The influence of obesity on protein dynamics is not clearly understood. We have designed experiments to test the hypothesis that obesity impairs the stimulation of tissue-specific protein synthesis following nutrient ingestion. C57BL/6J mice were randomized into two groups: group 1 (control, n = 16) were fed a low-fat, high-carbohydrate diet and group 2 (experimental, n = 16) were fed a high-fat, low-carbohydrate diet ad libitum for 9 weeks. On the experiment day, all mice were fasted for 6 hours and given an intraperitoneal injection of 2 H 2 O, they were then randomized into two sub-groups and either given a sham saline gavage or a liquid-meal challenge. Rates of protein synthesis were determined via the incorporation of [ 2 H]alanine (5 hours post-challenge) into total gastrocnemius muscle protein, total liver protein and plasma albumin. High fat feeding led to an increase in total body fat (p < 0.001) and epididymal fat pad weights (p < 0.001) and elevated fasting plasma glucose levels (p < 0.01). Diet-induced obesity (i) did not affect basal rates of skeletal muscle protein synthesis, but did impair the activation of skeletal muscle protein synthesis in response to nutrient ingestion (p < 0.05) and (ii) slightly reduced basal rates of synthesis of total hepatic proteins and plasma albumin (p = 0.10), but did not affect the synthesis of either in response to the meal challenge. In conclusion, there are alterations in tissue-specific protein metabolism in the C57BL/6J mouse model of diet-induced obesity. This model may prove to be helpful in future studies that explore the mechanisms that account for altered protein dynamics in obesity.

The goal of the study was to investigate the metabolism of levulinate (4‐ketopentanoate, LEV) which as a calcium salt, is used as an oral or intravenous source of calcium. We hypothesized that (i) levulinate is converted to gamma‐hydroxypentanoate (GHP), a new drug of abuse, analog of gamma‐hydroxybutyrate, and (ii) the formation of GHP from LEV is enhanced by ethanol. We investigated the metabolism of LEV and GHP in perfused rat livers and live rats. In both models, LEV was converted to GHP, and GHP was converted to LEV. This interconversion involves a cytosolic NADP‐dehydrogenase. Ethanol decreases the uptake of LEV and increases the formation of GHP from LEV, without affecting the [GHP]/[LEV] ratio. Thus, ethanol appears to inhibit both LEV and GHP catabolism, presumably at the level of 3‐hydroxyacyl‐CoA dehydrogenase. In livers perfused with LEV there was substantial accumulation of LEV‐CoA, GHP‐CoA and 4‐phospho‐GHP‐CoA. In parallel, the concentrations of acetyl‐CoA, malonyl‐CoA, HMG‐CoA methylmalonyl‐CoA and succinyl‐CoA markedly decreased. Thus, the metabolism of LEV and GHP result in substantial CoA trapping which can affect a number of processes. The conversion of LEV to GHP, a drug of abuse, and the stimulation of GHP formation by ethanol is a public health concern since calcium‐LEV is freely available. Supported by NIDDK RoadMap and by NIEHS.