Murine weight loss exhibits significant genetic variation during dietary restriction

Abstract

We present genetic analyses of murine weight loss during dietary restriction (DR) for females eating 60% ad libitum (AL). We examined 5 cohorts across 81 different strains (22 strains tested twice) that included the LXS and LSXSS recombinant inbred strains, the LXS parental strains ILS and ISS, and the classical inbreds 129S6, A, BALB/c, C57BL/6, C3H, and DBA. Weight loss exhibited highly significant genetic variation, with DR body weights ranging from ∼60 to ∼85% of AL body weight. This variation was not explained by the strain differences in absolute food intake, feces calorie content, motor activity, or AL body fat. Heritability was 40–50%, and several provisional quantitative trait loci were mapped. This variation can be used to test whether weight loss correlates with the health benefits of DR, independently of the reduction in calories. The genetic variation also implies the existence of genes that would be novel therapeutic targets, distinct from genes affecting AL body weight or body fat, for enhancing (or mitigating) weight loss during food restriction.

Weight loss resistance: A further consideration for the nutritional management of obese Equidae

“…Murine studies offer 'proof of concept' that, at least for mice, weight loss sensitivity during DR is under genetic control with a heritability of 40-50% (Rikke et al, 2006). An ability to identify WLR or WLS phenotypes among Equidae, may offer similar potential for directed therapeutics as well as suggesting a potential basis for selective breeding.…”

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

“…DR food intake in this study was carefully controlled to be 60% of AL, as determined separately for each strain, with each mouse housed singly (12,13,15). The food intake of each AL mouse was measured each week over the entire study, with the food weights being collected at approximately the same time of day each week.…”

“…More recently, we also demonstrated that there is marked genetic variation in the response of BW to DR, with the strain means for BW ranging from about 60 to 85% of the AL controls (15). The variation in these responses is not explained by trivial factors, such as the strain differences in absolute food intake, feces:food ratios, feces calorimetry, gross motor activity, or AL percent body fat (12,13,15). Therefore, in this study, we asked to what extent the T b and BW responses are being coordinately modulated in these strains.…”

“…Both result in health benefits, and each could play a role in the extension of life span under DR (1,14,15,17,18). However, uncoupling these responses to DR represents a major challenge, especially while trying to control for the effects of food intake and activity.…”

Calorie restriction and susceptibility to intact pathogens

“…Because so much is known about the effects of CR on laboratory rodents, they would initially be a useful host to use for research with intact pathogens. Of course, there is variation in response to CR even among inbred mouse strains (Turturro et al 1999;Brochmann et al 2003;Rikke et al 2003Rikke et al , 2006, as well as between males and females (Wu et al 2003a;Shi et al 2007). Mouse strain and sex also influence susceptibility to pathogens (Zuk and McKean 1996;Morales-Montor et al 2004;, and these effects are pathogen-specific.…”