Central and Metabolic Effects of High Fructose Consumption: Evidence from Animal and Human Studies

Fructose consumption has increased dramatically in the last 40 years, and its role in the pathogenesis of the metabolic syndrome has been implicated by many studies. It is most often encountered in the diet as sucrose [glucose and fructose] or high-fructose corn syrup [55% fructose]. At high levels, dietary exposure to fructose triggers a series of metabolic changes originating in the liver, leading to hepatic steatosis, hypertriglyceridemia, insulin resistance, and decreased leptin sensitivity. Fructose has been identified to alter biological pathways in other tissues including the central nervous system [CNS], adipose tissue, and the gastrointestinal system. Unlike glucose, consumption of fructose produces smaller increases in the circulating satiety hormone glucagon-like peptide 1 [GLP-1], and does not attenuate levels of the appetite suppressing hormone ghrelin. In the brain, fructose contributes to increased food consumption by activating appetite and reward pathways, and stimulating hypothalamic AMPK activity, a nutrient-sensitive regulator of food intake. Recent studies investigating the neurophysiological factors linking fructose consumption and weight gain in humans have demonstrated differential activation of brain regions that govern appetite, motivation and reward processing. Compared to fructose, glucose ingestion produces a greater reduction of hypothalamic neuronal activity, and increases functional connectivity between the hypothalamus and other reward regions of the brain, indicating that these two sugars regulate feeding behavior through distinct neural circuits. This review article outlines the current findings in fructose-feeding studies in both human and animal models, and discusses the central effects on the CNS that may lead to increased appetite and food intake

MicroRNAs: critical regulators of mRNA traffic and translational control with promising biotech and therapeutic applications

MicroRNAs [miRNAs] are a class of short, endogenously-initiated, non-coding RNAs that post-transcriptionally control gene expression via translational repression or mRNA turnover. MiRNAs have attracted much attention in recent years as they play critical roles in gene expression and are promising tools with many biotech and therapeutic applications. The molecular mechanisms underlying the translational control of mRNAs are not fully understood but emerging evidence point to a key role for microRNAs in this process. In this review, we discuss the potential role of miRNAs as regulators of mRNA traffic and translational control, focusing on molecular mechanisms of miRNA-mediated control of eukaryotic mRNA stability and translational efficiency. Translational control by miRNAs is often associated with silencing and repression of mRNAs via accumulation within cytoplasmic processing bodies [P-bodies], the site of mRNA storage and/or decay. Specific miRNAs can interact with the 3'UTR or 5'UTR of target mRNAs and regulate their stability as well as translational efficiency. A better understanding of these mechanisms is critical in advancing our knowledge of the role of these regulatory RNAs in modulating protein synthesis and controlling metabolic pathways in health and disease. The discovery of miRNAs and their important role in controlling many aspects of cell function and metabolism have led to considerable interest in biotech applications of miRNAs and their application in modulating specific gene expression. We thus highlight the growing biotech and therapeutic applications of miRNAs.

Mechanisms linking the metabolic syndrome and cardiovascular disease: role of hepatic insulin resistance

The worldwide prevalence of insulin resistant states such as the metabolic syndrome has grown rapidly over the past few decades. The metabolic syndrome is a constellation of common metabolic disorders that promote the development of atherosclerosis and cardiovascular disease. Studies in both human and animal models suggest that hepatic inflammation and insulin resistance are key initiating factors in the development of the metabolic syndrome. Chronic inflammation is known to be associated with visceral obesity and is characterized by production of abnormal adipokines and cytokines such as tumor necrosis factor a, interleukin-1 [IL-1], IL-6, leptin, and resistin. These factors inhibit insulin signaling in the liver [hepatocytes] by activating suppressors of cytokine signalling proteins; several kinases such as c-Jun N-terminal kinases, IKK-beta, and Protein kinase C; and protein tyrosine phosphatase 1B, that in turn impair insulin signaling at insulin receptor and insulin receptor substrate level. Hepatic insulin resistance in turn causes impaired suppression of glucose production by insulin in hepatocytes leading to hyperglycemia, induction of very low density lipoprotein production, and de novo lipogenesis. Increased production of C-reactive protein [CRP] and plasminogen activator inhibitor-1, both markers of an inflammatory state, is also observed in insulin resistance. All of the above metabolic abnormalities can directly or indirectly promote atherosclerosis. In particular, hyperglycemia induces endothelial dysfunction, cellular proliferation, changes in extracellular matrix conformation, and impairment of low density lipoproteins [LDL]-receptor-mediated lipoprotein uptake. Small dense LDLs have higher affinity to the intimal proteoglycans, leading to the penetration of more LDL particles into the arterial wall. CRP can also accelerate atherosclerosis by increasing the expression of PAI-1 and adhesion molecules in endothelial cells, inhibition of nitric oxide formation, and increasing LDL uptake into macrophages. In summary, hepatic insulin resistance is a critical early event that underlies the development of the metabolic syndrome and progression to atherosclerosis and cardiovascular disease

Overexpression of protein tyrosine phosphatase IB in HepG2 cells ameliorates insulin-mediated suppression of apolipoprotein B mRNA translation via its untranslated regions

The hepatic secretion of apolipoprotein B [apoB], containing lipoproteins, is known to be regulated by insulin, and the overproduction of these atherogenic lipoproteins occurs in insulin-resistant states. Protein tyrosine phosphatase 1B [PTP-1B] is a key regulator of hepatic insulin signaling and is also upregulated in insulin resistance. We aimed to investigate the role of PTP-1B in regulating apoB mRNA translational efficiency mediated by 5'/3' untranslated regions [UTRs] under conditions of insulin stimulation. Human hepatoma HepG2 cells were transfected with a vector carrying the firefly luciferase reporter gene and either a chimeric apoB mRNA encoding the 5'/3' untranslated region [5' LUC3' -pGL3] or a null sequence of length equivalent to apoB 5' UTR [LUC-pGL3]. The transfected cells were then infected with adenovirus carrying the mouse PTP-1B gene [AdPTP1B] in the absence or presence of insulin, and the cellular luciferase activity was determined. The RNA extracts from cells were transfected with constructs carrying 5'/3' apoB UTR, or a null sequence was also translated in vitro in a rabbit reticulocyte translation system. The luciferase activity of the cells transfected with constructs containing the apoB UTR sequences [5' LUC3'] was significantly higher than that of the control constructs carrying a null sequence [p<0.01, n=12]. Similar results were observed following in vitro translation studies showing a significantly higher expression of the 5'/3' UTR constructs [p<0.001, n=6]. Treatment with 100 nM insulin led to a significant reduction in the luciferase activity of the constructs carrying apoB 5'/3' UTR [p<0.0001, n=12]. The down regulation of the apoB mRNA translation mediated by insulin was mediated by the apoB 5'/3' UTR sequences since insulin did not affect the control constructs containing a null sequence. The infection of HepG2 cells expressing 5' LUC3' or control constructs with AdPTP-1B attenuated the inhibitory effect of insulin and led to higher levels of luciferase activity compared to the Ad beta-gal infected control cells [p<0.05, n=12]. However, the activity was lower than that in the control cells infected with 5' LUC3' -pGL3 but not treated with insulin [p<0.05, n=12]. Our data suggest that PTP-1B can potentially modulate apoB synthesis by blocking insulin-mediated inhibition of the apoB mRNA translation via its 5'/3' UTR sequences. We hypothesize that the PTP-1B-mediated attenuation of the insulin action can lead to the upregulation of the apoB mRNA translation and contribute to a lipoprotein overproduction in conditions such as insulin resistance