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Proline exacerbates hepatic gluconeogenesis via paraspeckle-dependent mRNA retention [RIP-Seq]

ABSTRACT: Type 2 Diabetes (T2D) is a global health issue characterized by abnormal blood glucose levels and often associated with excessive hepatic gluconeogenesis. Increased circulating non-essential amino acids (NEAAs) are consistently observed in T2D individuals; however, the specific contribution of each amino acid to T2D pathogenesis remains less understood. Here, we reported an unexpected role of the NEAA proline in coordinating hepatic glucose metabolism by modulating paraspeckle, a nuclear structure scaffolded by the long noncoding RNA Neat1. Mechanistically, proline diminished paraspeckles in hepatocytes, liberating the retained mRNA species into cytoplasm for translation, including the mRNAs of Ppargc1a and Foxo1, contributing to enhanced gluconeogenesis and hyperglycemia. We further demonstrated that the proline-paraspeckle-mRNA retention axis existed in diabetic liver samples, and intervening this axis via paraspeckle restoration significantly alleviated hyperglycemia in both female and male diabetic mouse models. Collectively, our results not only delineated a previously unappreciated proline-instigated, paraspeckle-dependent mRNA retention mechanism regulating gluconeogenesis, but also spotlighted proline and paraspeckle as potential targets for managing hyperglycemia.

ORGANISM(S): Mus musculus

PROVIDER: GSE252450 | GEO | 2024/11/26

REPOSITORIES: GEO

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Proline exacerbates hepatic gluconeogenesis via paraspeckle-dependent mRNA retention

Project description:Type 2 Diabetes (T2D) is a global health issue characterized by abnormal blood glucose levels and often associated with excessive hepatic gluconeogenesis. Increased circulating non-essential amino acids (NEAAs) are consistently observed in T2D individuals; however, the specific contribution of each amino acid to T2D pathogenesis remains less understood. Here, we reported an unexpected role of the NEAA proline in coordinating hepatic glucose metabolism by modulating paraspeckle, a nuclear structure scaffolded by the long noncoding RNA Neat1. Mechanistically, proline diminished paraspeckles in hepatocytes, liberating the retained mRNA species into cytoplasm for translation, including the mRNAs of Ppargc1a and Foxo1, contributing to enhanced gluconeogenesis and hyperglycemia. We further demonstrated that the proline-paraspeckle-mRNA retention axis existed in diabetic liver samples, and intervening this axis via paraspeckle restoration significantly alleviated hyperglycemia in both female and male diabetic mouse models. Collectively, our results not only delineated a previously unappreciated proline-instigated, paraspeckle-dependent mRNA retention mechanism regulating gluconeogenesis, but also spotlighted proline and paraspeckle as potential targets for managing hyperglycemia. This SuperSeries is composed of the SubSeries listed below.

2024-11-26 | GSE252452 | GEO

Proline exacerbates hepatic gluconeogenesis via paraspeckle-dependent mRNA retention [lncRNA-Seq]

2024-11-26 | GSE252451 | GEO

Silencing alanine transaminase 2 in diabetic liver attenuates hyperglycemia by reducing gluconeogenesis from amino acids

Project description:Hepatic gluconeogenesis from amino acids contributes significantly to diabetic hyperglycemia, but the molecular mechanisms involved are incompletely understood. Alanine transaminases (ALT1 and ALT2) catalyze the interconversion of alanine and pyruvate, which is required for gluconeogenesis from alanine. Hepatocyte-specific knockout of Gpt2 attenuated incorporation of 13C-alanine into newly synthesized glucose by hepatocytes. However, Gpt2 knockout in liver had no effect on glucose concentrations in lean mice, which may suggest that metabolic compensation is occurring.

2022-04-06 | GSE199975 | GEO

Dysfunction of the circadian clock in the renal tubule leads to enhanced renal gluconeogenesis and exacerbated hyperglycemia in diabetes

Project description:In diabetes, the kidney contributes to the development of diabetic hyperglycemia by increasing glucose reabsorption from the primary urine and by upregulating gluconeogenesis in the proximal tubule. However, these two processes are also controlled by the circadian clock, a mechanism that synchronizes a large number of specific renal functions with environmental daily cycles. Here, we investigated the (patho)physiological role of intrinsic renal tubule circadian clocks in the diabetic kidney. We demonstrate that diabetic mice devoid of the circadian transcriptional regulator BMAL1 in the renal tubule exhibit additional enhancement of renal gluconeogenesis, exacerbated hyperglycemia, increased glucosuria, polyuria and renal hypertrophy. Collectively, our results suggest that diabetic hyperglycemia can be worsened by dysfunction or misalignment of intrinsic renal circadian clocks.

2022-05-27 | GSE178319 | GEO

Silencing alanine transaminase 2 in diabetic liver attenuates hyperglycemia by reducing gluconeogenesis from amino acids

Project description:Silencing alanine transaminase 2 in diabetic liver attenuates hyperglycemia by reducing gluconeogenesis from amino acids

| PRJNA822390 | ENA

Hyperglycemia and a Common Variant of GCKR Are Associated with the Levels of Eight Amino Acids in 9,371 Finnish Men

Project description:Objective: Insulin regulates amino acid metabolism. We investigated whether glycemia and 43 genetic risk variants for hyperglycemia/type 2 diabetes affect amino acid levels in a large population-based cohort. Subjects and Methods: A total of 9,371 non-diabetic or newly-diagnosed type 2 diabetic Finnish men from the population-based METSIM Study were studied. Proton NMR spectroscopy was used to measure plasma levels of 8 amino acids. Genotyping of 42 SNPs and mRNA microarray analysis from 200 subcutaneous adipose tissue samples were performed. Results: Increasing fasting and/or 2-hour plasma glucose levels were associated with increasing levels of alanine, valine, leucine, isoleucine, phenylalanine and tyrosine, and decreasing levels of histidine and glutamine. We also found significant correlations between insulin sensitivity (Matsuda ISI) and expression of genes regulating amino acid metabolism. Only one SNP (rs780094 in GCKR) of the 42 risk SNPs for type 2 diabetes or hyperglycemia was significantly associated with the levels of alanine, isoleucine, and glutamine. Conclusions : We observed that the levels of branched-chain, aromatic amino acids and alanine increased and the levels of glutamine and histidine decreased with increasing glycemia. These associations seemed to be mediated by insulin resistance, at least in part. GCKR rs780094 was significantly associated with several amino acids. Total RNA was obtained from subcutaneous fat biopsies from 200 people participating in the METSIM study (4 samples were replicated for a total of 204 arrays).

2012-04-01 | E-GEOD-32512 | biostudies-arrayexpress

Hyperglycemia and a Common Variant of GCKR Are Associated with the Levels of Eight Amino Acids in 9,371 Finnish Men

2012-04-02 | GSE32512 | GEO

Quantitative phosphoproteomics reveals diverse stimuli activate distinct signaling pathways during neutrophil activation

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2022-08-11 | PXD029046 | Pride

Systemic metabolic alterations correlate with islet-level prostaglandin E2 production and signaling mechanisms that predict beta-cell dysfunction in a mouse model of type 2 diabetes

Project description:The transition from β-cell compensation to β-cell failure is not well understood. Previous works by our group and others have demonstrated a role for Prostaglandin EP3 receptor (EP3), encoded by the Ptger3 gene, in the loss of functional β-cell mass in T2D. The primary endogenous EP3 ligand is the arachidonic acid metabolite, prostaglandin E2 (PGE2). Pancreatic islet EP3 expression, expression of PGE2 synthetic enzymes, and/or PGE2 excretion itself have all been shown as up-regulated in primary mouse and human islets isolated from animals or human organ donors with established T2D as compared to non-diabetic controls. In this study, we took advantage of a rare and fleeting phenotype in which a subset of Black and Tan BRachyury (BTBR) mice homozygous for the Leptinob/ob mutation—a strong genetic model of T2D—were entirely protected from fasting hyperglycemia even with equal obesity and insulin resistance as their hyperglycemic littermates. Utilizing this model, we found numerous alterations in full-body metabolic parameters in T2D-protected mice (e.g., gut microbiome composition, circulating pancreatic and incretin hormones, and markers of systemic inflammation) that correlate with improvements in EP3-mediated β-cell dysfunction.

2021-09-09 | PXD022624 | Pride

Periodontal pathogen induces entero-hepatic metabolic derangements in type 2 diabetic mouse model

Project description:This is the first report of the metabolic and metaproteomic integrated changes in the gut and liver by the swallowed periodontopathogen. Periodontal disease pathogen Porphyromonas gingivalis are observed in faeces as peptides level in proteomic analysis and make changes in bowel microbial composition in db/db mouse. Orally Periodontal disease pathogen throwing as experimental periodontal disease model make gluconeogenesis in db/db mouse liver and hyperglycemia. Multi-omics analysis reveal Pg decreasing in energy metabolism and glucagon store in db/db mouse liver. These findings suggest that periodontal treatment improving oral microbiota can make diabetic hyperglycemia ameliorate in liver and support these diabetes treatments credibly.

2021-09-21 | PXD021851 | JPOST Repository

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