Chronic Activation of Hepatic Nrf2 Has No Major Effect on Fatty Acid and Glucose Metabolism in Adult Mice

Brachs, Sebastian; Winkel, Angelika F.; Polack, James; Tang, Hui; Brachs, Maria; Margerie, Daniel; Brunner, Bodo; Jahn‐Hofmann, Kerstin; Ruetten, Hartmut; Spranger, Joachim; Schmoll, Dieter

doi:10.1371/journal.pone.0166110

Cited by 7 publications

(5 citation statements)

References 38 publications

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“…In knockdown models, the DNA remains intact, and so such a compensatory mechanism would not be triggered (31). Similar discrepancies between ASO-KD and genetic knockout have previously been described (17,(31)(32)(33)(34)(35).…”

Section: Discussionmentioning

confidence: 54%

Genetic Nicotinamide N-Methyltransferase (Nnmt) Deficiency in Male Mice Improves Insulin Sensitivity in Diet-Induced Obesity but Does Not Affect Glucose Tolerance

et al. 2018

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Antisense oligonucleotide knockdown (ASO-KD) of nicotinamide N-methyltransferase (NNMT) in high-fat diet (HFD)–fed mice has been reported to reduce weight gain and plasma insulin levels and to improve glucose tolerance. Using NNMT-ASO-KD or NNMT knockout mice (NNMT−/−), we tested the hypothesis that Nnmt deletion protects against diet-induced obesity and its metabolic consequences in males and females on obesity-inducing diets. We also examined samples from a human weight reduction (WR) study for adipose NNMT (aNNMT) expression and plasma 1-methylnicotinamide (MNAM) levels. In Western diet (WD)–fed female mice, NNMT-ASO-KD reduced body weight, fat mass, and insulin level and improved glucose tolerance. Although NNMT−/− mice fed a standard diet had no obvious phenotype, NNMT−/− males fed an HFD showed strongly improved insulin sensitivity (IS). Furthermore, NNMT−/− females fed a WD showed reduced weight gain, less fat, and lower insulin levels. However, no improved glucose tolerance was observed in NNMT−/− mice. Although NNMT expression in human fat biopsy samples increased during WR, corresponding plasma MNAM levels significantly declined, suggesting that other mechanisms besides aNNMT expression modulate circulating MNAM levels during WR. In summary, upon NNMT deletion or knockdown in males and females fed different obesity-inducing diets, we observed sex- and diet-specific differences in body composition, weight, and glucose tolerance and estimates of IS.

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Section: Discussionmentioning

confidence: 54%

Genetic Nicotinamide N-Methyltransferase (Nnmt) Deficiency in Male Mice Improves Insulin Sensitivity in Diet-Induced Obesity but Does Not Affect Glucose Tolerance

et al. 2018

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“…Body composition was determined by nuclear magnetic resonance using a Bruker Minispec instrument (Bruker, Woodlands, TX, USA). Real-time metabolic analyses were conducted using a combined indirect calorimetry system (TSE Systems, GmbH, Bad Homburg, Germany) as previously described ( 26 ).…”

Section: Methodsmentioning

confidence: 99%

Distinct Housing Conditions Reveal a Major Impact of Adaptive Immunity on the Course of Obesity-Induced Type 2 Diabetes

et al. 2018

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Obesity is associated with adipose tissue inflammation, insulin resistance, and the development of type 2 diabetes (T2D). However, our knowledge is mostly based on conventional murine models and promising preclinical studies rarely translated into successful therapies. There is a growing awareness of the limitations of studies in laboratory mice, housed in abnormally hygienic specific pathogen-free (SPF) conditions, as relevant aspects of the human immune system remain unappreciated. Here, we assessed the impact of housing conditions on adaptive immunity and metabolic disease processes during high-fat diet (HFD). We therefore compared diet-induced obesity in SPF mice with those housed in non-SPF, so-called “antigen exposed” (AE) conditions. Surprisingly, AE mice fed a HFD maintained increased insulin levels to compensate for insulin resistance, which was reflected in islet hyperplasia and improved glucose tolerance compared to SPF mice. By contrast, we observed higher proportions of effector/memory T cell subsets in blood and liver of HFD AE mice accompanied by the development of non-alcoholic steatohepatitis-like liver pathology. Thus, our data demonstrate the impact of housing conditions on metabolic alterations. Studies in AE mice, in which physiological microbial exposure was restored, could provide a tool for revealing therapeutic targets for immune-based interventions for T2D patients.

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“…I identified another dataset reporting liver gene expression profiles of mice injected with scrambled or liver-specific siRNA against Keap1 , the gene encoding the main negative regulator of NRF2 (GSE80956 [ 16 ]). I found a clear induction of the NRF2 targets gene signature in the mice treated with the liver-specific Keap1 siRNA ( figure 1 b ).…”

Section: Resultsmentioning

confidence: 99%

Identification of putative calorie restriction mimetics using mammalian gene expression profiles

Vazquez

2020

Open Biol.

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Obesity is a risk factor for cardiovascular diseases, diabetes and cancer. In theory, the obesity problem could be solved by the adherence to a calorie-restricted diet, but that is not generally achieved in practice. An alternative is a pharmacological approach, using compounds that trigger the same metabolic changes associated with calorie restriction. Here, I expand in the pharmacological direction by identifying compounds that induce liver gene signature profiles that mimic those induced by calorie restriction. Using gene expression profiles from mice and rat, I identify corticosteroids, PPAR agonists and some antibacterial/antifungal as candidate compounds mimicking the response to calorie restriction in the liver gene signatures.

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Chronic Activation of Hepatic Nrf2 Has No Major Effect on Fatty Acid and Glucose Metabolism in Adult Mice

Cited by 7 publications

References 38 publications

Genetic Nicotinamide N-Methyltransferase (Nnmt) Deficiency in Male Mice Improves Insulin Sensitivity in Diet-Induced Obesity but Does Not Affect Glucose Tolerance

Genetic Nicotinamide N-Methyltransferase (Nnmt) Deficiency in Male Mice Improves Insulin Sensitivity in Diet-Induced Obesity but Does Not Affect Glucose Tolerance

Distinct Housing Conditions Reveal a Major Impact of Adaptive Immunity on the Course of Obesity-Induced Type 2 Diabetes

Identification of putative calorie restriction mimetics using mammalian gene expression profiles

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