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

Abstract

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.

Effect of dietary restriction on metabolic, anatomic and molecular traits in mice depends on the initial level of basal metabolic rate (BMR)

“…A number of recent studies have called attention to the importance of intraspecific genetic variation in response to DR [including cases when DR actually shortens lifespan (Rikke et al, 2003;Rikke and Johnson, 2007;Liao et al, 2010;Rikke et al, 2010)]. In the present study, we demonstrate that genetically based differences in MR can account for equivocal results of the studies on directional effects of DR on metabolism.…”

“…This indicates that both BMR and PMR are largely underlined by different metabolic pathways, and that they are independently affected by DR treatment (see also Rikke and Johnson, 2007). Indeed, except for the heart, changes in the masses of other metabolically active internal organs are likely to contribute to changes in BMR, rather than PMR (Książek et al, 2004;Gębczynski and Konarzewski, 2011).…”

Caloric restriction

“…All these effects influence heat balance and hence T b by elevating heat production. However, an additional potential effect is via increased rates of heat loss because of modulated heat dissipation, and studies in both rats and mice have concluded that this is the major factor driving strain differences in the T b response to CR (Duffy et al, 1990a,b;Rikke and Johnson, 2007). Fig.…”

Relevance of animal models to human eating disorders and obesity

“…The literature describing experimental undernutrition in animals is too vast to be covered here. Recent studies describing the involvement of several genes in regulating differences in the physiological adaptations to dietary restriction, however (Rikke and Johnson 2007), offer possibilities for investigating variations in the human response to fasting.…”