Figure 3.

Selective dietary nutrient uptake and increased production of glycerol and succinate elicited by WD across all context-specific hepatic models in this study

(A) Schematic illustrating relation between input and output carbon fluxes in the context of flux balance analysis (FBA) experiments shown in panels B, E, F and Figure S3. C_moles^DIET represents the carbon flux for each metabolite that is available from the diet to [MMRN^Hep] and was calculated based on the known diet composition and daily diet consumption per mouse (Tables S1and S6 and Figure S1A). The dashed line represents a computational pseudo-boundary set to allow influx of metabolites from the diet into the extracellular space of the model. For a given metabolite, C_moles^INFLUX and C_moles^EFFLUX denote the flux of carbons of this metabolite taken up or produced, respectively, by [MMRN^Hep].

(B) C_moles^DIET values of each of the major dietary nutrient classes (carbohydrates, lipids and amino acids) in CD and WD. Corresponding values of individual nutrient components is shown in Figure S3A. C_moles^INFLUX and C_moles^EFFLUX for [MMRN^Hep] and csGSMMs models provided with either CD or WD.

(C) Amounts of glycerol in DEN^PT and DEN^T tissues from mice fed WD compared to respective tissues from CD-fed mice measured by GC-MS. Data are represented as mean ± SD. Numbers above bars indicate p values determined by a two-tailed Mann-Whitney test (n = 5–15 mice).

(D) Amounts of succinate in DEN^PT and DEN^T tissues from mice fed WD compared to respective tissues from CD-fed mice measured by GC-MS. Data are represented as mean ± SD. Numbers above bars indicate p values determined by a two-tailed Mann-Whitney test (n = 5–15 mice).

(E) Systematic Diet Component Swap (SyDiCoS) to assess the role of WD components on glycerol and succinate production flux in csGSMMs. C_moles^DIET values for all three major diet component classes (carbohydrates, lipids and amino acids) in the WD were swapped individually or in combination with the corresponding C_moles^DIET values in CD while leaving the remaining dietary C_moles^DIET values of the WD unaltered. The swapped component(s) are indicated by black dots on the left. The color scale represents the ratio of glycerol production flux or succinate production flux in models provided with the swapped diet relative to the respective fluxes in models provided with WD, calculated for each csGSMM shown at the bottom of panel (F).

(F) Assessment of the role of glucose or fructose from WD on glycerol and succinate production. csGSMMs shown at the bottom were provided WD containing only glucose or fructose (using their respective C_moles^DIET values found in WD) as indicated by the black dots on the left, or both sugars (equivalent to the original WD composition) while leaving the C_moles^DIET values for lipids and amino acids in WD unaltered. The color scale represents the ratio of glycerol production flux or succinate production flux in models provided with the modified WD inputs relative to the respective fluxes in models using the original WD composition, calculated for each csGSMM shown at the bottom.

(G) Metabolic pathways that lead to increased production of glycerol and succinate in WD from fructose and FAs, respectively, derived from inspection of the flux distributions of csGMMS under various SyDiCoS conditions (panels E, F and Table S7). FAs: fatty acids; 3 PG: 3-phosphyglycerate; Pyr: pyruvate; F1P: fructose 1-phosphate; GA: glyceraldehyde; αKG: α-ketoglutarate; OAA: oxaloacetate.