Transomics analysis reveals allosteric and gene regulation axes for altered hepatic glucose-responsive metabolism in obesity

2020 ◽  
Vol 13 (660) ◽  
pp. eaaz1236
Author(s):  
Toshiya Kokaji ◽  
Atsushi Hatano ◽  
Yuki Ito ◽  
Katsuyuki Yugi ◽  
Miki Eto ◽  
...  
Keyword(s):  
Gene Expression ◽  
Metabolic Enzymes ◽  
Liver Metabolism ◽  
Metabolic Enzyme ◽  
Oral Glucose ◽  
Obese Mice ◽  
Wild Type ◽  
Glucose Administration ◽  
Metabolic Reactions ◽  
Allosteric Regulators

Impaired glucose tolerance associated with obesity causes postprandial hyperglycemia and can lead to type 2 diabetes. To study the differences in liver metabolism in healthy and obese states, we constructed and analyzed transomics glucose-responsive metabolic networks with layers for metabolites, expression data for metabolic enzyme genes, transcription factors, and insulin signaling proteins from the livers of healthy and obese mice. We integrated multiomics time course data from wild-type and leptin-deficient obese (ob/ob) mice after orally administered glucose. In wild-type mice, metabolic reactions were rapidly regulated within 10 min of oral glucose administration by glucose-responsive metabolites, which functioned as allosteric regulators and substrates of metabolic enzymes, and by Akt-induced changes in the expression of glucose-responsive genes encoding metabolic enzymes. In ob/ob mice, the majority of rapid regulation by glucose-responsive metabolites was absent. Instead, glucose administration produced slow changes in the expression of carbohydrate, lipid, and amino acid metabolic enzyme–encoding genes to alter metabolic reactions on a time scale of hours. Few regulatory events occurred in both healthy and obese mice. Thus, our transomics network analysis revealed that regulation of glucose-responsive liver metabolism is mediated through different mechanisms in healthy and obese states. Rapid changes in allosteric regulators and substrates and in gene expression dominate the healthy state, whereas slow changes in gene expression dominate the obese state.

scholarly journals Trans-omic analysis reveals allosteric and gene regulation-axes for altered glucose-responsive liver metabolism associated with obesity

2019 ◽  
Author(s):  
Toshiya Kokaji ◽  
Atsushi Hatano ◽  
Yuki Ito ◽  
Katsuyuki Yugi ◽  
Miki Eto ◽  
...  
Keyword(s):  
Gene Expression ◽  
Transcriptional Regulation ◽  
Liver Metabolism ◽  
Metabolic Enzyme ◽  
Obese Mice ◽  
Glucose Administration ◽  
Healthy State ◽  
Rapid Changes ◽  
Metabolic Reactions ◽  
Allosteric Regulators

AbstractImpaired glucose tolerance associated with obesity causes postprandial hyperglycemia and can lead to type 2 diabetes. To study the differences in liver metabolism in the healthy and obese states, we constructed and analyzed trans-omic glucose-responsive metabolic networks with layers for metabolites, expression data for metabolic enzyme genes, transcription factors, and insulin signaling proteins from the livers of healthy and obese mice. We integrated multi-omic time-course data from wild-type (WT) and leptin-deficient obese (ob/ob) mice after orally administered glucose. In WT mice, metabolic reactions were rapidly regulated (within 10 minutes of oral glucose administration) primarily by glucose-responsive metabolites, especially ATP and NADP+, which functioned as allosteric regulators and substrates of metabolic enzymes, and by Akt-dependent glucose-responsive genes encoding metabolic enzymes. Inob/obmice, most rapid regulation by glucose-responsive metabolites was absent; instead, glucose administration produced slow changes in the expression of metabolic enzyme-encoding genes to alter metabolic reactions in a time scale of hours. Few common regulatory events occurred in both the healthy and obese mice. Thus, our trans-omic network analysis revealed regulation of liver metabolism in response to glucose is mediated through different mechanisms in the healthy and obese states: Rapid changes in allosteric regulators and substrates and in gene expression dominate the healthy state, and slow transcriptional regulation dominates the obese state.One Sentence SummaryRapid changes in regulatory metabolites and gene expression dominate the healthy state, and slow transcriptional regulation dominates the obese state.

scholarly journals High Carbohydrate Diet Increased Glucose Transporter Protein Levels in Jejunum but Did Not Lead to Enhanced Post-Exercise Skeletal Muscle Glycogen Recovery

Nutrients ◽  
2021 ◽  
Vol 13 (7) ◽  
pp. 2140
Author(s):  
Yumiko Takahashi ◽  
Yutaka Matsunaga ◽  
Hiroki Yoshida ◽  
Terunaga Shinya ◽  
Ryo Sakaguchi ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Glucose Transporter ◽  
High Carbohydrate Diet ◽  
Oral Glucose ◽  
Carbohydrate Diet ◽  
Post Exercise ◽  
Glucose Administration ◽  
Protein Levels ◽  
High Carbohydrate ◽  
Glucose Transporter 2

We examined the effect of dietary carbohydrate intake on post-exercise glycogen recovery. Male Institute of Cancer Research (ICR) mice were fed moderate-carbohydrate chow (MCHO, 50%cal from carbohydrate) or high-carbohydrate chow (HCHO, 70%cal from carbohydrate) for 10 days. They then ran on a treadmill at 25 m/min for 60 min and administered an oral glucose solution (1.5 mg/g body weight). Compared to the MCHO group, the HCHO group showed significantly higher sodium-D-glucose co-transporter 1 protein levels in the brush border membrane fraction (p = 0.003) and the glucose transporter 2 level in the mucosa of jejunum (p = 0.004). At 30 min after the post-exercise glucose administration, the skeletal muscle and liver glycogen levels were not significantly different between the two diet groups. The blood glucose concentration from the portal vein (which is the entry site of nutrients from the gastrointestinal tract) was not significantly different between the groups at 15 min after the post-exercise glucose administration. There was no difference in the total or phosphorylated states of proteins related to glucose uptake and glycogen synthesis in skeletal muscle. Although the high-carbohydrate diet significantly increased glucose transporters in the jejunum, this adaptation stimulated neither glycogen recovery nor glucose absorption after the ingestion of post-exercise glucose.

scholarly journals The AML-associated K313 mutation enhances C/EBPα activity by leading to C/EBPα overexpression

2021 ◽  
Vol 12 (7) ◽  
Author(s):  
Ian Edward Gentle ◽  
Isabel Moelter ◽  
Mohamed Tarek Badr ◽  
Konstanze Döhner ◽  
Michael Lübbert ◽  
...  
Keyword(s):  
Gene Expression ◽  
Cell Culture ◽  
Transcription Factor ◽  
Transcription Factors ◽  
Transcriptional Activity ◽  
Target Gene ◽  
Wild Type ◽  
Elevated Expression ◽  
Factor C ◽  
Acute Myeloid

AbstractMutations in the transcription factor C/EBPα are found in ~10% of all acute myeloid leukaemia (AML) cases but the contribution of these mutations to leukemogenesis is incompletely understood. We here use a mouse model of granulocyte progenitors expressing conditionally active HoxB8 to assess the cell biological and molecular activity of C/EBPα-mutations associated with human AML. Both N-terminal truncation and C-terminal AML-associated mutations of C/EBPα substantially altered differentiation of progenitors into mature neutrophils in cell culture. Closer analysis of the C/EBPα-K313-duplication showed expansion and prolonged survival of mutant C/EBPα-expressing granulocytes following adoptive transfer into mice. C/EBPα-protein containing the K313-mutation further showed strongly enhanced transcriptional activity compared with the wild-type protein at certain promoters. Analysis of differentially regulated genes in cells overexpressing C/EBPα-K313 indicates a strong correlation with genes regulated by C/EBPα. Analysis of transcription factor enrichment in the differentially regulated genes indicated a strong reliance of SPI1/PU.1, suggesting that despite reduced DNA binding, C/EBPα-K313 is active in regulating target gene expression and acts largely through a network of other transcription factors. Strikingly, the K313 mutation caused strongly elevated expression of C/EBPα-protein, which could also be seen in primary K313 mutated AML blasts, explaining the enhanced C/EBPα activity in K313-expressing cells.

Induction of renal phosphoenolpyruvate carboxykinase mRNA: suppressive effect of glucose

1989 ◽  
Vol 257 (1) ◽  
pp. F145-F151
Author(s):  
A. S. Pollock
Keyword(s):  
Metabolic Acidosis ◽  
Phosphoenolpyruvate Carboxykinase ◽  
Suppressive Effect ◽  
Oral Glucose ◽  
Prolonged Fasting ◽  
Glucose Loading ◽  
Glucose Administration ◽  
Liver And Kidney ◽  
Gluconeogenic Enzyme ◽  
Effect Of Glucose

The mRNA for the important gluconeogenic enzyme phosphoenolpyruvate carboxykinase (GTP) (PEPCK; EC 4.1.1.32) is expressed in liver and kidney. In the kidney, acidosis is a unique and potent stimulus, whereas insulin, the major counterregulatory hormone of gluconeogenesis, has no effect. In this study, we find that oral glucose administration to rats rapidly decreases the abundance of renal PEPCK mRNA by 50–72%. This reduction takes place in normal euglycemic, in insulin-induced hypoglycemic, and in streptozotocin-induced hyperglycemic diabetic animals. The effect of glucose is not seen in the presence of metabolic acidosis, whether induced by NH4Cl or by prolonged fasting. Therefore, it appears that oral glucose loading is a physiological suppressor of renal PEPCK message abundance, although not in acidosis.

Leuconostoc pseudomesenteroides improves microbiota dysbiosis and liver metabolism imbalance and ameliorates the correlation between dihydroceramide and strains of Firmicutes and Proteobacteria in high fat diet obese mice

2020 ◽  
Vol 11 (8) ◽  
pp. 6855-6865
Author(s):  
Mengzhen Sun ◽  
Qiya Wang ◽  
Maomao Zhang ◽  
Guohua Zhang ◽  
Tao Wu ◽  
...  
Keyword(s):  
Molecular Mechanism ◽  
High Fat Diet ◽  
Liver Metabolism ◽  
Fermented Foods ◽  
Obese Mice ◽  
High Fat ◽  
Leuconostoc Pseudomesenteroides

Leuconostoc pseudomesenteroides is widely isolated from fermented foods; however, the underlying molecular mechanism behind its anti-obesity function has rarely been studied.

Enhanced plasma norepinephrine response to upright posture and oral glucose administration in elderly human subjects

Metabolism ◽  
1980 ◽  
Vol 29 (6) ◽  
pp. 532-539 ◽  
Author(s):  
James B. Young ◽  
John W. Rowe ◽  
Johanna A. Pallotta ◽  
David Sparrow ◽  
Lewis Landsberg
Keyword(s):  
Human Subjects ◽  
Plasma Norepinephrine ◽  
Oral Glucose ◽  
Upright Posture ◽  
Glucose Administration

scholarly journals Effects of the domestic thyroid stimulating hormone receptor (TSHR) variant on the hypothalamic-pituitary-thyroid axis and behavior in chicken

Genetics ◽  
2021 ◽  
Vol 217 (1) ◽  
Author(s):  
Amir Fallahshahroudi ◽  
Martin Johnsson ◽  
Enrico Sorato ◽  
S J Kumari A Ubhayasekera ◽  
Jonas Bergquist ◽  
...  
Keyword(s):  
Gene Expression ◽  
Hormone Receptor ◽  
Thyroid Stimulating Hormone ◽  
Phenotypic Traits ◽  
Wild Type ◽  
Data Set ◽  
Red Junglefowl ◽  
Pituitary Thyroid Axis ◽  
And Behavior ◽  
Stimulating Hormone

Abstract Domestic chickens are less fearful, have a faster sexual development, grow bigger, and lay more eggs than their primary ancestor, the red junglefowl. Several candidate genetic variants selected during domestication have been identified, but only a few studies have directly linked them with distinct phenotypic traits. Notably, a variant of the thyroid stimulating hormone receptor (TSHR) gene has been under strong positive selection over the past millennium, but it’s function and mechanisms of action are still largely unresolved. We therefore assessed the abundance of the domestic TSHR variant and possible genomic selection signatures in an extensive data set comprising multiple commercial and village chicken populations as well as wild-living extant members of the genus Gallus. Furthermore, by mean of extensive backcrossing we introgressed the wild-type TSHR variant from red junglefowl into domestic White Leghorn chickens and investigated gene expression, hormone levels, cold adaptation, and behavior in chickens possessing either the wild-type or domestic TSHR variant. While the domestic TSHR was the most common variant in all studied domestic populations and in one of two red junglefowl population, it was not detected in the other Gallus species. Functionally, the individuals with the domestic TSHR variant had a lower expression of the TSHR in the hypothalamus and marginally higher in the thyroid gland than wild-type TSHR individuals. Expression of TSHB and DIO2, two regulators of sexual maturity and reproduction in birds, was higher in the pituitary gland of the domestic-variant chickens. Furthermore, the domestic variant was associated with higher activity in the open field test. Our findings confirm that the spread of the domestic TSHR variant is limited to domesticated chickens, and to a lesser extent, their wild counterpart, the red junglefowl. Furthermore, we showed that effects of genetic variability in TSHR mirror key differences in gene expression and behavior previously described between the red junglefowl and domestic chicken.

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