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Insulin-independent regulation of hepatic triglyceride synthesis by fatty acids.

ABSTRACT: A central paradox in type 2 diabetes is the apparent selective nature of hepatic insulin resistance--wherein insulin fails to suppress hepatic glucose production yet continues to stimulate lipogenesis, resulting in hyperglycemia, hyperlipidemia, and hepatic steatosis. Although efforts to explain this have focused on finding a branch point in insulin signaling where hepatic glucose and lipid metabolism diverge, we hypothesized that hepatic triglyceride synthesis could be driven by substrate, independent of changes in hepatic insulin signaling. We tested this hypothesis in rats by infusing [U-(13)C] palmitate to measure rates of fatty acid esterification into hepatic triglyceride while varying plasma fatty acid and insulin concentrations independently. These experiments were performed in normal rats, high fat-fed insulin-resistant rats, and insulin receptor 2'-O-methoxyethyl chimeric antisense oligonucleotide-treated rats. Rates of fatty acid esterification into hepatic triglyceride were found to be dependent on plasma fatty acid infusion rates, independent of changes in plasma insulin concentrations and independent of hepatocellular insulin signaling. Taken together, these results obviate a paradox of selective insulin resistance, because the major source of hepatic lipid synthesis, esterification of preformed fatty acids, is primarily dependent on substrate delivery and largely independent of hepatic insulin action.

SUBMITTER: Vatner DF

PROVIDER: S-EPMC4313795 | biostudies-literature | 2015 Jan

REPOSITORIES: biostudies-literature

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Insulin-independent regulation of hepatic triglyceride synthesis by fatty acids.

Vatner Daniel F DF Majumdar Sachin K SK Kumashiro Naoki N Petersen Max C MC Rahimi Yasmeen Y Gattu Arijeet K AK Bears Mitchell M Camporez João-Paulo G JP Cline Gary W GW Jurczak Michael J MJ Samuel Varman T VT Shulman Gerald I GI

Proceedings of the National Academy of Sciences of the United States of America 20150106 4

A central paradox in type 2 diabetes is the apparent selective nature of hepatic insulin resistance--wherein insulin fails to suppress hepatic glucose production yet continues to stimulate lipogenesis, resulting in hyperglycemia, hyperlipidemia, and hepatic steatosis. Although efforts to explain this have focused on finding a branch point in insulin signaling where hepatic glucose and lipid metabolism diverge, we hypothesized that hepatic triglyceride synthesis could be driven by substrate, inde ...[more]

PMID: 25564660

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Project description:1. Adipose tissues from rats fed a balanced diet were incubated in the presence of glucose (20mm) with the following additions: insulin, anti-insulin serum, insulin+acetate, insulin+pyruvate, insulin+lactate, insulin+phenazine methosulphate, insulin+oleate+albumin, insulin+adrenaline+albumin, insulin+6-N-2'-O-dibutyryl 3':5'-cyclic AMP+albumin. 2. Measurements were made of the whole tissue concentrations of adenine nucleotides, hexose phosphates, triose phosphates, glycerol 1-phosphate, 3 phosphoglycerate, 6-phosphogluconate, long-chain fatty acyl-CoA, acid-soluble CoA, citrate, isocitrate, malate and 2-oxoglutarate, and of the release into the incubation medium of lactate, pyruvate and glycerol after 1h of incubation. 3. Fluxes of [(14)C]glucose carbon through the major pathways of glucose metabolism were calculated from the yields of (14)C in various products after 2h of incubation. Fluxes of [(14)C]acetate, [(14)C]pyruvate or [(14)C]lactate carbon in the presence of glucose were also determined. 4. Measurements were also made of the whole-tissue concentrations of metabolites in tissues taken directly from Nembutal-anaesthetized rats. 5. Whole tissue mass-action ratios for phosphofructokinase, phosphoglucose isomerase and the combined (aldolasextriose phosphate isomerase) reaction were similar in vivo and in vitro. The reactants of phosphofructokinase appeared to be far from mass-action equilibrium. In vitro, the reactants of hexokinase also appeared to be far from mass-action equilibrium. 6. Correlation of observed changes in glycolytic flux with changes in fructose 6-phosphate concentration suggested that phosphofructokinase may show regulatory behaviour. The enzyme appeared to be activated in the presence of oleate or adrenaline and to be inhibited in the presence of lactate or pyruvate. 7. Evidence is presented that the reactants of lactate dehydrogenase and glycerol 1-phosphate dehydrogenase may be near to mass-action equilibrium in the cytoplasm. 8. No satisfactory correlations could be drawn between the whole-tissue concentrations of long-chain fatty acyl-CoA, citrate and glycerol 1-phosphate and the observed rates of triglyceride and fatty acid synthesis. Under the conditions employed, the concentration of glycerol 1-phosphate appeared to depend mainly on the cytoplasmic [NAD(+)]/[NADH] ratios. 9. Calculated hexose monophosphate pathway flux rates roughly correlated with fatty acid synthesis rates and with whole tissue [6-phosphogluconate]/[glucose 6-phosphate] ratios. The relative rates of production of NADPH for fatty acid synthesis by the hexose monophosphate pathway and by the ;malic enzyme' are discussed. It is suggested that all NADH produced in the cytoplasm may be used in that compartment for reductive synthesis of fatty acids, lactate or glycerol 1-phosphate.

Project description:Resveratrol (3,5,4-trihydroxystilbene) is a natural polyphenolic compound found in grapes and red wine and has been shown to exert protective effects on the liver preventing lipid accumulation induced by a high-fat diet. However, no studies have shown that the nutritional resveratrol intake by the parental generation has modified lipogenesis in an adult offspring. The aim of this study was to investigate whether maternal resveratrol intake during lactation affects lipogenesis in adult male rat offspring, and if it does, what is the molecular mechanistic basis. Six male pups born from mothers given a control diets during lactation (CC group) and six male pups born from mothers given a control diet as well as resveratrol during lactation (CR group) were fed a standard diet until sacrifice at 36 weeks. Adult male offspring from mothers given resveratrol during lactation (CR group) had lower body weight from the fourth week of lactation until adulthood, but no significant change was observed in the relative food intake. Low levels of plasma triacylglycerol were found in the CR group compared to the CC group. Histopathological analysis of the livers of adult male rat offspring revealed lipid accumulation in hepatocytes in the CC group, whereas lipid droplets were rare in the CR group. Hepatic protein levels of AMPK-phosphorylated at ser403, Sirt1, and Nampt in the CR group were upregulated significantly compared to the CC group. These results indicated the maternal resveratrol intake during lactation-induced activation of AMPK through Sirt1 upregulation. In this study, significant upregulation of the levels of precursor of sterol regulatory element binding protein-1c (SREBP-1c) and downregulation of the ratio of active-SREBP-1c/precusor-SREBP-1c were observed in the CR group compared to the CC group. These results suggested that proteolytic processing of SREBP-1c was suppressed by AMPK in the livers of the CR group. It is well known that SREBP-1c regulates the lipogenic pathway by activating genes involved in triglyceride and fatty acid synthesis. The present study showed significant downregulation of hepatic fatty acid synthase (FAS) and acetyl-CoA carboxylase (ACC) levels in the CR group. These results indicated that maternal resveratrol intake during lactation suppressed SREBP-1c cleavage and nuclear translocation and repressed SREBP-1c target gene expression such as FAS and ACC in the livers of adult male offspring. These changes attenuate hepatic triacylglycerol and fatty acid synthesis in adult male offspring.

Dataset Information

Insulin-independent regulation of hepatic triglyceride synthesis by fatty acids.

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Insulin-independent regulation of hepatic triglyceride synthesis by fatty acids.

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