Preserved protein synthesis in the heart in response to acute fasting and chronic food restriction despite reductions in liver and skeletal muscle.

Whole body protein synthesis is reduced during the fed-to-fasted transition and in cases of chronic dietary restriction; however, less is known about tissue-specific alterations. We have assessed the extent to which protein synthesis in cardiac muscle responds to dietary perturbations compared with liver and skeletal muscle by applying a novel (2)H(2)O tracer method to quantify tissue-specific responses of protein synthesis in vivo. We hypothesized that protein synthesis in cardiac muscle would be unaffected by acute fasting or food restriction, whereas protein synthesis in the liver and gastrocnemius muscle would be reduced when there is a protein-energy deficit. We found that, although protein synthesis in liver and gastrocnemius muscle was significantly reduced by acute fasting, there were no changes in protein synthesis in the left ventricle of the heart for either the total protein pool or in isolated mitochondrial or cytosolic compartments. Likewise, a chronic reduction in calorie intake, induced by food restriction, did not affect protein synthesis in the heart, whereas protein synthesis in skeletal muscle and liver was decreased. The later observations are supported by changes in the phosphorylation state of two critical mediators of protein synthesis (4E-BP1 and eIF2alpha) in the respective tissues. We conclude that cardiac protein synthesis is maintained in cases of nutritional perturbations, in strong contrast to liver and gastrocnemius muscle, where protein synthesis is decreased by acute fasting or chronic food restriction.

Diet-induced obesity alters protein synthesis: tissue-specific effects in fasted versus fed mice.

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 after nutrient ingestion. C57BL/6J mice were randomized into 2 groups: group 1 (control, n = 16) was fed a low-fat, high-carbohydrate diet, whereas group 2 (experimental, n = 16) was 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 2 subgroups 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 postchallenge) into total gastrocnemius muscle protein, total liver protein, and plasma albumin. High-fat feeding led to an increase in total body fat (P < .001) and epididymal fat pad weights (P < .001) and elevated fasting plasma glucose levels (P < .01). Diet-induced obesity (a) 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 < .05), and (b) slightly reduced basal rates of synthesis of total hepatic proteins and plasma albumin (P = .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.

Mice with a deletion in the gene for CCAAT/enhancer-binding protein beta are protected against diet-induced obesity.

The CCAAT/enhancer-binding protein beta (C/EBPbeta) is required for adipocyte differentiation and maturation. We have studied the role of the transcription factor, C/EBPbeta, in the development of diet-induced obesity. Mice with a deletion in the gene for C/EBPbeta (C/EBPbeta(-/-)) and wild-type mice were fed a high-fat diet (60% fat) for 12 weeks. The C/EBPbeta(-/-) mice lost body fat, whereas the wild-type mice increased their total body fat on a high-fat diet. The C/EBPbeta(-/-) mice had lower levels of blood triglycerides, free fatty acids, cholesterol, and hepatic triglyceride accumulation compared with the wild-type mice, thus protecting them from diet-induced obesity and fatty liver on a high-fat diet. Deletion of C/EBPbeta gene resulted in greatly reducing hepatic lipogenic genes, acetyl CoA carboxylase, and fatty acid synthase and increasing the expression of beta-oxidation genes in the brown adipose tissue. CO(2) production was significantly higher in the C/EBPbeta(-/-) mice as was the level of uncoupling protein (UCP)-1 and UCP-3 in the muscle. In conclusion, the transcription factor C/EBPbeta is an important regulator in controlling lipid metabolism and in the development of diet-induced obesity.