Modulation of Gene Expression Profiles by Hyperosmolarity and Insulin

Schäfer, Christine; Gehrmann, Thor; Richter, Lisa; Keitel, Verena; Köhrer, Karl; Häussinger, Dieter; Schliess, Freimut

doi:10.1159/000107522

Cited by 10 publications

(9 citation statements)

References 49 publications

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“…Potential intermediates may include gluconeogenesis, glycogen breakdown, insulin sensitivity, mitochondrial function, ATP and NADPH generation, and sympathetic activation [6–9, 14–17] (see Figure 1). Reduced mitochondrial ATP production is associated with both hyperosmotic conditions and insulin resistance [15, 65].…”

Section: Discussionmentioning

confidence: 99%

“…Cell swelling can lower endogenous blood glucose and free amino acid concentrations, by down-regulating gluconeogenesis, glycogenolysis, and proteolysis [6–9]. At the same time, cell swelling may accelerate glucose clearance by improving insulin sensitivity [8, 9]. Elevated carbohydrate and insulin concentrations prioritize carbohydrate oxidation over fat oxidation, i.e.…”

Section: Introductionmentioning

confidence: 99%

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Qualitative and/or Quantitative Drinking Water Recommendations for Pediatric Obesity Treatment

Stookey¹

2014

J Obes Weight Loss Ther

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Objective The qualitative recommendation to ‘drink water instead of caloric beverages’ may facilitate pediatric obesity treatment by lowering total energy intake. The quantitative recommendation to ‘drink enough water to dilute urine’ might further facilitate weight loss by increasing fat oxidation via cell hydration-mediated changes in insulin. Methods This 8 week randomized intervention tested whether both qualitative-plus-quantitative (QQ) drinking water recommendations result in more weight loss than the qualitative recommendation alone (Q) in 25 children (9–12y) with body mass index at or above the 85th Percentile, given a reduced glycemic diet and usual physical activity. Random urine osmolality, saliva insulin, and body weight were assessed weekly. Mixed models explored if insulin mediated an effect of urine osmolality on weight loss. Results In intention-to-treat analyses, QQ and Q participants did not differ significantly with respect to level of urine osmolality, saliva insulin, or weight loss. Only 4 out of 16 QQ participants complied with instruction to drink enough water to dilute urine, however. In completers analyses, the compliant QQ participants, who diluted urine osmolality from 910 ± 161 mmol/kg at baseline to below 500 mmol/kg over time (8 week mean±SE: 450 ± 67 mmol/kg), had significantly lower saliva insulin over time (8 week mean±SE: 13 ± 8 pmol/l vs. 22 ± 4 pmol/l) and greater weight loss (mean ± SE: −3.3 ± 0.7kg vs. −2.0 ± 0.5 kg) than compliant Q participants (7 out of 9 participants) who maintained elevated urine osmolality over time (8- week mean±SE: 888 ± 41 mmol/kg). Urine osmolality below 500 mmol/kg was significantly associated with weight loss. Change in saliva insulin partially explained the association. Conclusions QQ recommendations may increase weight loss for those able to dilute urine. Work is warranted to pursue cell hydration effects of drinking water for pediatric obesity treatment.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Qualitative and/or Quantitative Drinking Water Recommendations for Pediatric Obesity Treatment

Stookey¹

2014

J Obes Weight Loss Ther

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“…Insulin has been shown to stimulate cellular K ϩ uptake by activation of a Na ϩ /H ϩ exchanger, Na ϩ -K ϩ -2Cl Ϫ cotransport, and Na ϩ K ϩ / ATPase (19 -21). The stimulation of cellular K ϩ uptake was shown to be required for the effect of the hormone on the regulation of metabolism (19 -21) and on gene expression (43). Moreover, the K ϩ uptake may confer support for cell survival (7,8,16,46,48).…”

Section: Discussionmentioning

confidence: 99%

Enhanced insulin sensitivity of gene-targeted mice lacking functional KCNQ1

Boini

Graf²,

Hennige³

et al. 2009

American Journal of Physiology-Regulatory, Integrative and Comp

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The pore-forming K+-channel α-subunit KCNQ1 is expressed in a wide variety of tissues including heart, skeletal muscle, liver, and epithelia. Most recent evidence revealed an association of the KCNQ1 gene with the susceptibility to type 2 diabetes. KCNQ1 participates in the regulation of cell volume, which is, in turn, critically important for the regulation of metabolism by insulin. The present study explored the influence of KCNQ1 on insulin-induced cellular K+ uptake and glucose metabolism. Insulin (100 nM)-induced K+ uptake was determined in isolated perfused livers from KCNQ1-deficient mice ( kcnq1−/−) and their wild-type littermates ( kcnq1+/+). Moreover, plasma glucose and insulin levels, intraperitoneal glucose (3 g/kg) tolerance, insulin (0.15 U/kg)-induced hypoglycemia, and peripheral uptake of radiolabeled 3H-deoxy-glucose were determined in both genotypes. Insulin-stimulated hepatocellular K+ uptake was significantly more sustained in isolated perfused livers from kcnq1−/− mice than from kcnq1+/+mice. The decline of plasma glucose concentration following an intraperitoneal injection of insulin was again significantly more sustained in kcnq1−/− than in kcnq1+/+ mice. Both fasted and nonfasted plasma glucose and insulin concentrations were significantly lower in kcnq1−/− than in kcnq1+/+mice. Following an intraperitoneal glucose injection, the peak plasma glucose concentration was significantly lower in kcnq1−/− than in kcnq1+/+mice. Uptake of 3H-deoxy-glucose into skeletal muscle, liver, kidney and lung tissue was significantly higher in kcnq1−/− than in kcnq1+/+mice. In conclusion, KCNQ1 counteracts the stimulation of cellular K+ uptake by insulin and thereby influences K+-dependent insulin signaling on glucose metabolism. The observations indicate that KCNQ1 is a novel molecule affecting insulin sensitivity of glucose metabolism.

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“…Previous screens identified many hypertonicity-induced genes, including those regulated by NFAT5. Most of those screens employed DNA microarrays, for example (17,20,24,31). Recently, the development of RNA sequencing (RNA-Seq) has provided a means for a more comprehensive profiling of gene expression than previous methods, including DNA microarrays (3).…”

mentioning

confidence: 99%

RNA-Seq analysis of high NaCl-induced gene expression

Yokoyama

Yang

Zhu

et al. 2015

Physiological Genomics

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High extracellular NaCl is known to change expression of numerous genes, many of which are regulated by the osmoprotective transcription factor nuclear factor of activated T cells-5 (NFAT5). In the present study we employed RNA-Seq to provide a comprehensive, unbiased account of genes regulated by high NaCl in mouse embryonic fibroblast cells (MEFs). To identify genes regulated by NFAT5 we compared wild-type MEFs (WT-MEFs) to MEFs in which mutation of the NFAT5 gene inhibits its transcriptional activity (Null-MEFs). In WT-MEFs adding NaCl to raise osmolality from 300 to 500 mosmol/kg for 24 h increases expression of 167 genes and reduces expression of 412. Raising osmolality through multiple passages (adapted cells) increases expression of 196 genes and reduces expression of 528. In Null-MEFs, after 24 h of high NaCl, expression of 217 genes increase and 428 decrease, while in adapted Null-MEFs 143 increase and 622 decrease. Fewer than 10% of genes are regulated in common between WT-and null-MEFs, indicating a profound difference in regulation of highNaCl induced genes induced by NFAT5 compared with those induced in the absence of NFAT5. Based on our findings we suggest a mechanism for this phenomenon, which had previously been unexplained. The NFAT5 DNA-binding motif (osmotic response element) is overrepresented in the vicinity of genes that NFAT5 upregulates, but not genes that it downregulates. We used Gene Ontology and manual curation to determine the function of the genes targeted by NFAT5, revealing many novel consequences of NFAT5 transcriptional activity.NFAT5; hypertonicity; GO analysis; osmotic; RNA HYPERTONICITY, WHICH IS INDUCED by high extracellular concentrations of solutes such as NaCl, can damage and even kill cells, but cells generally protect themselves by responses including accumulation of compatible organic osmolytes (reviewed in Ref.2). The highest interstitial concentrations of NaCl in mammals occur in their renal medullas, consequent to the operation of the urinary concentrating mechanism, but interstitial NaCl can be elevated in other tissues as well, although not nearly to as great an extent in the renal medulla.Hypertonicity decreases gene expression in general (30) but also increases expression of many genes (8). Nuclear factor of activated T cells-5 (NFAT5) (16, 22) is a transcription factor that increases expression of genes clearly involved in osmoprotection, but also of other genes in which the connection is not obvious (9). Previous screens identified many hypertonicity-induced genes, including those regulated by NFAT5. Most of those screens employed DNA microarrays, for example (17,20,24,31). Recently, the development of RNA sequencing (RNA-Seq) has provided a means for a more comprehensive profiling of gene expression than previous methods, including DNA microarrays (3).In the present study we employed RNA-Seq to provide a comprehensive, unbiased account of genes regulated by high NaCl in mouse embryonic fibroblast cells (MEFs). To distinguish which of the genes are regulated b...

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Modulation of Gene Expression Profiles by Hyperosmolarity and Insulin

Cited by 10 publications

References 49 publications

Qualitative and/or Quantitative Drinking Water Recommendations for Pediatric Obesity Treatment

Qualitative and/or Quantitative Drinking Water Recommendations for Pediatric Obesity Treatment

Enhanced insulin sensitivity of gene-targeted mice lacking functional KCNQ1

RNA-Seq analysis of high NaCl-induced gene expression

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