Roles of Fatty Acid oversupply and impaired oxidation in lipid accumulation in tissues of obese rats

Abstract

To test the roles of lipid oversupply versus oxidation in causing tissue lipid accumulation associated with insulin resistance/obesity, we studied in vivo fatty acid (FA) metabolism in obese (Obese) and lean (Lean) Zucker rats. Indices of local FA utilization and storage were calculated using the partially metabolizable [9,10-(3)H]-(R)-2-bromopalmitate ((3)H-R-BrP) and [U-(14)C]-palmitate ((14)C-P) FA tracers, respectively. Whole-body FA appearance (R a ) was estimated from plasma (14)C-P kinetics. Whole-body FA oxidation rate (R ox) was assessed using (3)H2O production from (3)H-palmitate infusion, and tissue FA oxidative capacity was evaluated ex vivo. In the basal fasting state Obese had markedly elevated FA levels and R a , associated with elevated FA utilization and storage in most tissues. Estimated rates of muscle FA oxidation were not lower in obese rats and were similarly enhanced by contraction in both lean and obese groups. At comparable levels of FA availability, achieved by nicotinic acid, R ox was lower in Obese than Lean. In Obese rats, FA oxidative capacity was 35% higher than that in Lean in skeletal muscle, 67% lower in brown fat and comparable in other organs. In conclusion, lipid accumulation in non-adipose tissues of obese Zucker rats appears to result largely from systemic FA oversupply.

Figure 1

Whole-body FA metabolism in lean (Lean) and obese (Obese) Zucker rats. R _a plasma FA appearance rate. Results are expressed as mean ± SE (n = 6 rats per group). **P < 0.01, ***P < 0.001 versus Lean.

Figure 2

Relationship between in vivo flux of FA into storage in skeletal muscle and plasma FA level. Circles represent results from Lean, while squares represent results from Obese animals. Results for white quadriceps muscle (gray symbols, W) and red quadriceps muscle (black symbols, R) are plotted for individual animals (n = 6 rats per group). Straight lines represent linear regression equations.

Figure 3

Dependence of FA oxidation (R _ox) on both the rate of FA appearance, R _a (a), and FA level (b), in lean and obese Zucker rats. FA availability has been pharmacologically manipulated using the antilipolytic agent nicotinic acid to generate a range of FA levels (n = 2-3 rats per dose).

Figure 4

FA oxidation capacity of individual tissues, determined ex vivo, based on the ability of tissue homogenates to oxidize palmitate. Results are expressed as mean ± SE (n = 5 per group). *P < 0.05, **P < 0.01, ***P < 0.001 versus Lean.

Figure 5

Relationship between FA uptake and FA oxidation capacity by individual tissues in lean (grey symbols) and obese (black symbols) Zucker rats. FA uptake has been calculated from R _f* data (see Results section). The broken line indicates equality of uptake and oxidation capacity. FA uptake in the skeletal muscle, EDL (extensor digitorum longus), was assessed in the quiescent state and during sustainable twitch contractions: arrows indicate the effect of contraction.