ChREBP regulates fructose-induced glucose production independently of insulin signaling
Mi-Sung Kim, … , Michelle Lai, Mark A. Herman
Mi-Sung Kim, … , Michelle Lai, Mark A. Herman
Published September 26, 2016
Citation Information: J Clin Invest. 2016;126(11):4372-4386. https://doi.org/10.1172/JCI81993.
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Research Article Endocrinology Metabolism

ChREBP regulates fructose-induced glucose production independently of insulin signaling

Abstract

Obese, insulin-resistant states are characterized by a paradoxical pathogenic condition in which the liver appears to be selectively insulin resistant. Specifically, insulin fails to suppress glucose production, yet successfully stimulates de novo lipogenesis. The mechanisms underlying this dysregulation remain controversial. Here, we hypothesized that carbohydrate-responsive element-binding protein (ChREBP), a transcriptional activator of glycolytic and lipogenic genes, plays a central role in this paradox. Administration of fructose increased hepatic hexose-phosphate levels, activated ChREBP, and caused glucose intolerance, hyperinsulinemia, hypertriglyceridemia, and hepatic steatosis in mice. Activation of ChREBP was required for the increased expression of glycolytic and lipogenic genes as well as glucose-6-phosphatase (G6pc) that was associated with the effects of fructose administration. We found that fructose-induced G6PC activity is a major determinant of hepatic glucose production and reduces hepatic glucose-6-phosphate levels to complete a homeostatic loop. Moreover, fructose activated ChREBP and induced G6pc in the absence of Foxo1a, indicating that carbohydrate-induced activation of ChREBP and G6PC dominates over the suppressive effects of insulin to enhance glucose production. This ChREBP/G6PC signaling axis is conserved in humans. Together, these findings support a carbohydrate-mediated, ChREBP-driven mechanism that contributes to hepatic insulin resistance.

Authors

Mi-Sung Kim, Sarah A. Krawczyk, Ludivine Doridot, Alan J. Fowler, Jennifer X. Wang, Sunia A. Trauger, Hye-Lim Noh, Hee Joon Kang, John K. Meissen, Matthew Blatnik, Jason K. Kim, Michelle Lai, Mark A. Herman

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Figure 11

Fructose activates ChREBP and induces G6PC and glycerol intolerance independently of FOXO1A.

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Fructose activates ChREBP and induces G6PC and glycerol intolerance inde...
Five-hour-fasted, 8- to 10-week-old CTL and Foxo1a-LKO mice were gavaged with water or fructose (4 g/kg body weight) and sacrificed 100 minutes later. (A–C) Hepatic gene expression was measured by qPCR (n = 3 or 4 per group). *P < 0.05 compared with water; #P < 0.05 compared with WT. Values are the mean ± SEM. (D) Weight gain of male CTL and Foxo1a-LKO mice fed chow versus HFrD for 4 weeks (n = 6–8/group). (E) Glucose tolerance test and (F) glycerol tolerance test. *P < 0.05 for chow vs. HFrD within genotype with area under the curve (AUC) for this cohort. †P < 0.05 main effect of HFrD; #P < 0.05 vs. chow-LKO. (G) Hepatic G6PC activity from ad libitum–fed mice. n = 3–6/group, *P < 0.05 within genotype versus chow. Values and bars are means ± SEM. All P values were obtained by 2-way ANOVA.