Dataset Information

Metformin Impairs Intestinal Fructose Metabolism

ABSTRACT: Objective: To investigate the effects of metformin on intestinal carbohydrate metabolism in vivo. Method: Male mice preconditioned with a high-fat, high-sucrose diet were treated orally with metformin or a control solution for two weeks. Fructose metabolism, glucose production from fructose, and production of other fructose-derived metabolites were assessed using stably labeled fructose as a tracer. Results: Metformin treatment decreased intestinal glucose levels and reduced incorporation of fructose-derived metabolites into glucose. This was associated with decreased intestinal fructose metabolism as indicated by decreased enterocyte F1P levels and diminished labeling of fructose-derived metabolites. Metformin also reduced fructose delivery to the liver. Proteomic analysis revealed that metformin coordinately down-regulated proteins involved carbohydrate metabolism including those involved in fructolysis and glucose production within intestinal tissue. Conclusion: Metformin reduces intestinal fructose metabolism, and this is associated with broad-based changes in intestinal enzyme and protein levels involved in sugar metabolism indicating that metformin's effects on sugar metabolism are pleiotropic.

ORGANISM(S): Mus Musculus (mouse)

SUBMITTER: Mark A. Herman

PROVIDER: PXD041833 | JPOST Repository | Sat Apr 27 00:00:00 BST 2024

REPOSITORIES: jPOST

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Publications

Pyruvate-supported flux through medium-chain ketothiolase promotes mitochondrial lipid tolerance in cardiac and skeletal muscles.

Koves Timothy R TR Zhang Guo-Fang GF Davidson Michael T MT Chaves Alec B AB Crown Scott B SB Johnson Jordan M JM Slentz Dorothy H DH Grimsrud Paul A PA Muoio Deborah M DM

Cell metabolism 20230414 6

Even-chain acylcarnitine (AC) metabolites, most of which are generated as byproducts of incomplete fatty acid oxidation (FAO), are viewed as biomarkers of mitochondrial lipid stress attributable to one or more metabolic bottlenecks in the β-oxidation pathway. The origins and functional implications of FAO bottlenecks remain poorly understood. Here, we combined a sophisticated mitochondrial phenotyping platform with state-of-the-art molecular profiling tools and multiple two-state mouse models of ...[more]

PMID: 37060901

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Project description:Background: Prolonged lactation provides substantial health benefits, possibly because of galactose as part of milk sugar lactose. Isocaloric replacement of dietary glucose [16 energy%(en%)] with galactose within a normal diet (64en% carbohydrates) during a 3-wk postweaning period provided substantial benefits on short- and long-term physiologic and metabolic parameters at the whole-body level and liver in female mice, which might be attributable to intestinal function. Objectives: This study aimed to investigate if partial dietary replacement of glucose with galactose alters intestinal metabolism underlying hepatic health effects. Methods: Proximal intestinal mucosa gene profiles in female mice were analyzed using RNAseq technology, validated, and correlated with hepatic health parameters. Results: Transcriptome analysis revealed that the presence of galactose primarily affected the pathways involved in energy metabolism. A consistently higher expression was observed in the subset of mitochondrial transcripts (78 of 80, all P.adj < 0.1). Oxidative phosphorylation (OXPHOS) represented the most upregulated process (all top 10 pathways) independent of the total mitochondrial mass (P = 0.75). Moreover, galactose consistently upregulated carbohydrate metabolism pathways, specifically glycolysis till acetyl-CoA production and fructose metabolism. Also, the expression of transcripts involved in these pathways was negatively correlated with circulating serum amyloid A3 protein, a marker of hepatic inflammation [R (-0.61, -0.5), P (0.002, 0.01)]. Accordingly, CD163+ cells were decreased in the liver. Additionally, the expression of key fructolytic enzymes in the small intestinal mucosa was negatively correlated with triglyceride accumulation in the liver [R (-0.45, -0.4), P (0.03, 0.05)]. Conclusions: To our knowledge, our results show for the first time the role of galactose as an OXPHOS activator in vivo. Moreover, the concept of intestinal cells acting as the body's metabolic gatekeeper is strongly supported, as they alter substrate availability and thereby contribute to the maintenance of metabolic homeostasis, protecting other organs, as evidenced by their potential ability to shield the liver from the potentially detrimental effects of fructose.

Dataset Information

Metformin Impairs Intestinal Fructose Metabolism

Publications

Pyruvate-supported flux through medium-chain ketothiolase promotes mitochondrial lipid tolerance in cardiac and skeletal muscles.

Similar Datasets

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