Mammals and birds adapt to prolonged fasting by mobilizing fat stores and minimizing protein loss. This strategy ends with an increase in protein utilization associated with behavioural changes promoting food foraging. Using the Zucker rat as a model, we have investigated the effect of severe obesity on this pattern of protein loss during long-term fasting. Two interactions between the initial adiposity and protein utilization were found. First, protein conservation was more effective in obese than in lean rats: fatty rats had a three times lower daily nitrogen excretion and proportion of energy expenditure deriving from proteins, and a lower daily protein loss in various muscles. This phase of protein sparing is moreover nine times longer in the fatty rats. Second, obese animals did not show the late increase in nitrogen excretion that occurred in their lean littermates. Total body protein loss during starvation was larger in fatty rats (57% versus 29%) and, accordingly, total protein loss was greater in their muscles. At the end of the experiment, lean and obese rats had lost 98% and 82%, respectively, of their initial lipid reserves, and fatty rats still had an obese body composition. These results support the hypothesis that in severely obese humans and animals a lethal cumulative protein loss is reached long before the exhaustion of fat stores, while the phase of protein conservation is still continuing. In contrast, in lean rats, survival of fasting seems to depend on the availability of lipid fuels.(ABSTRACT TRUNCATED AT 250 WORDS)