Sugar Making Sugar: Gluconeogenesis Triggered by Fructose via a Hypothalamic-Adrenal-Corticosterone Circuit

Extract

Investigations of interconnecting physiological pathways are complex and await our complete understanding. One such pathway is the cellular use of hexose sugars as fuel to generate energy in the form of ATP and reducing equivalents. The complex balance of enzymes and substrates involved in this process is highly regulated and poised to affect multiple pathways in a dizzying network of biochemical reactions when the equilibrium is disturbed (1, 2). Although our bodies are primed to use glucose, consuming fructose, a molecule almost identical to glucose, adds an additional level of complexity to the system (3). In the current issue of Endocrinology, the work of Kinote et al. (4) have added insight to the effects of fructose metabolism by understanding one circuit in its network of circuits; the involvement of corticosterone.

Increased consumption of fructose as a sweetener in the form of high-fructose corn syrup (HFCS) has made it to the headlines in recent years due to its apparent association with increased obesity and type 2 diabetes mellitus in the general population, but more so in the younger generation (2, 3, 5). Indeed, the war of words wages on our TV screens at home as to its benefits or its detriments. HFCS contains a mixture of the monosaccharides glucose and fructose, artificially generated from corn starch (6) to mimic the natural ratio of these molecules found in sucrose. Consumption of fructose at these high levels can trigger a cascade of events originating in the liver, which include lipogenesis and gluconeogenesis that lead to triglyceridemia, hepatic steatosis, and insulin resistance (5, 7–11).