Determining the contribution of a high-fructose corn syrup formulation to hepatic glycogen synthesis during ad-libitum feeding in mice
Excessive sugar intake including high-fructose corn syrup (HFCS) is implicated in the rise of obesity, insulin resistance and non-alcoholic fatty liver disease. Liver glycogen synthesis is influenced by both fructose and insulin signaling. Therefore, the effect of HFCS on hepatic glycogenesis was evaluated in mice feeding ad-libitum. Using deuterated water: the fraction of glycogen derived from triose-P sources, Krebs cycle substrates, and direct pathway + cycling, was measured in 9 normal-chow fed mice (NC) and 12 mice fed normal chow plus a 55% fructose/45% glucose mix in the drinking water at 30% w/v (HFCS-55). This was enriched with [U-13C]fructose or [U-13C]glucose to determine the contribution of each to glycogenesis. For NC, direct pathway + cycling, Krebs cycle, and triose-P sources accounted for 66 ± 0.7%, 23 ± 0.8% and 11 ± 0.4% of glycogen synthesis, respectively. HFCS-55 mice had similar direct pathway + cycling (64 ± 1%) but lower Krebs cycle (12 ± 1%, p < 0.001) and higher triose-P contributions (24 ± 1%, p < 0.001). HFCS-55-fructose contributed 17 ± 1% via triose-P and 2 ± 0% via Krebs cycle. HFCS-55-glucose contributed 16 ± 3% via direct pathway and 1 ± 0% via Krebs cycle. In conclusion, HFCS-55 supplementation resulted in similar hepatic glycogen deposition rates. Indirect pathway contributions shifted from Krebs cycle to Triose-P sources reflecting HFCS-55-fructose utilization, while HFCS-55-glucose was incorporated almost exclusively by the direct pathway. ; Te authors acknowledge fnancial support from the Portuguese Foundation for Science and Technology (Research Grant FCT-FEDER-02/SAICT/2017/028147). Structural funding for the Center for Neurosciences and Cell Biology and the UC-NMR facility is supported in part by FEDER—European Regional Development Fund through the COMPETE Programme, Centro 2020 Regional Operational Programme, and the Portuguese Foundation for Science and Technology through Grants UIDB/04539/2020; POCI-01-0145-FEDER-007440; REEQ/481/QUI/2006, RECI/QEQ-QFI/0168/2012, CENTRO-07-CT62-FEDER-002012, and Rede Nacional de Ressonancia Magnética Nuclear. GDB is supported by the European Union's Horizon 2020 Research and Innovation programme under the Marie Skłodowska-Curie Grant Agreement No. 722619 (Project FOIE GRAS). GDN and ANT are supported by Marie Skłodowska-Curie Grant Agreement No. 721236 (Project TREATMENT). ; Peer reviewed