Roles for fructose-2,6-bisphosphate in the control of fuel metabolism: Beyond its allosteric effects on glycolytic and gluconeogenic enzymes

Fructose-2,6-bisphosphate (F26P₂) was identified as a regulator of glucose metabolism over 25 years ago. A truly bifunctional enzyme, 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase (6PFK2/FBP2), with two active sites synthesizes F26P₂ from fructose-6-phosphate (F6P) and ATP or degrades F26P₂ to F6P and P_i. In the classic view, F26P₂ regulates glucose metabolism by allosteric effects on 6-phosphofructo-1-kinase (6PFK1, activation) and fructose-1,6-bisphosphatase (FBPase, inhibition). When levels of F26P₂ are high, glycolysis is enhanced and gluconeogenesis is inhibited. In this regard, altering levels of F26P₂ via 6PFK2/FBP2 overexpression has been used for metabolic modulation, and has been shown capable of restoring euglycemia in rodent models of diabetes. Recently, a number of novel observations have suggested that F26P₂ has much broader effects on the enzymes of glucose metabolism. This is evidenced by the effects of F26P₂ on the gene expression of two key glucose metabolic enzymes, glucokinase (GK) and glucose-6-phosphatase (G6Pase). When levels of F26P₂ are elevated in the liver, the gene expression and protein amount of GK is increased whereas G6Pase is decreased. These coordinated changes in GK and G6Pase protein illustrate how F26P₂ regulates glucose metabolism. F26P₂ also affects the gene expression of enzymes related to lipid metabolism. When F26P₂ levels are elevated in liver, the expression of two key lipogenic enzymes, acetyl-CoA carboxylase 1 (ACC1) and fatty acid synthase (FAS) is reduced, contributing to a unique coordinated decrease in lipogenesis. When combined, F26P₂ effects on glucose and lipid metabolism provide cooperative regulation of fuel metabolism. The regulatory roles for F26P₂ have also expanded to transcription factors, as well as certain key proteins (enzymes) of signaling and/or energy sensoring. Although some effects may be secondary to changes in metabolite levels, high levels of F26P₂ have been shown to regulate protein amount and/or phosphorylation state of hepatic nuclear factor 1-α (HNF1α), carbohydrate response element binding protein (ChREBP), peroxisome proliferators-activated receptor α (PPARα), and peroxisome proliferators-activated receptor γ co-activator 1β (PGC1β), as well as Akt and AMP-activated protein kinase (AMPK). Importantly, changes in these transcription factors, signaling proteins, and sensor proteins are produced in a way that appropriately coordinates whole body fuel metabolism.