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Pank1 deletion in leptin-deficient mice reduces hyperglycaemia and hyperinsulinaemia and modifies global metabolism without affecting insulin resistance.

ABSTRACT: Pantothenate kinase (PANK) is the first enzyme in CoA biosynthesis. Pank1-deficient mice have 40% lower liver CoA and fasting hypoglycaemia, which results from reduced gluconeogenesis. Single-nucleotide polymorphisms in the human PANK1 gene are associated with insulin levels, suggesting a link between CoA and insulin homeostasis. We determined whether Pank1 deficiency (1) modified insulin levels, (2) ameliorated hyperglycaemia and hyperinsulinaemia, and (3) improved acute glucose and insulin tolerance of leptin (Lep)-deficient mice.Serum insulin and responses to glucose and insulin tolerance tests were determined in Pank1-deficient mice. Levels of CoA and regulating enzymes were measured in liver and skeletal muscle of Lep-deficient mice. Double Pank1/Lep-deficient mice were analysed for the diabetes-related phenotype and global metabolism.Pank1-deficient mice had lower serum insulin and improved glucose tolerance and insulin sensitivity compared with wild-type mice. Hepatic and muscle CoA was abnormally high in Lep-deficient mice. Pank1 deletion reduced hepatic CoA but not muscle CoA, reduced serum glucose and insulin, but did not normalise body weight or improve acute glucose tolerance or protein kinase B phosphorylation in Lep-deficient animals. Pank1/Lep double-deficient mice exhibited reduced whole-body metabolism of fatty acids and amino acids and had a greater reliance on carbohydrate use for energy production.The results indicate that Pank1 deficiency drives a whole-body metabolic adaptation that improves aspects of the diabetic phenotype and uncouples hyperglycaemia and hyperinsulinaemia from obesity in leptin-deficient mice.

SUBMITTER: Leonardi R

PROVIDER: S-EPMC4618598 | biostudies-literature | 2014 Jul

REPOSITORIES: biostudies-literature

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Pank1 deletion in leptin-deficient mice reduces hyperglycaemia and hyperinsulinaemia and modifies global metabolism without affecting insulin resistance.

Leonardi Roberta R Rock Charles O CO Jackowski Suzanne S

Diabetologia 20140430 7

<h4>Aims/hypothesis</h4>Pantothenate kinase (PANK) is the first enzyme in CoA biosynthesis. Pank1-deficient mice have 40% lower liver CoA and fasting hypoglycaemia, which results from reduced gluconeogenesis. Single-nucleotide polymorphisms in the human PANK1 gene are associated with insulin levels, suggesting a link between CoA and insulin homeostasis. We determined whether Pank1 deficiency (1) modified insulin levels, (2) ameliorated hyperglycaemia and hyperinsulinaemia, and (3) improved acute ...[more]

PMID: 24781151

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Project description:Several post-translational modifications figure prominently in ventricular remodeling. The beta-O-linkage of N-acetylglucosamine (O-GlcNAc) to proteins has emerged as an important signal in the cardiovascular system. Although there are limited insights about the regulation of the biosynthetic pathway that gives rise to the O-GlcNAc post-translational modification, much remains to be elucidated regarding the enzymes, such as O-GlcNAc transferase (OGT) and O-GlcNAcase (OGA), which regulate the presence/absence of O-GlcNAcylation. Recently, we showed that the transcription factor, E2F1, could negatively regulate OGT and OGA expression in vitro. The present study sought to determine whether E2f1 deletion would improve post-infarct ventricular function by de-repressing expression of OGT and OGA. Male and female mice were subjected to non-reperfused myocardial infarction (MI) and followed for 1 or 4 week. MI significantly increased E2F1 expression. Deletion of E2f1 alone was not sufficient to alter OGT or OGA expression in a naïve setting. Cardiac dysfunction was significantly attenuated at 1-week post-MI in E2f1-ablated mice. During chronic heart failure, E2f1 deletion also attenuated cardiac dysfunction. Despite the improvement in function, OGT and OGA expression was not normalized and protein O-GlcNAcyltion was not changed at 1-week post-MI. OGA expression was significantly upregulated at 4-week post-MI but overall protein O-GlcNAcylation was not changed. As an alternative explanation, we also performed guided transcriptional profiling of predicted targets of E2F1, which indicated potential differences in cardiac metabolism, angiogenesis, and apoptosis. E2f1 ablation increased heart size and preserved remote zone capillary density at 1-week post-MI. During chronic heart failure, cardiomyocytes in the remote zone of E2f1-deleted hearts were larger than wildtype. These data indicate that, overall, E2f1 exerts a deleterious effect on ventricular remodeling. Thus, E2f1 deletion improves ventricular remodeling with limited impact on enzymes regulating O-GlcNAcylation.

Project description:BackgroundIt is now widely recognized that radiotherapy of thoracic and chest wall tumors increases the long-term risk of cardiovascular damage although the underlying mechanisms are not fully elucidated. There is increasing evidence that microvascular damage is involved. Endoglin, an accessory receptor for TGF-β1, is highly expressed in damaged endothelial cells and may play a crucial role in cell proliferation and revascularization of damaged heart tissue. We have therefore specifically examined the role of endoglin in microvascular damage and repair in the irradiated heart.Materials & methodsA single dose of 16 Gy was delivered to the heart of adult Eng(+/+) or Eng(+/-) mice and damage was evaluated at 4, 20 and 40 weeks, relative to age-matched controls. Gated single photon emission computed tomography (gSPECT) was used to measure cardiac geometry and function, and related to histo-morphology, microvascular damage (detected using immuno- and enzyme-histochemistry) and gene expression (detected by microarray and real time PCR).ResultsGenes categorized according to known inflammatory and immunological related disease were less prominently regulated in irradiated Eng(+/-) mice compared to Eng(+/+) littermates. Fibrosis related genes, TGF-β1, ALK 5 and PDGF, were only upregulated in Eng(+/+) mice during the early phase of radiation-induced cardiac damage (4 weeks). In addition, only the Eng(+/+) mice showed significant upregulation of collagen deposition in the early fibrotic phase (20 weeks) after irradiation. Despite these differences in gene expression, there was no reduction in inflammatory invasion (CD45+cells) of irradiated Eng(+/-) hearts. Microvascular damage (microvascular density, alkaline phosphatase and von-Willebrand-Factor expression) was also similar in both strains.ConclusionEng(+/-) mice displayed impaired early inflammatory and fibrotic responses to high dose irradiation compared to Eng(+/+) littermates. This did not result in significant differences in microvascular damage or cardiac function between the strains.

Dataset Information

Pank1 deletion in leptin-deficient mice reduces hyperglycaemia and hyperinsulinaemia and modifies global metabolism without affecting insulin resistance.

Publications

Pank1 deletion in leptin-deficient mice reduces hyperglycaemia and hyperinsulinaemia and modifies global metabolism without affecting insulin resistance.

Similar Datasets

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