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Fructose Alters Intermediary Metabolism of Glucose in Human Adipocytes and Diverts Glucose to Serine Oxidation in the One-Carbon Cycle Energy Producing Pathway.

Varma V, Boros LG, Nolen GT, Chang CW, Wabitsch M, Beger RD, Kaput J - Metabolites (2015)

Bottom Line: However, glucose-derived 13CO2 negatively correlated with 13C labeled glutamate, 13C palmitate, and M+1 labeled lactate.Contrarily, a positive correlation was observed between glucose-derived 13CO2 formed and 13C oleate and doses of fructose which indicate the elongation and desaturation of palmitate to oleate for storage.Collectively, these results suggest that fructose preferentially drives glucose through serine oxidation glycine cleavage (SOGC pathway) one-carbon cycle for NAD+/NADP+ production that is utilized in fructose-induced lipogenesis and storage in adipocytes.

View Article: PubMed Central - PubMed

Affiliation: Biomarkers and Alternate Models branch, Division of Systems Biology, National Center for Toxicological Research, Jefferson, AR 72079, USA. vijayalakshmi.varma@fda.hhs.gov.

ABSTRACT
Increased consumption of sugar and fructose as sweeteners has resulted in the utilization of fructose as an alternative metabolic fuel that may compete with glucose and alter its metabolism. To explore this, human Simpson-Golabi-Behmel Syndrome (SGBS) preadipocytes were differentiated to adipocytes in the presence of 0, 1, 2.5, 5 or 10 mM of fructose added to a medium containing 5 mM of glucose representing the normal blood glucose concentration. Targeted tracer [1,2-13C2]-d-glucose fate association approach was employed to examine the influence of fructose on the intermediary metabolism of glucose. Increasing concentrations of fructose robustly increased the oxidation of [1,2-13C2]-d-glucose to 13CO2 (p < 0.000001). However, glucose-derived 13CO2 negatively correlated with 13C labeled glutamate, 13C palmitate, and M+1 labeled lactate. These are strong markers of limited tricarboxylic acid (TCA) cycle, fatty acid synthesis, pentose cycle fluxes, substrate turnover and NAD+/NADP+ or ATP production from glucose via complete oxidation, indicating diminished mitochondrial energy metabolism. Contrarily, a positive correlation was observed between glucose-derived 13CO2 formed and 13C oleate and doses of fructose which indicate the elongation and desaturation of palmitate to oleate for storage. Collectively, these results suggest that fructose preferentially drives glucose through serine oxidation glycine cleavage (SOGC pathway) one-carbon cycle for NAD+/NADP+ production that is utilized in fructose-induced lipogenesis and storage in adipocytes.

No MeSH data available.


Related in: MedlinePlus

Schematic of the flow of glucose carbons in the presence of added fructose in adipocytes. The red arrows indicate pathways with increased flow of glucose carbons and the green arrows indicate pathways where the flow of glucose carbons are decreased or not significantly altered. PC, pyruvate carboxylase; PDH, pyruvate Dehydrogenase; OAA, oxaloacetate; THF, tetrahydrofolate; SHMT2, serine hydroxymethyltransferase (mitochondria); CH2-THF, Methyltetrahydrofolate; CH+-THF, 5, 10-methenyl THF; MTHFD2L, methylenetetrahydrofolate dehydrogenase (NADP, mitochondria); MTHFD2, methylenetetrahydrofolate dehydrogenase (NAD) methenyl tetrahydrofolate cyclohydrolase (mitochondria); CHO-THF, 10-formyl THF; MTHFD1L, formyltetrahydrofolate synthetase (mitochondria); MFT, mitochondrial folate transporter (SLC25A32); FOR, formate; MTHFD1, methylenetetrahydrofolate dehydrogenase (NADP) methenyl tetrahydrofolate cyclohydrolase, formyltetrahydrofolate synthetase (cytosol); MTHFD1L, formyltetrahydrofolate synthetase (mitochondria); SHMT1, serine hydroxymethyltransferase (cytosol); NNT, nicotinamide nucleotide transhydrogenase. P-(Glycine cleavage system protein P (glycine dehydrogenase (decarboxylating)); L—Glycine cleavage system protein L (dihydrolipoamide dehydrogenase); T—Glycine cleavage system protein (aminomethyltransferase). The SOGC pathway portion in the figure has been adapted from [28]. This figure does not reflect equilibrium or steady state distributions. It only shows glucose flux relationships by surrogates based on isotopic labeling.
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metabolites-05-00364-f005: Schematic of the flow of glucose carbons in the presence of added fructose in adipocytes. The red arrows indicate pathways with increased flow of glucose carbons and the green arrows indicate pathways where the flow of glucose carbons are decreased or not significantly altered. PC, pyruvate carboxylase; PDH, pyruvate Dehydrogenase; OAA, oxaloacetate; THF, tetrahydrofolate; SHMT2, serine hydroxymethyltransferase (mitochondria); CH2-THF, Methyltetrahydrofolate; CH+-THF, 5, 10-methenyl THF; MTHFD2L, methylenetetrahydrofolate dehydrogenase (NADP, mitochondria); MTHFD2, methylenetetrahydrofolate dehydrogenase (NAD) methenyl tetrahydrofolate cyclohydrolase (mitochondria); CHO-THF, 10-formyl THF; MTHFD1L, formyltetrahydrofolate synthetase (mitochondria); MFT, mitochondrial folate transporter (SLC25A32); FOR, formate; MTHFD1, methylenetetrahydrofolate dehydrogenase (NADP) methenyl tetrahydrofolate cyclohydrolase, formyltetrahydrofolate synthetase (cytosol); MTHFD1L, formyltetrahydrofolate synthetase (mitochondria); SHMT1, serine hydroxymethyltransferase (cytosol); NNT, nicotinamide nucleotide transhydrogenase. P-(Glycine cleavage system protein P (glycine dehydrogenase (decarboxylating)); L—Glycine cleavage system protein L (dihydrolipoamide dehydrogenase); T—Glycine cleavage system protein (aminomethyltransferase). The SOGC pathway portion in the figure has been adapted from [28]. This figure does not reflect equilibrium or steady state distributions. It only shows glucose flux relationships by surrogates based on isotopic labeling.

Mentions: An alternate fate of pyruvate formed from glucose is the conversion of pyruvate to lactate [42]. Lactate production by adipose tissue is dependent on the nutritional state and availability of the precursor glucose [46]. Glucose can be metabolized to lactate in adipose tissue which can provide lactate for hepatic glycogen synthesis. The glucose to lactate conversion can occur to a markedly higher extent in diabetic and obese states [47]. The study reported here revealed that fructose robustly triggered the conversion of glucose to lactate at concentrations of 5 mM and higher resulting in the increased release of lactate from these adipocytes. Although 5 mM of fructose affected glucose to lactate labeling (Figure 3A) and glycogen labeling (Figure 3B), it affected RNA labeling in a non-dose responsive manner. These changes are consistent with molecular crowding stimulated by increasing concentrations of fructose. Specifically, fructose diverted glucose from usual pathways of glucose disposition including fatty acid synthesis, oxidative decarboxylation, or from being deposited into glycogen, and from the cellular pentose to being disposed as lactate. Such responses are consistent with a large and rapid switch as described previously for crowded systems using 1,2 13C2-d-glucose as the single tracer [48]. The other fates of glucose-6 phosphate include its conversion to glycogen via glycogen synthesis or its shunting into the pentose phosphate pathway resulting in the production of ribose for nucleotide synthesis. Although adipocytes are primarily the site for lipid storage and contain glycogen only in small amounts, this pathway has been demonstrated in adipocytes although at low levels compared to the liver and skeletal muscle [49,50]. Glycogen is thought to operate in the transition from the fasted to fed state by coordinating glucose and lipid metabolism in adipocytes [27]. Increased glycogen resulting from refeeding may provide a cue to stop lipolysis that is normally active during conditions of fasting and to enable the adipocyte to metabolically reset prior to shifting back to triglyceride synthesis. The increasing concentrations of fructose, which parallels a fed state, dramatically decreased the conversion of glucose to glycogen at all concentrations of fructose. The minor small decreased amount of glucose–derived ribose observed at different concentrations of fructose is consistent with the fact that ribose is not needed in high concentrations in differentiated adipocytes. These data were consistent with the flux of glucose to the SOGC pathway for oxidation in the presence of fructose (Figure 5).


Fructose Alters Intermediary Metabolism of Glucose in Human Adipocytes and Diverts Glucose to Serine Oxidation in the One-Carbon Cycle Energy Producing Pathway.

Varma V, Boros LG, Nolen GT, Chang CW, Wabitsch M, Beger RD, Kaput J - Metabolites (2015)

Schematic of the flow of glucose carbons in the presence of added fructose in adipocytes. The red arrows indicate pathways with increased flow of glucose carbons and the green arrows indicate pathways where the flow of glucose carbons are decreased or not significantly altered. PC, pyruvate carboxylase; PDH, pyruvate Dehydrogenase; OAA, oxaloacetate; THF, tetrahydrofolate; SHMT2, serine hydroxymethyltransferase (mitochondria); CH2-THF, Methyltetrahydrofolate; CH+-THF, 5, 10-methenyl THF; MTHFD2L, methylenetetrahydrofolate dehydrogenase (NADP, mitochondria); MTHFD2, methylenetetrahydrofolate dehydrogenase (NAD) methenyl tetrahydrofolate cyclohydrolase (mitochondria); CHO-THF, 10-formyl THF; MTHFD1L, formyltetrahydrofolate synthetase (mitochondria); MFT, mitochondrial folate transporter (SLC25A32); FOR, formate; MTHFD1, methylenetetrahydrofolate dehydrogenase (NADP) methenyl tetrahydrofolate cyclohydrolase, formyltetrahydrofolate synthetase (cytosol); MTHFD1L, formyltetrahydrofolate synthetase (mitochondria); SHMT1, serine hydroxymethyltransferase (cytosol); NNT, nicotinamide nucleotide transhydrogenase. P-(Glycine cleavage system protein P (glycine dehydrogenase (decarboxylating)); L—Glycine cleavage system protein L (dihydrolipoamide dehydrogenase); T—Glycine cleavage system protein (aminomethyltransferase). The SOGC pathway portion in the figure has been adapted from [28]. This figure does not reflect equilibrium or steady state distributions. It only shows glucose flux relationships by surrogates based on isotopic labeling.
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metabolites-05-00364-f005: Schematic of the flow of glucose carbons in the presence of added fructose in adipocytes. The red arrows indicate pathways with increased flow of glucose carbons and the green arrows indicate pathways where the flow of glucose carbons are decreased or not significantly altered. PC, pyruvate carboxylase; PDH, pyruvate Dehydrogenase; OAA, oxaloacetate; THF, tetrahydrofolate; SHMT2, serine hydroxymethyltransferase (mitochondria); CH2-THF, Methyltetrahydrofolate; CH+-THF, 5, 10-methenyl THF; MTHFD2L, methylenetetrahydrofolate dehydrogenase (NADP, mitochondria); MTHFD2, methylenetetrahydrofolate dehydrogenase (NAD) methenyl tetrahydrofolate cyclohydrolase (mitochondria); CHO-THF, 10-formyl THF; MTHFD1L, formyltetrahydrofolate synthetase (mitochondria); MFT, mitochondrial folate transporter (SLC25A32); FOR, formate; MTHFD1, methylenetetrahydrofolate dehydrogenase (NADP) methenyl tetrahydrofolate cyclohydrolase, formyltetrahydrofolate synthetase (cytosol); MTHFD1L, formyltetrahydrofolate synthetase (mitochondria); SHMT1, serine hydroxymethyltransferase (cytosol); NNT, nicotinamide nucleotide transhydrogenase. P-(Glycine cleavage system protein P (glycine dehydrogenase (decarboxylating)); L—Glycine cleavage system protein L (dihydrolipoamide dehydrogenase); T—Glycine cleavage system protein (aminomethyltransferase). The SOGC pathway portion in the figure has been adapted from [28]. This figure does not reflect equilibrium or steady state distributions. It only shows glucose flux relationships by surrogates based on isotopic labeling.
Mentions: An alternate fate of pyruvate formed from glucose is the conversion of pyruvate to lactate [42]. Lactate production by adipose tissue is dependent on the nutritional state and availability of the precursor glucose [46]. Glucose can be metabolized to lactate in adipose tissue which can provide lactate for hepatic glycogen synthesis. The glucose to lactate conversion can occur to a markedly higher extent in diabetic and obese states [47]. The study reported here revealed that fructose robustly triggered the conversion of glucose to lactate at concentrations of 5 mM and higher resulting in the increased release of lactate from these adipocytes. Although 5 mM of fructose affected glucose to lactate labeling (Figure 3A) and glycogen labeling (Figure 3B), it affected RNA labeling in a non-dose responsive manner. These changes are consistent with molecular crowding stimulated by increasing concentrations of fructose. Specifically, fructose diverted glucose from usual pathways of glucose disposition including fatty acid synthesis, oxidative decarboxylation, or from being deposited into glycogen, and from the cellular pentose to being disposed as lactate. Such responses are consistent with a large and rapid switch as described previously for crowded systems using 1,2 13C2-d-glucose as the single tracer [48]. The other fates of glucose-6 phosphate include its conversion to glycogen via glycogen synthesis or its shunting into the pentose phosphate pathway resulting in the production of ribose for nucleotide synthesis. Although adipocytes are primarily the site for lipid storage and contain glycogen only in small amounts, this pathway has been demonstrated in adipocytes although at low levels compared to the liver and skeletal muscle [49,50]. Glycogen is thought to operate in the transition from the fasted to fed state by coordinating glucose and lipid metabolism in adipocytes [27]. Increased glycogen resulting from refeeding may provide a cue to stop lipolysis that is normally active during conditions of fasting and to enable the adipocyte to metabolically reset prior to shifting back to triglyceride synthesis. The increasing concentrations of fructose, which parallels a fed state, dramatically decreased the conversion of glucose to glycogen at all concentrations of fructose. The minor small decreased amount of glucose–derived ribose observed at different concentrations of fructose is consistent with the fact that ribose is not needed in high concentrations in differentiated adipocytes. These data were consistent with the flux of glucose to the SOGC pathway for oxidation in the presence of fructose (Figure 5).

Bottom Line: However, glucose-derived 13CO2 negatively correlated with 13C labeled glutamate, 13C palmitate, and M+1 labeled lactate.Contrarily, a positive correlation was observed between glucose-derived 13CO2 formed and 13C oleate and doses of fructose which indicate the elongation and desaturation of palmitate to oleate for storage.Collectively, these results suggest that fructose preferentially drives glucose through serine oxidation glycine cleavage (SOGC pathway) one-carbon cycle for NAD+/NADP+ production that is utilized in fructose-induced lipogenesis and storage in adipocytes.

View Article: PubMed Central - PubMed

Affiliation: Biomarkers and Alternate Models branch, Division of Systems Biology, National Center for Toxicological Research, Jefferson, AR 72079, USA. vijayalakshmi.varma@fda.hhs.gov.

ABSTRACT
Increased consumption of sugar and fructose as sweeteners has resulted in the utilization of fructose as an alternative metabolic fuel that may compete with glucose and alter its metabolism. To explore this, human Simpson-Golabi-Behmel Syndrome (SGBS) preadipocytes were differentiated to adipocytes in the presence of 0, 1, 2.5, 5 or 10 mM of fructose added to a medium containing 5 mM of glucose representing the normal blood glucose concentration. Targeted tracer [1,2-13C2]-d-glucose fate association approach was employed to examine the influence of fructose on the intermediary metabolism of glucose. Increasing concentrations of fructose robustly increased the oxidation of [1,2-13C2]-d-glucose to 13CO2 (p < 0.000001). However, glucose-derived 13CO2 negatively correlated with 13C labeled glutamate, 13C palmitate, and M+1 labeled lactate. These are strong markers of limited tricarboxylic acid (TCA) cycle, fatty acid synthesis, pentose cycle fluxes, substrate turnover and NAD+/NADP+ or ATP production from glucose via complete oxidation, indicating diminished mitochondrial energy metabolism. Contrarily, a positive correlation was observed between glucose-derived 13CO2 formed and 13C oleate and doses of fructose which indicate the elongation and desaturation of palmitate to oleate for storage. Collectively, these results suggest that fructose preferentially drives glucose through serine oxidation glycine cleavage (SOGC pathway) one-carbon cycle for NAD+/NADP+ production that is utilized in fructose-induced lipogenesis and storage in adipocytes.

No MeSH data available.


Related in: MedlinePlus