Physiological genetics of dietary restriction: uncoupling the body temperature and body weight responses.

Numerous physiological and molecular changes accompany dietary restriction (DR), which has been a major impediment to elucidating the causal basis underlying DR's many health benefits. Two major metabolic responses to DR that potentially underlie many of these changes are the body temperature (T(b)) and body weight (BW) responses. These responses also represent an especially difficult challenge to uncouple during DR. We demonstrate in this study, using two recombinant inbred (RI) panels of mice (the LXS and LSXSS) that naturally occurring genetic variation serves as a powerful tool for modulating T(b) and BW independently during DR. The correlation coefficient between the two responses was essentially zero, with R = -0.04 in the LXS and -0.03 in the LSXSS, the latter averaged across replicate cohorts. This study is also the first to report that there is highly significant (P = 10(-10)) strain variation in the T(b) response to DR in the LXS (51 strains tested), with strain means ranging from 2 to 4 degrees C below normal. The results suggest that the strain variation in the T(b) response to DR is largely due to differences in the rate of heat loss rather than heat production (i.e., metabolic rate). This variation can thus be used to assess the long-term effects of lower T(b) independent of BW or metabolic rate, as well as independent of food intake and motor activity as previously shown. These results also suggest that murine genetic variation may be useful for uncoupling many more responses to DR.