Food restriction paradigms are widely used in animal studies to investigate systems involved in energy regulation. We have observed behavioural, physiological and molecular differences in response to food restriction in three inbred mouse strains, C57BL/6J, A/J and DBA/2J. These are the progenitors of chromosome substitution and recombinant inbred mouse strains used for mapping complex traits. DBA/2J and A/J mice increased their locomotor activity during food restriction and both displayed a decrease in body temperature, but the decrease was significantly larger in DBA/2J compared to A/J mice. C57BL/6J mice did not increase their locomotor activity, and displayed a large decrease in their body temperature. The large decline in body temperature during food restriction in DBA/2J and C57BL/6J strains was associated with a robust reduction plasma leptin levels. DBA/2J mice showed a marked decrease in white and brown adipose tissue masses and an up-regulation of the anti-thermogenic hypothalamic Neuropeptide Y Y1 receptor. In contrast, A/J mice showed a reduction in body temperature to a lesser extent that may be explained by down regulation of the thermogenic melanocortin 3 receptor and by behavioural thermoregulation as a consequence of their increased locomotor activity. These data indicate that genetic background is an important parameter in controlling an animal’s adaptation strategy in response to food restriction. Therefore, mouse genetic mapping populations based on these progenitor lines are highly valuable for investigating mechanisms underlying strain dependent differences in behavioural physiology that are seen during reduced food availability.