Journal article
Divergent effects of glucose and fructose on hepatic lipogenesis and insulin signaling
The Journal of clinical investigation, Vol.127(11), pp.4059-4074
11/01/2017
DOI: 10.1172/JCI94585
PMCID: PMC5663363
PMID: 28972537
Abstract
Overconsumption of high-fat diet (HFD) and sugar-sweetened beverages are risk factors for developing obesity, insulin resistance, and fatty liver disease. Here we have dissected mechanisms underlying this association using mice fed either chow or HFD with or without fructose- or glucose-supplemented water. In chow-fed mice, there was no major physiological difference between fructose and glucose supplementation. On the other hand, mice on HFD supplemented with fructose developed more pronounced obesity, glucose intolerance, and hepatomegaly as compared to glucose-supplemented HFD mice, despite similar caloric intake. Fructose and glucose supplementation also had distinct effects on expression of the lipogenic transcription factors ChREBP and SREBP1c. While both sugars increased ChREBP-β, fructose supplementation uniquely increased SREBP1c and downstream fatty acid synthesis genes, resulting in reduced liver insulin signaling. In contrast, glucose enhanced total ChREBP expression and triglyceride synthesis but was associated with improved hepatic insulin signaling. Metabolomic and RNA sequence analysis confirmed dichotomous effects of fructose and glucose supplementation on liver metabolism in spite of inducing similar hepatic lipid accumulation. Ketohexokinase, the first enzyme of fructose metabolism, was increased in fructose-fed mice and in obese humans with steatohepatitis. Knockdown of ketohexokinase in liver improved hepatic steatosis and glucose tolerance in fructose-supplemented mice. Thus, fructose is a component of dietary sugar that is distinctively associated with poor metabolic outcomes, whereas increased glucose intake may be protective.
Details
- Title: Subtitle
- Divergent effects of glucose and fructose on hepatic lipogenesis and insulin signaling
- Creators
- Samir Softic - Boston Children's HospitalManoj K Gupta - Joslin Diabetes CenterGuo-Xiao Wang - Joslin Diabetes CenterShiho Fujisaka - Joslin Diabetes CenterBrian T O'Neill - University of IowaTata Nageswara Rao - University Hospital of BaselJennifer Willoughby - Alnylam PharmaceuticalsCarole Harbison - Alnylam PharmaceuticalsKevin Fitzgerald - Alnylam PharmaceuticalsOlga Ilkayeva - Duke UniversityChristopher B Newgard - Duke UniversityDavid E Cohen - Cornell UniversityC Ronald Kahn - Joslin Diabetes Center
- Resource Type
- Journal article
- Publication Details
- The Journal of clinical investigation, Vol.127(11), pp.4059-4074
- DOI
- 10.1172/JCI94585
- PMID
- 28972537
- PMCID
- PMC5663363
- ISSN
- 0021-9738
- eISSN
- 1558-8238
- Grant note
- R01 DK048873 / NIDDK NIH HHS R01 DK031036 / NIDDK NIH HHS P30 DK036836 / NIDDK NIH HHS R01 DK033201 / NIDDK NIH HHS P30 DK034854 / NIDDK NIH HHS K08 DK100543 / NIDDK NIH HHS R01 DK103046 / NIDDK NIH HHS R37 DK048873 / NIDDK NIH HHS R01 DK056626 / NIDDK NIH HHS R37 DK031036 / NIDDK NIH HHS K12 HD000850 / NICHD NIH HHS
- Language
- English
- Date published
- 11/01/2017
- Academic Unit
- Endocrinology and Metabolism; Internal Medicine
- Record Identifier
- 9984360146402771
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