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

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.

Challenging metabolic tissues with fructose: tissue‐specific and sex‐specific responses

“…Using the SGBS (Simpson–Golabi–Behmel syndrome, a congenital overgrowth syndrome) human preadipocyte cell line, Varma et al . (, b ) recently performed a series of detailed metabolic studies examining the influence of fructose on intermediary carbohydrate metabolism. Making use of stable isotope tracers, they were able to trace the fate of fructose within SGBS cells.…”

Oral dextrose reduced procedural pain without altering cellular ATP metabolism in preterm neonates: a prospective randomized trial

“…More recently, the effect of fructose on glucose metabolism was investigated in adipocytes from human Simpson-Golabi-Behmel syndrome [23]. In the presence of 5 mM glucose representing normal blood glucose concentration, fructose was shown to divert glucose metabolism away from glycolysis and oxidative phosphorylation, reducing ATP synthesis [23]. Glucose metabolism was also shown to be diverted away from glycogenesis, gluconeogenesis, ribose-phosphate synthesis, and nucleotide synthesis [23].…”

“…In the presence of 5 mM glucose representing normal blood glucose concentration, fructose was shown to divert glucose metabolism away from glycolysis and oxidative phosphorylation, reducing ATP synthesis [23]. Glucose metabolism was also shown to be diverted away from glycogenesis, gluconeogenesis, ribose-phosphate synthesis, and nucleotide synthesis [23]. Instead, glucose was metabolized to lactate and diverted to serine oxidation glycine cleavage pathway (SOGC), a pathway utilized for lipogenesis and storage [23].…”

“…Glucose metabolism was also shown to be diverted away from glycogenesis, gluconeogenesis, ribose-phosphate synthesis, and nucleotide synthesis [23]. Instead, glucose was metabolized to lactate and diverted to serine oxidation glycine cleavage pathway (SOGC), a pathway utilized for lipogenesis and storage [23]. The diversion of glucose to the SOGC pathway resulted in lower ATP synthesis due to diminished mitochondrial energy metabolism [23].…”

“…Instead, glucose was metabolized to lactate and diverted to serine oxidation glycine cleavage pathway (SOGC), a pathway utilized for lipogenesis and storage [23]. The diversion of glucose to the SOGC pathway resulted in lower ATP synthesis due to diminished mitochondrial energy metabolism [23]. It will be important to determine if this effect occurs in other cell types since fructose is also taken up and metabolized by skeletal muscle cells and renal cortical cells [24][25][26].…”