We thank Masotti (1) for his interest and comment in this issue of Diabetes on our recently published article (2). In his letter, Masotti proposed, on the basis of our study findings and those from his own laboratory, that the glycolytic/gluconeogenic pathways may play an integral role in body weight regulation.
Fructose-1,6-bisphosphate is not only the key substrate in gluconeogenesis for fructose-6-phosphate production but is also the substrate for the production of glyceraldehyde-3-phosphate and dihydroxyacetone phosphate via the enzyme aldolase A (ALDOA)—a glycolytic-pathway activated reaction. Masotti and colleagues (3) recently demonstrated that increased expression of microRNA-122 was associated with the development of nonalcoholic fatty liver disease in rats fed a high-fat diet or a high-fat and high-fructose diet for 3 months. The target genes of microRNA-122 included those involved in carbohydrate metabolism, among others, with ALDOA significantly elevated. This led the authors to postulate that increased glycolytic flux may be associated with the obesity seen in these rats. Since our study showed that pharmacologically inhibiting fructose-1,6-bisphosphatase (FBPase) led to an increase in body weight in both the FBPase transgenic and NZO mouse, glycolysis would be increased, which would support Masotti’s hypothesis of glycolysis being involved in body weight gain. Although this is an interesting concept there are some caveats in drawing these conclusions. Firstly, we have evidence to show that increasing gluconeogenesis through overexpression of one of the other three gluconeogenic enzymes, phosphoenolpyruvate carboxykinase, specifically in the kidney and liver of rats causes hepatic and peripheral insulin resistance, glucose intolerance, obesity, increased adiposity, and hyperphagia (4,5). This is in contrast to the FBPase transgenic mice, which demonstrate a lean phenotype associated with reduced adiposity and reduced food intake. These mice do not exhibit the classical perturbations in glucose metabolism as would be expected and in fact only present with increased glucose production from glycerol, which appears to serve the purpose of increasing the production of fructose-6-phosphate from fructose-1,6-bisphosphate to shunt through the hexosamine biosynthesis pathway. Moreover, in 2005 a study was published that reported reduced body weight in mice with increased liver glycolysis via adenoviral overexpression of either glucokinase or 6-phosphofructokinase-2/fructose-2,6-bisphosphatase (enzyme opposing FBPase) but were found to be modulated by different pathways (6).
While it may be attractive to speculate that the glycolytic/gluconeogenic pathways can alter body weight, the evidence demonstrates that it is the site at which these pathways are manipulated that gives rise to the different body weight patterns via activation of alternate downstream pathways. Consuming a high-fat diet leads to changes in many other metabolic pathways, as demonstrated by Masotti and colleagues (3), and it may be the interaction between these pathways that leads to obesity rather than an individual pathway. The bioinformatics finding that some liver miRNA-targeted genes (i.e., NTF3) are able to communicate with the hypothalamus to alter expression of appetite-regulating genes adds further support to our conclusion of a liver-brain axis and the importance of liver in regulating appetite and body weight. Additional investigation into this liver-brain communication will enhance our understanding into the intricacies behind body weight regulation.
ACKNOWLEDGMENTS
No potential conflicts of interest relevant to this article were reported.
