The metabolic complications of obesity are distributed throughout the body, yet studies assessing its impact on metabolic fluxes have primarily focused on single tissues. Here we use a 13C tracer approach to simultaneously quantify metabolic flux dysregulation in the liver, skeletal muscle, and heart induced by Western diet (WD) feeding in a mouse model of obesity. Male wildtype (WT) and Mc4r-/- mice (KO) were fed chow until 8wks of age, when ∼50% of the KO cohort transitioned to WD (KO+WD) for 8wks. KO and KO+WD had increased adiposity, hepatic steatosis, HOMA-IR, and reduced glucose tolerance relative to WT by 16wks of age; however, only KO+WD had extensive liver fibrosis. Stable- and radio-labeled isotopes were infused and blood was sampled from fasted, conscious, and unrestrained mice (n ≥ 6 per group) through jugular vein and carotid artery catheters, respectively. Metabolic fluxes were estimated by fitting an integrated mathematical model of liver, skeletal muscle, and cardiac metabolism to 13C enrichment measurements of plasma and tissue metabolites taken at the end of the infusion. Endogenous glucose production was elevated in both KO cohorts, with WD further increasing hepatic gluconeogenic and citric acid cycle (CAC) fluxes. Glycolytic, anaplerotic, and CAC fluxes were lower in the skeletal muscle of KO and KO+WD compared to WT, which coincided with a decrease and increase in gene expression of glycolytic and β-oxidation enzymes, respectively. In the heart, however, WD feeding increased glycolytic and CAC fluxes as well as the gene expression of glycolytic and β-oxidation enzymes. Thus, cardiac and skeletal muscles exhibit discordant flux adaptations in obese, WD-fed mice, as WD accelerates aerobic glycolysis and terminal oxidation in the heart but not skeletal muscle. We expect the multi-organ fluxomics platform described here to broadly benefit research to understand systemic metabolism in health and disease.
C.M.Hasenour: Employee; Eli Lilly and Company. M.Rahim: None. T.Bednarski: None. D.R.Banerjee: None. J.Young: Consultant; Pfizer Inc., Research Support; Merck & Co., Inc., Stock/Shareholder; Metalytics, Inc.
National Institutes of Health (R01DK106348, U01CA235508, T32DK101003)