Fructose in fetal cord blood and its relationship with maternal and 48-hour-newborn blood concentrations

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)

Metabolic syndrome signs in Wistar rats submitted to different high-fructose ingestion protocols

In search of an adequate model for the human metabolic syndrome, the metabolic characteristics of Wistar rats were analysed after being submitted to different protocols of high fructose ingestion. First, two adult rat groups (aged 90 d) were studied: a control group (C1; n 6) received regular rodent chow (Labina, Purina) and a fructose group (F1; n 6) was fed on regular rodent chow. Fructose was administered as a 10 % solution in drinking water. Second, two adult rat groups (aged 90 d) were evaluated: a control group (C2; n 6) was fed on a balanced diet (AIN-93G) and a fructose group (F2; n 6) was fed on a purified 60 % fructose diet. Finally, two young rat groups (aged 28 d) were analysed: a control group (C3; n 6) was fed on the AIN-93G diet and a fructose group (F3; n 6) was fed on a 60 % fructose diet. After 4-8 weeks, the animals were evaluated. Glucose tolerance, peripheral insulin sensitivity, blood lipid profile and body fat were analysed. In the fructose groups F2 and F3 glucose tolerance and insulin sensitivity were lower, while triacylglycerolaemia was higher than the respective controls C2 and C3 (P < 0.05). Blood total cholesterol, HDL and LDL as well as body fat showed change only in the second protocol. In conclusion, high fructose intake is more effective at producing the signs of the metabolic syndrome in adult than in young Wistar rats. Additionally, diet seems to be a more effective way of fructose administration than drinking water.

Mammalian triokinase and dihydroxyacetone kinase are the same enzyme

It is widely accepted that the ATP-dependent phosphorylation of D-glyceraldehyde in the fructokinase pathway of fructose metabolism requires the enzyme “triokinase”. However, experimental data on this enzyme are remarkably scarce. The enzyme has been purified from a variety of sources and peptides derived from the pig kidney enzyme show high similarity to human dihydroxyacetone kinase – an enzyme which also has FMN cyclase activity in high manganese ion concentrations. The properties of the two enzymes are also highly similar. Therefore it is proposed that mammalian triokinase and dihydroxyacetone kinase are, in fact, the same enzyme. This has consequences for investigations of normal and aberrant fructose metabolism and for the teaching of biochemistry in medical and science courses.

Frutose em humanos: Efeitos metabólicos, utilização clínica e erros inatos associados

This article reviews the metabolism of fructose and sorbitol, their main clinical indications and the consequences of inadequate use. Fructose, an important carbohydrate in the diet, is present mostly in fruits and vegetables; it can also be synthesized from glucose in the organism, through the sorbitol. Fructose is known for its metabolism's inherent errors, whose clinical manifestations are potentially serious, as well as for its use as a glucose substitute in the diabetic patients' diet, due to its metabolism not being dependent from insulin. In the last years, especially in developed countries, the consumption of fructose has increased considerably, due to its use as a sweetener in industrialized foods. However, adverse side-effects may occur with the excessive ingestion of fructose, such as the increase in blood's triglycerides and cholesterol. Therefore, to know which are the patients' normal blood levels is quite important for establishing the safe amount of fructose to be prescribed, as well as for allowing the screening of metabolism diseases associated with fructose.

Determinação dos níveis sangüíneos de frutose em recém-nascidos de termo com pesos adequados para a idade gestacional com 48 horas de vida

Pós-graduação em Pediatria - FMB

Zuckertransport und Regulation des Hexosestoffwechsels bei Oenococcus oeni

Das Milchsäurebakterium Oenococcus oeni, welches für den biologischen Säureabbau im Wein eingesetzt wird, verstoffwechselt Hexosen über den Phosphoketolaseweg. Dabei können beträchtliche Mengen Acetat entstehen. Die Ursachen dafür wurden untersucht, insbesondere der Fructosestoffwechsel. Außerdem wurde der Hexosetransport untersucht, über den bei O. oeni noch nichts bekannt war. Die Aufnahme von Hexosen in die Zelle erfolgt mit hoher Affinität (KM=10 µM) über einen Symport mit H+, aber mit sehr niedriger spezifischer Aktivität (Vmax=9 U / g TG). Zusätzlich werden Hexosen mit ausreichender Aktivität über (vermutlich erleichterte) Diffusion in die Zelle transportiert, allerdings nur bei hohen Hexosekonzentrationen. Es wurden Gene gefunden, die für ein Hexose- Phosphotransferasesystem kodieren, welches in O. oeni keine bedeutende Rolle beim Transport spielt, aber vermutlich eine regulative Funktion hat. Zur Bildung von Essigsäure tragen verschiedene Faktoren bei: Der Ethanolweg, der in der heterofermentativen Milchsäuregärung die Reoxidation von NAD(P)H bewerkstelligt, ist durch die niedrige spezifische Aktivität der Acetaldehyddehydrogenase limitiert. Diese Limitierung wird noch verstärkt, wenn die zellulären Gehalte von Coenzym A aufgrund von Pantothensäuremangel niedrig sind. O. oeni umgeht durch Bildung von Erythrit die Limitierung, und Acetylphosphat wird nicht zu Ethanol reduziert, sondern als Acetat ausgeschieden. Bei Cofermentation von Hexosen mit externen Elektronenakzeptoren, wie Fructose, Pyruvat oder Sauerstoff, werden letztere zur Reoxidation von NAD(P)H genutzt, und als Folge wird Acetat ausgeschieden. Der Fluss von Fructose in den Phosphoketolaseweg wird durch das Enzym Phosphoglucoseisomerase verhindert, wenn dieses durch 6-Phosphogluconat gehemmt wird. Als Konsequenz wird Fructose im Mannitweg reduziert, was die Bildung von Essigsäure im Phosphoketolaseweg fördert. Bei niedrigen Wachstums- und Stoffwechselraten, z.B. bei C-Limitierung, ist der Ethanolweg nicht limitierend für den Stoffwechsel, und Hexosen werden über heterofermentative Milchsäuregärung umgesetzt, ohne daß Acetat entsteht. Pyruvat kann gleichzeitig als Elektronenakzeptor und als Energiequelle dienen: O. oeni ist in der Lage, Pyruvat mittels Disproportionierung zu Lactat und Acetat+CO2 zu fermentieren, und dabei Energie zu konservieren (0,5 ATP / Pyruvat).

Muscle glycogen metabolism changes in rats fed early postnatal a fructose-rich diet after maternal protein malnutrition: effects of acute physical exercise at the maximal lactate steady-state intensity

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)

A 4-wk high-fructose diet alters lipid metabolism without affecting insulin sensitivity or ectopic lipids in healthy humans

BACKGROUND: High fructose consumption is suspected to be causally linked to the epidemics of obesity and metabolic disorders. In rodents, fructose leads to insulin resistance and ectopic lipid deposition. In humans, the effects of fructose on insulin sensitivity remain debated, whereas its effect on ectopic lipids has never been investigated. OBJECTIVE: We assessed the effect of moderate fructose supplementation on insulin sensitivity (IS) and ectopic lipids in healthy male volunteers (n = 7). DESIGN: IS, intrahepatocellular lipids (IHCL), and intramyocellular lipids (IMCL) were measured before and after 1 and 4 wk of a high-fructose diet containing 1.5 g fructose . kg body wt(-1) . d(-1). Adipose tissue IS was evaluated from nonesterified fatty acid suppression, hepatic IS from suppression of hepatic glucose output (6,6-2H2-glucose), and muscle IS from the whole-body glucose disposal rate during a 2-step hyperinsulinemic euglycemic clamp. IHCL and IMCL were measured by 1H magnetic resonance spectroscopy. RESULTS: Fructose caused significant (P < 0.05) increases in fasting plasma concentrations of triacylglycerol (36%), VLDL-triacylglycerol (72%), lactate (49%), glucose (5.5%), and leptin (48%) without any significant changes in body weight, IHCL, IMCL, or IS. IHCL were negatively correlated with triacylglycerol after 4 wk of the high-fructose diet (r = -0.78, P < 0.05). CONCLUSION: Moderate fructose supplementation over 4 wk increases plasma triacylglycerol and glucose concentrations without causing ectopic lipid deposition or insulin resistance in healthy humans.

Deep dermal burn injury results in scarless wound healing in the ovine fetus

Early to mid-term fetuses heal cutaneous incisional wounds without scars; however, fetal response to burn injury has not been ascertained. We present a fetal model of thermal injury and subsequent analysis of fetal and lamb response to burn injury. A reproducible deep dermal burn injury was created in the fetus by application of water at 66 degrees C for 7 seconds, and at 82 degrees C for 10 seconds to the lamb. Macroscopically, the area of fetal scald was undetectable from day 7 post injury, while all lamb scalds were readily identified and eventually healed with scarring. Using a five-point histopathology scoring system for alteration in tissue morphology, differences were detected between control and scalded skin at all stages in lamb postburn, but no difference was detected in the fetal model after day 7. There were also large differences in content of alpha-smooth muscle actin and transforming growth factor-beta1 between control and scalded lamb and these differences were statistically significant at day 14 (P < 0.01). This novel model of fetal and lamb response to deep dermal injury indicates that the fetus heals a deep burn injury in a scarless fashion. Further elucidation of this specific fetal process of burn injury repair may lead to improved outcome for patients with burn injury.

Low carbon fuels and commodity chemicals from waste gases – systematic approach to understand energy metabolism in a model acetogen

Gas fermentation using acetogenic bacteria offers a promising route for the sustainable production of low carbon fuels and commodity chemicals from abundant, inexpensive C1 feedstocks including industrial waste gases, syngas, reformed methane or methanol. Clostridium autoethanogenum is a model gas fermenting acetogen that produces fuel ethanol and 2,3-butanediol, a precursor for nylon and rubber. Acetogens have already been used in large scale industrial fermentations, they are ubiquitous and known to play a prominent role in the global carbon cycle. Still, they are considered to live on the thermodynamic edge of life and potential energy constraints when growing on C1 gases pose a major challange for the commercial production of fuels and chemicals. We have developed a systematic platform to investigate acetogenic energy metabolism, exemplified here by experiments contrasting heterotrophic and autotrophic metabolism. The platform is built from complete omics technologies, augmented with genetic tools and complemented by a manually curated genome-scale mathematical model. Together the tools enable the design and development of new, energy efficient pathways and strains for the production of chemicals and advanced fuels via C1 gas fermentation. As a proof-of-platform, we investigated heterotrophic growth on fructose versus autotrophic growth on gas that demonstrate the role of the Rnf complex and Nfn complex in maintaining growth using the Wood–Ljungdahl pathway. Pyruvate carboxykinase was found to control the rate-limiting step of gluconeogenesis and a new specialized glyceraldehyde-3-phosphate dehydrogenase was identified that potentially enhances anabolic capacity by reducing the amount of ATP consumed by gluconeogenesis. The results have been confirmed by the construction of mutant strains.

Fructose Chemistry

Fructose is a six-carbon ketose monosaccharide. In aqueous solution and in the crystalline form, the majority of the molecules form ring structures. Of these, the six-membered pyranose form is the most abundant; however, about one-quarter of the molecules are in the five-membered, furanose form. While many of its reactions are similar to those of glucose, the presence of a ketone group in the chain, and the relative ease with which the molecule forms a five-membered furanose ring affects its chemistry and biochemistry. Specific pathways are required to enable organisms to exploit fructose in energy metabolism; these require the enzyme fructokinase and involve the conversion of fructose to glycolytic intermediates. Similarly, specific pathways for the biosynthesis of fructose and fructose-containing polymers, such as inulin, are required. Non-enzymatic glycation (fructation) by fructose has not been as extensively studied as the corresponding reactions with glucose. Nevertheless, especially in diabetic patients and fructose-rich foodstuffs, this reaction is likely to be important.

In utero exposure to cigarette chemicals induces sex-specific disruption of one-carbon metabolism and DNA methylation in the human fetal liver

Background: Maternal smoking is one of the most important modifiable risk factors for low birthweight, which is strongly associated with increased cardiometabolic disease risk in adulthood. Maternal smoking reduces the levels of the methyl donor vitamin B12 and is associated with altered DNA methylation at birth. Altered DNA methylation may be an important mechanism underlying increased disease susceptibility; however, the extent to which this can be induced in the developing fetus is unknown.

Methods: In this retrospective study, we measured concentrations of cobalt, vitamin B12, and mRNA transcripts encoding key enzymes in the 1-carbon cycle in 55 fetal human livers obtained from 11 to 21 weeks of gestation elective terminations and matched for gestation and maternal smoking. DNA methylation was measured at critical regions known to be susceptible to the in utero environment. Homocysteine concentrations were analyzed in plasma from 60 fetuses.

Results: In addition to identifying baseline sex differences, we found that maternal smoking was associated with sex-specific alterations of fetal liver vitamin B12, plasma homocysteine and expression of enzymes in the 1-carbon cycle in fetal liver. In the majority of the measured parameters which showed a sex difference, maternal smoking reduced the magnitude of that difference. Maternal smoking also altered DNA methylation at the imprinted gene IGF2 and the glucocorticoid receptor (GR/NR3C1).

Conclusions: Our unique data strengthen studies linking in utero exposures to altered DNA methylation by showing, for the first time, that such changes are present in fetal life and in a key metabolic target tissue, human fetal liver. Furthermore, these data propose a novel mechanism by which such changes are induced, namely through alterations in methyl donor availability and changes in 1-carbon metabolism.