Time Course of Molecular and Metabolic Events in the Development of Insulin Resistance in Fructose-Fed Rats.
We aimed to determine the time-course of metabolic changes related to the early onset of insulin resistance (IR), trying to evidence breaking points preceding the appearance of the clinical IR phenotype. The model chosen was the fructose (FRU)-fed rat compared to controls fed with starch. We focused on the hepatic metabolism after 0, 5, 12, 30, or 45 days of FRU intake. The hepatic molecular metabolic changes followed indeed a multistep trajectory rather than a continuous progression. After 5 d of FRU feeding, we observed deep modifications in the hepatic metabolism, driven by the induction of lipogenic genes and important glycogen depletion. Thereafter, a steady-state period between days 12 and 30 was observed, characterized by a switch from carbohydrate to lipid utilization at the hepatic level and increased insulin levels aiming at alleviating lipid accumulation and hyperglycemia, respectively. The FRU-fed animals were only clinically IR at day 45 (altered homeostasis model assessment-estimated insulin resistance and muscle glucose transport). Furthermore, the urine metabolome revealed even earlier metabolic trajectory changes that precede the hepatic alterations. We identified several candidate metabolites linked to the tryptophan-nicotinamide metabolism and the installation of fasting hyperglycemia that suggest a role of this metabolic pathway on the development of the IR phenotype in the FRU-fed rats.
Clermont Université , Université d'Auvergne, Unité de Nutrition Humaine, BP 10448, F-63000 Clermont-Ferrand, France.|INRA, UMR 1019, UNH, CRNH Auvergne , F-63000 Clermont-Ferrand, France.
Sergio
S
Polakof
Clermont Université , Université d'Auvergne, Unité de Nutrition Humaine, BP 10448, F-63000 Clermont-Ferrand, France.|INRA, UMR 1019, UNH, CRNH Auvergne , F-63000 Clermont-Ferrand, France.
Dominique
D
Dardevet
Clermont Université , Université d'Auvergne, Unité de Nutrition Humaine, BP 10448, F-63000 Clermont-Ferrand, France.|INRA, UMR 1019, UNH, CRNH Auvergne , F-63000 Clermont-Ferrand, France.|INRA, UMR 1019, Plateforme d'Exploration du Métabolisme, UNH , F-63000 Clermont-Ferrand, France.
Bernard
B
Lyan
Clermont Université , Université d'Auvergne, Unité de Nutrition Humaine, BP 10448, F-63000 Clermont-Ferrand, France.|INRA, UMR 1019, UNH, CRNH Auvergne , F-63000 Clermont-Ferrand, France.
Laurent
L
Mosoni
Clermont Université , Université d'Auvergne, Unité de Nutrition Humaine, BP 10448, F-63000 Clermont-Ferrand, France.|INRA, UMR 1019, UNH, CRNH Auvergne , F-63000 Clermont-Ferrand, France.
Eva
E
Gatineau
Clermont Université , Université d'Auvergne, Unité de Nutrition Humaine, BP 10448, F-63000 Clermont-Ferrand, France.|INRA, UMR 1019, UNH, CRNH Auvergne , F-63000 Clermont-Ferrand, France.|INRA, UMR 1019, Plateforme d'Exploration du Métabolisme, UNH , F-63000 Clermont-Ferrand, France.
Jean-François
JF
Martin
Clermont Université , Université d'Auvergne, Unité de Nutrition Humaine, BP 10448, F-63000 Clermont-Ferrand, France.|INRA, UMR 1019, UNH, CRNH Auvergne , F-63000 Clermont-Ferrand, France.|INRA, UMR 1019, Plateforme d'Exploration du Métabolisme, UNH , F-63000 Clermont-Ferrand, France.
Estelle
E
Pujos-Guillot
Clermont Université , Université d'Auvergne, Unité de Nutrition Humaine, BP 10448, F-63000 Clermont-Ferrand, France.|INRA, UMR 1019, UNH, CRNH Auvergne , F-63000 Clermont-Ferrand, France.
Andrzej
A
Mazur
Clermont Université , Université d'Auvergne, Unité de Nutrition Humaine, BP 10448, F-63000 Clermont-Ferrand, France.|INRA, UMR 1019, UNH, CRNH Auvergne , F-63000 Clermont-Ferrand, France.
Blandine
B
Comte
D000818:Animals; D050260:Carbohydrate Metabolism; D005632:Fructose / Q000008:administration & dosage / Q000494:pharmacology*; D006943:Hyperglycemia / Q000378:metabolism; D007333:Insulin Resistance; D050356:Lipid Metabolism; D008099:Liver / Q000378:metabolism; D008660:Metabolism; D055432:Metabolomics; D009536:Niacinamide / Q000378:metabolism; D051381:Rats; D013997:Time Factors; D014364:Tryptophan / Q000378:metabolism
D009536:Niacinamide; D005632:Fructose; D014364:Tryptophan
fructose; glucose and lipid metabolism; insulin resistance; liver; urine metabolomics