Increased Fatty Acid Uptake and Altered Fatty Acid Metabolism in Insulin-Resistant Muscle of Obese Zucker Rats

Abstract

Altered muscle fatty acid (FA) metabolism may contribute to the presence of muscle insulin resistance in the genetically obese Zucker rat. To determine whether FA uptake and disposal are altered in insulin-resistant muscle, we measured palmitate uptake, oxidation, and incorporation into di-and triglycerides in isolated rat hindquarters, as well as muscle plasma membrane fatty acid-binding protein (FABP PM ) content of lean (n ‫؍‬ 16, fa/؉) and obese (n ‫؍‬ 15, fa/fa) Zucker rats (12 weeks of age). Hindquarters were perfused with 7 mmol/l glucose, 1,000 mol/l albumin-bound palmitate, and albumin-bound [1-14 C]palmitate at rest (no insulin). Glucose uptake was 42% lower in the obese than in the lean rats and indicated the presence of muscle insulin resistance. Fractional and total rates of palmitate uptake were 42 and 74% higher in the obese than in the lean rats and were associated with higher muscle FABP PM content (r 2 ‫؍‬ 0.69, P < 0.05). The percentage of palmitate oxidized was not significantly different between groups. FA disposal to storage was altered according to fiber type. When compared with lean rats, the rate of triglyceride synthesis in red muscle was 158% higher in obese rats, and the rate of palmitate incorporation into diglycerides in white muscle was 93% higher in obese rats. Pre-and postperfusion muscle triglyceride levels were higher in both red and white muscles of the obese rats. These results show that increased FA uptake and altered FA disposal to storage may contribute to the development of muscle insulin resistance in obese Zucker rats.

Impaired Fat Oxidation After a Single High-Fat Meal in Insulin-Sensitive Nondiabetic Individuals With a Family History of Type 2 Diabetes

“…Because no differences were observed in serum FFAs, this study also suggests that fatty acid uptake into skeletal muscle was not altered in nondiabetic relatives of individuals with type 2 diabetes. This has previously been reported to be similar or increased in obese rodent models and humans (12,29) and may eventually result in increased triglyceride storage within skeletal muscle (3). Also of note, a small but significantly higher glucose response was observed in relatives of individuals with type 2 diabetes in response to the high-fat meal.…”

Increased Efficiency of Fatty Acid Uptake Contributes to Lipid Accumulation in Skeletal Muscle of High Fat-Fed Insulin-Resistant Rats

“…This effect is apparently not restricted to our dietary model of insulin resistance. In a recent study of Zucker rats using the perfused hindlimb preparation (29), both FA uptake and oxidation were increased proportionately in obese rats compared with controls, such that the percentage of FA oxidized was similar in insulin-resistant and control groups. There was a tendency in the current study for a greater proportion of FA to be directed to storage in the muscle of HFF when FA levels were raised.…”

AMPKα2deficiency uncovers time dependency in the regulation of contraction-induced palmitate and glucose uptake in mouse muscle

“…On the day of the experiment, mice were anesthetized by an intraperitoneal injection of ketamine-xylazine cocktail (20 mg/kg body wt). Surgical preparation for the hindlimb perfusion was performed as previously described (38,49,50). Before placement of the perfusion catheters, heparin (15 IU) was injected into the inferior vena cava.…”