newly reported catalytic activity of CocH3 against ghrelin [33], we would like to know whether repeated dosing of CocH3-Fc(M3) could be effective for obesity treatment and why CocH3 is active against ghrelin. For these purposes, in the present study, we examined the effects of weekly dosing of 1 mg/kg CocH3-Fc(M3) on the body weights of C57BL/6 mice fed a high-fat diet.…”

Section: Introductionmentioning

confidence: 99%

Potential anti-obesity effects of a long-acting cocaine hydrolase

Zheng

Deng

Zhang

et al. 2016

Chemico-Biological Interactions

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A long-acting cocaine hydrolase, known as CocH3-Fc(M3), engineered from human butyrylcholinesterase (BChE) was tested, in this study, for its potential anti-obesity effects. Mice on a high-fat diet gained significantly less body weight when treated weekly with 1 mg/kg CocH3-Fc(M3) compared to control mice, though their food intake was similar. There is no correlation between the average body weight and the average food intake, which is consistent with the previously reported observation in BChE knockout mice. In addition, molecular modeling was carried out to understand how ghrelin binds with CocH3, showing that ghrelin binds with CocH3 in a similar mode as ghrelin binding with wild-type human BChE. The similar binding structure mode explains why CocH3 has a similar catalytic activity against ghrelin.

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Radiometric assay of ghrelin hydrolase activity and 3H-ghrelin distribution into mouse tissues

Cited by 8 publications

References 44 publications

Physiological roles for butyrylcholinesterase: A BChE-ghrelin axis

Physiological roles for butyrylcholinesterase: A BChE-ghrelin axis

Butyrylcholinesterase regulates central ghrelin signaling and has an impact on food intake and glucose homeostasis

Potential anti-obesity effects of a long-acting cocaine hydrolase

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