Genetic identification of thiosulfate sulfurtransferase as an adipocyte-expressed antidiabetic target in mice selected for leanness

Morton, Nicholas M.; Beltram, Jasmina; Carter, Roderick N.; Michailidou, Zoi; Gorjanc, Gregor; McFadden, C; Barrios-Llerena, Martin E.; Rodríguez‐Cuenca, Sergio; Gibbins, Matthew T.G.; Aird, Rhona; Moreno-Navarrete, José María; Munger, Steven C.; Svenson, Karen L.; Gastaldello, Annalisa; Ramage, Lynne; Naredo, Gregorio; Zeyda, Maximilian; Wang, Zhao V.; Howie, A F; Saari, Aila; Sipilä, Petra; Stulnig, Thomas M.; Gudnason, Vilmundur; Kenyon, Christopher J.; Seckl, Jonathan R.; Walker, Brian R.; Webster, Scott P.; Dunbar, Donald R.; Churchill, Gary A.; Vidal-Puig, António; Fernández‐Real, José Manuel; Emilsson, Valur; Horvat, Simon

doi:10.1038/nm.4115

Cited by 63 publications

(87 citation statements)

References 50 publications

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“…Hence, even if a gene that has been knockouted is a QTG for a QTL with small phenotypic effects, the results of quantitative complementation tests would not always reach statistical significance. Another approach is to use a simple transgenic overexpression of a candidate gene, which has recently been proved efficient for positional cloning of a tail suspension QTL [5] and an adiposity QTL [7] in mice. We are now planning to perform a quantitative complementation test and/or a simple overexpression experiment using the Ly75 cDNA of M .…”

Section: Discussionmentioning

confidence: 99%

“…Until now, large numbers of QTLs and genetic variants for complex disease traits including obesity have been reported in humans and model animals, and they have been deposited in databases such as the NHGRI-EBI GWAS Catalog [1] and the Mouse Genome Database (MGD) [2]. However, it is still challenging to identify causal quantitative trait genes (QTGs) and causal quantitative trait nucleotides (QTNs) for so-called QTLs with relatively small phenotypic effects [3,4], though there have been several successful examples [4–7]. …”

Section: Introductionmentioning

confidence: 99%

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Identification of a Putative Quantitative Trait Gene for Resistance to Obesity in Mice Using Transcriptome Analysis and Causal Inference Tests

Ishikawa

2017

PLoS ONE

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It is still challenging to identify causal genes governing obesity. Pbwg1.5, a quantitative trait locus (QTL) for resistance to obesity, was previously discovered from wild Mus musculus castaneus mice and was fine-mapped to a 2.1-Mb genomic region of mouse chromosome 2, where no known gene with an effect on white adipose tissue (WAT) has been reported. The aim of this study was to identify a strong candidate gene for Pbwg1.5 by an integration approach of transcriptome analysis (RNA-sequencing followed by real-time PCR analysis) and the causal inference test (CIT), a statistical method to infer causal relationships between diplotypes, gene expression and trait values. Body weight, body composition and biochemical traits were measured in F2 mice obtained from an intercross between the C57BL/6JJcl strain and a congenic strain carrying Pbwg1.5 on the C57BL/6JJcl background. The F2 mice showed significant diplotype differences in 12 traits including body weight, WAT weight and serum cholesterol/triglyceride levels. The transcriptome analysis revealed that Ly75, Pla2r1, Fap and Gca genes were differentially expressed in the liver and that Fap, Ifih1 and Grb14 were differentially expressed in WAT. However, CITs indicated statistical evidence that only the liver Ly75 gene mediated between genotype and WAT. Ly75 expression was negatively associated with WAT weight. The results suggested that Ly75 is a putative quantitative trait gene for the obesity-resistant Pbwg1.5 QTL discovered from the wild M. m. castaneus mouse. The finding provides a novel insight into a better understanding of the genetic basis for prevention of obesity.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Identification of a Putative Quantitative Trait Gene for Resistance to Obesity in Mice Using Transcriptome Analysis and Causal Inference Tests

Ishikawa

2017

PLoS ONE

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“…The detoxification of cyanide to thiocyanide may also be performed by other rhodanese‐domain‐containing enzymes like MPST, for which this capacity has indeed been reported (Yadav et al, ). Interestingly, rhodanese has been identified as a candidate in obesity resistance, linking sulfur catabolism to other metabolic processes (Morton et al, ).…”

Section: Deficiencies In Cysteine Catabolismmentioning

confidence: 99%

Homeostatic impact of sulfite and hydrogen sulfide on cysteine catabolism

Kohl

Mellis

Schwarz

2018

British J Pharmacology

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Cysteine is one of the two key sulfur-containing amino acids with important functions in redox homeostasis, protein functionality and metabolism. Cysteine is taken up by mammals via their diet and can also be derived from methionine via the transsulfuration pathway. The cellular concentration of cysteine is kept within a narrow range by controlling its synthesis and degradation. There are two pathways for the catabolism of cysteine leading to sulfate, taurine and thiosulfate as terminal products. The oxidative pathway produces taurine and sulfate, while the H S pathway involves different enzymatic reactions leading to the formation and clearance of H S, an important signalling molecule in mammals, resulting in thiosulfate and sulfate. Sulfite is a common intermediate in both catabolic pathways. Sulfite is considered as cytotoxic and produces neurotoxic S-sulfonates. As a result, a deficiency in the terminal steps of cysteine or H S catabolism leads to severe forms of encephalopathy with the accumulation of sulfite and H S in the body. This review links the homeostatic regulation of both cysteine catabolic pathways to sulfite and H S.

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“…Deficiency in TST markedly exacerbates, whereas TST activation by thiosulfate administration ameliorates, diabetes in mice [57]. TST expression level in human adipose tissue is correlated positively with adipose insulin sensitivity and negatively with fat mass, suggesting TST activation may be beneficial for type II diabetes.…”

Section: H 2 S Catabolismmentioning

confidence: 98%

Emerging pharmacological tools to control hydrogen sulfide signaling in critical illness

Marutani

Ichinose

2020

ICMx

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Hydrogen sulfide (H 2 S) has long been known as a toxic environmental hazard. Discovery of physiological roles of H 2 S as a neurotransmitter by Kimura and colleagues triggered an intensive research in the biological roles of H 2 S in the past decades. Manipulation of H 2 S levels by inhibiting H 2 S synthesis or administration of H 2 S-releasing molecules revealed beneficial as well as harmful effects of H 2 S. As a result, it is now established that H 2 S levels are tightly controlled and too much or too little H 2 S levels cause harm. Nonetheless, translation of sulfide-based therapy to clinical practice has been stymied due to the very low therapeutic index of sulfide and the incomplete understanding of endogenous sulfide metabolism. One potential strategy to circumvent this problem is to use a safe and stable sulfide metabolite that may mediate effects of H 2 S. Alternatively, endogenous sulfide levels may be controlled using specific sulfide scavengers. In this review article, the role of endogenous H 2 S production and catabolism will be briefly reviewed followed by an introduction of thiosulfate and H 2 S scavengers as novel pharmacological tools to control H 2 S-dependent signaling.

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Genetic identification of thiosulfate sulfurtransferase as an adipocyte-expressed antidiabetic target in mice selected for leanness

Cited by 63 publications

References 50 publications

Identification of a Putative Quantitative Trait Gene for Resistance to Obesity in Mice Using Transcriptome Analysis and Causal Inference Tests

Identification of a Putative Quantitative Trait Gene for Resistance to Obesity in Mice Using Transcriptome Analysis and Causal Inference Tests

Homeostatic impact of sulfite and hydrogen sulfide on cysteine catabolism

Emerging pharmacological tools to control hydrogen sulfide signaling in critical illness

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