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A growing body of evidence supports a role for tissue-to-diet 15N and 13C discrimination factors (&Delta, 15N and &Delta, 13C), as biomarkers of metabolic adaptations to nutritional stress, but the underlying mechanisms remain poorly understood. In obese rats fed ad libitum or subjected to gradual caloric restriction (CR), under a maintained protein intake, we measured &Delta, 13C levels in tissue proteins and their constitutive amino acids (AA) and the expression of enzymes involved in the AA metabolism. CR was found to lower protein mass in the intestine, liver, heart and, to a lesser extent, some skeletal muscles. This was accompanied by &Delta, 15N increases in urine and the protein of the liver and plasma, but &Delta, 15N decreases in the proteins of the heart and the skeletal muscles, alongside &Delta, 13C decreases in all tissue proteins. In Lys, &Delta, 15N levels rose in the plasma, intestine, and some muscles, but fell in the heart, while in Ala, and to a lesser extent Glx and Asx, &Delta, 13C levels fell in all these tissues. In the liver, CR was associated with an increase in the expression of genes involved in AA oxidation. During CR, the parallel rises of &Delta, 15N in urine, liver, and plasma proteins reflected an increased AA catabolism occurring at the level of the liver metabolic branch point, while &Delta, 15N decreases in cardiac and skeletal muscle proteins indicated increased protein and AA catabolism in these tissues. Thus, an increased protein and AA catabolism results in opposite &Delta, 15N effects in splanchnic and muscular tissues. In addition, the &Delta, 13C decrease in all tissue proteins, reflects a reduction in carbohydrate (CHO) oxidation and routing towards non-indispensable AA, to achieve fuel economy.