Fructose 1-phosphate, an evolutionary signaling molecule of abundancy

Evidence is accumulating that specifically fructose exerts adverse cardiometabolic effects in humans. Recent experimental studies have shown that fructose not only serves as a substrate for, among others, intrahepatic lipid formation, but also has a signaling function. It is postulated that fructose 1-phosphate (F1-P) has evolved as a signaling molecule of abundancy that stimulates nutrient absorption, lipid storage, and reproduction. Such a role would provide an explanation for why fructose contributes to the pathogenesis of evolutionary mismatch diseases, including nonalcoholic fatty liver disease (NAFLD), cardiovascular disease, polycystic ovary syndrome (PCOS), and colorectal cancer, in the current era of nutritional abundance. It is anticipated that reducing F1-P, by either pharmacological inhibition of ketohexokinase (KHK) or societal measures, will mitigate the risk of these diseases.