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High salt intake causes leptin resistance and obesity in mice by stimulating endogenous fructose production and metabolism.

ABSTRACT: Dietary guidelines for obesity typically focus on three food groups (carbohydrates, fat, and protein) and caloric restriction. Intake of noncaloric nutrients, such as salt, are rarely discussed. However, recently high salt intake has been reported to predict the development of obesity and insulin resistance. The mechanism for this effect is unknown. Here we show that high intake of salt activates the aldose reductase-fructokinase pathway in the liver and hypothalamus, leading to endogenous fructose production with the development of leptin resistance and hyperphagia that cause obesity, insulin resistance, and fatty liver. A high-salt diet was also found to predict the development of diabetes and nonalcoholic fatty liver disease in a healthy population. These studies provide insights into the pathogenesis of obesity and diabetes and raise the potential for reduction in salt intake as an additional interventional approach for reducing the risk for developing obesity and metabolic syndrome.

SUBMITTER: Lanaspa MA

PROVIDER: S-EPMC5866545 | biostudies-literature | 2018 Mar

REPOSITORIES: biostudies-literature

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High salt intake causes leptin resistance and obesity in mice by stimulating endogenous fructose production and metabolism.

Lanaspa Miguel A MA Kuwabara Masanari M Andres-Hernando Ana A Li Nanxing N Cicerchi Christina C Jensen Thomas T Orlicky David J DJ Roncal-Jimenez Carlos A CA Ishimoto Takuji T Nakagawa Takahiko T Rodriguez-Iturbe Bernardo B MacLean Paul S PS Johnson Richard J RJ

Proceedings of the National Academy of Sciences of the United States of America 20180305 12

Dietary guidelines for obesity typically focus on three food groups (carbohydrates, fat, and protein) and caloric restriction. Intake of noncaloric nutrients, such as salt, are rarely discussed. However, recently high salt intake has been reported to predict the development of obesity and insulin resistance. The mechanism for this effect is unknown. Here we show that high intake of salt activates the aldose reductase-fructokinase pathway in the liver and hypothalamus, leading to endogenous fruct ...[more]

PMID: 29507217

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Project description:BackgroundHigh-temperature bioethanol production benefits from yeast thermotolerance. Salt stress could induce obvious cross-protection against heat stress of Pichia kudriavzevii, contributing to the improvement of its thermotolerance and bioethanol fermentation. However, the underlying mechanisms of the cross-protection remain poorly understood.ResultsSalt stress showed obvious cross-protection for thermotolerance and high-temperature ethanol production of P. kudriavzevii observed by biomass, cell morphology and bioethanol production capacity. The biomass and ethanol production of P. kudriavzevii at 45 °C were, respectively, improved by 2.6 and 3.9 times by 300 mmol/L NaCl. Metabolic network map showed that salt stress obviously improved the key enzymes and intermediates in carbohydrate metabolism, contributing to the synthesis of bioethanol, ATP, amino acids, nucleotides, and unsaturated fatty acids, as well as subsequent intracellular metabolisms. The increasing trehalose, glycerol, HSPs, and ergosterol helped maintain the normal function of cell components. Heat stress induced serious oxidative stress that the ROS-positive cell rate and dead cell rate, respectively, rose from 0.5% and 2.4% to 28.2% and 69.2%, with the incubation temperature increasing from 30 to 45 °C. The heat-induced ROS outburst, oxidative damage, and cell death were obviously inhibited by salt stress, especially the dead cell rate which fell to only 20.3% at 300 mmol/L NaCl. The inhibiting oxidative damage mainly resulted from the abundant synthesis of GSH and GST, which, respectively, increased by 4.8 and 76.1 times after addition of 300 mmol/L NaCl. The improved bioethanol production was not only due to the improved thermotolerance, but resulted from the up-regulated alcohol dehydrogenases and down-regulated aldehyde dehydrogenases by salt stress.ConclusionThe results provide a first insight into the mechanisms of the improved thermotolerance and high-temperature bioethanol production of P. kudriavzevii by salt stress, and provide important information to construct genetic engineering yeasts for high-temperature bioethanol production.

Project description:BackgroundInterleukin-1? (IL-1?) is one of the most important cytokine secreted by activated microglia as it orchestrates the vicious cycle of inflammation by inducing the expression of various other pro-inflammatory cytokines along with its own production. Microglia-mediated IL-1? production is a tightly regulated mechanism which involves the activation of nucleotide-binding oligomerization domain leucine-rich repeat and pyrin domain-containing 3 (NLRP3) inflammasome pathway. Our previous study suggests the critical role of heat shock protein 60 (HSP60) in IL-1?-induced inflammation in microglia through TLR4-p38 MAPK axis. However, whether HSP60 regulates endogenous IL-1? production is not known. Therefore, to probe the underlying mechanism, we elucidate the role of HSP60 in endogenous IL-1? production.MethodsWe used in vitro (N9 murine microglial cells) and in vivo (BALB/c mouse) models for our study. HSP60 overexpression and knockdown experiment was done to elucidate the role of HSP60 in endogenous IL-1? production by microglia. Western blotting and quantitative real-time PCR was performed using N9 cells and BALB/c mice brain, to analyze various proteins and transcript levels. Reactive oxygen species levels and mitochondrial membrane depolarization in N9 cells were analyzed by flow cytometry. We also performed caspase-1 activity assay and enzyme-linked immunosorbent assay to assess caspase-1 activity and IL-1? production, respectively.ResultsHSP60 induces the phosphorylation and nuclear localization of NF-?B both in vitro and in vivo. It also induces perturbation in mitochondrial membrane potential and enhances reactive oxygen species (ROS) generation in microglia. HSP60 further activates NLRP3 inflammasome by elevating NLRP3 expression both at RNA and protein levels. Furthermore, HSP60 enhances caspase-1 activity and increases IL-1? secretion by microglia. Knockdown of HSP60 reduces the IL-1?-induced production of IL-1? both in vitro and in vivo. Also, we have shown for the first time that knockdown of HSP60 leads to decreased IL-1? production during Japanese encephalitis virus (JEV) infection, which eventually leads to decreased inflammation and increased survival of JEV-infected mice.ConclusionHSP60 mediates microglial IL-1? production by regulating NLRP3 inflammasome pathway and reduction of HSP60 leads to reduction of inflammation in JEV infection.

Dataset Information

High salt intake causes leptin resistance and obesity in mice by stimulating endogenous fructose production and metabolism.

Publications

High salt intake causes leptin resistance and obesity in mice by stimulating endogenous fructose production and metabolism.

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