Editor, Cell Metabolism
RE: The role of peroxisome proliferator-activated receptor gamma coactivator-1 beta in the pathogenesis of fructose-induced insulin resistance.
Editor:
Perspective is lacking in the recent paper by Nagai et al. (2009), in which the authors propose PGC-1beta knockdown as a novel therapeutic treatment, having demonstrated that it prevents hypertriglyceridemia and hepatic/peripheral insulin resistance associated with increased de novo lipogenesis induced by high-fructose diets in the rat.
One justification for this study is the unsubstantiated presumption that dietary fructose overexposure is an important cause of obesity. The authors depict a narrow and distorted view, however, by presenting data on fructose intake only in isolation from other macronutrient intake trends. An examination of USDA-ERS loss-adjusted food availability data reveals that added sweeteners as a percentage of total calories – including fructose from sucrose, HFCS, honey and fruit juice concentrates – increased at the same rate as total calories (+23% vs +24%) over the past 35 years; total fats and cereals increased at a faster rate (+29% and +27%, respectively) (White, 2008). Since fats are more calorific than carbohydrates (9 vs 4 kcal/g), fats added more than 6-times the calories to the diet than did added sugars over this time period.
A second justification is the purported link between high-fructose diets and hypertriglyceridemia, nonalcoholic fatty liver disease, insulin resistance and increased hepatic lipogenesis. The authors again fail to add the much-needed perspective that the overwhelming majority of cited studies, whether in humans or animals, used highly artificial dietary constructs at unphysiologic levels that do not model real world human diets. Marriott recently estimated mean total fructose intake as a percent of energy at 9.1% (Marriott et al., 2009). The predominance of published human and animal metabolic studies test 15-30% and 60-65% fructose as a percent of energy, respectively, in the absence of glucose. Nagai’s own experimental protocol compared 66.8% of calories from fructose to glucose from starch. Since the fructose:glucose ratio in the human diet is estimated at 0.79 (Forshee et al., 2007), these experimental designs clearly exaggerate fructose exposures and do not properly simulate the half fructose-half glucose composition of contemporary caloric sweeteners (sucrose, HFCS, honey and fruit juice concentrates). Extrapolation of such experimental outcomes to human metabolic consequences is highly speculative and clearly inappropriate.
Significant metabolic perturbations have yet to be demonstrated in the typical human diet, characterized by moderate fructose levels in the presence of abundant glucose. Thus, the novel therapeutic approach of Nagai et al. is of dubious significance, given the lack of evidence that this is a valid medical concern.
References
- Forshee, R.A., Storey, M.L., Allison, D.B., Glinsmann, W.H., Hein, G.L., Lineback, D.R., Miller, S.A., Nicklas, T.A., Weaver, G.A., and White, J.S. (2007). A critical examination of the evidence relating high fructose corn syrup and weight gain. Crit Rev Food Sci Nutr 47, 561-582.
- Marriott, B.P., Cole, N., and Lee, E. (2009). National estimates of dietary fructose intake increased from 1977 to 2004 in the United States. J Nutr 139, 1228S-1235S.
- Nagai, Y., Yonemitsu, S., Erion, D.M., Iwasaki, T., Stark, R., Weismann, D., Dong, J., Zhang, D., Jurczak, M.J., Loffler, M.G., Cresswell, J., Yu, X.X., Murray, S.F., Bhanot, S., Monia, B.P., Bogan, J.S., Samuel, V., and Shulman, G.I. (2009). The role of peroxisome proliferator-activated receptor gamma coactivator-1 beta in the pathogenesis of fructose-induced insulin resistance. Cell Metab 9, 252-264.
- White, J.S. (2008). Straight talk about high-fructose corn syrup: what it is and what it ain’t. Am J Clin Nutr 88, 1716S-1721S.