University of Massachusetts Medical School Faculty Publications
UMMS Affiliation
Program in Molecular Medicine; UMass Metabolic Network
Publication Date
2016-11-01
Document Type
Article
Disciplines
Cellular and Molecular Physiology | Endocrinology
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.
Rights and Permissions
Publisher PDF posted as allowed by the publisher's author rights policy at http://content-assets.jci.org/admin/forms/jcicopyright.pdf.
DOI of Published Version
10.1172/JCI81993
Source
J Clin Invest. 2016 Nov 1;126(11):4372-4386. doi: 10.1172/JCI81993. Epub 2016 Sep 26. Link to article on publisher's site.
Related Resources
Journal/Book/Conference Title
The Journal of clinical investigation
PubMed ID
27669460
Repository Citation
Kim, Mi-Sung; Krawczyk, Sarah A.; Doridot, Ludivine; Fowler, Alan J.; Wang, Jennifer X.; Trauger, Sunia A.; Noh, Hye Lim; Kang, Hee Joon; Meissen, John K.; Blatnik, Matthew; Kim, Jason K.; Lai, Michelle; and Herman, Mark A., "ChREBP Regulates Fructose-induced Glucose Production Independently of Insulin Signaling" (2016). University of Massachusetts Medical School Faculty Publications. 1045.
https://escholarship.umassmed.edu/faculty_pubs/1045