Sex-specific systemic metabolic predictors of resistance to calorie restriction-induced weight loss in obese Diversity Outbred mice

Authors: PAULES, EVAN - University Of North Carolina; VERHAGUE, MELISSA - University Of North Carolina; LULLA, ANJU - University Of North Carolina; MEYER, KATIE - University Of North Carolina; COLEMAN, MICHAEL - University Of North Carolina; ALBRIGHT, JODY - University Of North Carolina; Bennett, Brian; NORTH, KARI - University Of North Carolina; HOWARD, ANNIE-GREEN - University Of North Carolina; GORDON-LARSEN, PENNY - University Of North Carolina; TRUJILLO-GONZALEZ, ISIS - University Of North Carolina; FRENCH, JOHN - University Of North Carolina; HURSTING, STEVEN - University Of North Carolina

Submitted to: American Journal of Physiology - Regulatory Integrative and Comparative Physiology
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 4/9/2025
Publication Date: 4/18/2025
Citation: Paules, E.M., Verhague, M., Lulla, A.A., Meyer, K., Coleman, M.F., Albright, J., Bennett, B.J., North, K.E., Howard, A., Gordon-Larsen, P., Trujillo-Gonzalez, I., French, J.E., Hursting, S.D. 2025. Sex-specific systemic metabolic predictors of resistance to calorie restriction-induced weight loss in obese Diversity Outbred mice. American Journal of Physiology - Regulatory Integrative and Comparative Physiology. https://doi.org/10.1152/ajpregu.00220.2024.
DOI: https://doi.org/10.1152/ajpregu.00220.2024

Interpretive Summary: This study addresses the complexity of obesity and the urgent need for personalized weight loss strategies. Calorie restriction (CR) is identified as a cost-effective approach, but its effectiveness varies, lacking predictive guidance. Researchers use the Diversity Outbred (DO) mouse model, mirroring human genetic variability, to study CR responses. Examining 300 DO mice after 12 weeks of diet-induced obesity followed by 8 weeks of CR, significant heterogeneity is observed in weight, body composition, and metabolic parameters. Lower levels of leptin, adiponectin, and resistin distinguish CR responders from nonresponders in both sexes. The study suggests that circulating levels of these hormones can predict responsiveness to CR-induced weight loss, offering insights for more personalized and effective weight management strategies in genetically diverse populations with obesity.

Technical Abstract: Objective Calorie restriction (CR) is a well-established weight loss strategy that has been limited in its use in humans due to heterogeneity in body mass responses. Using obese Diversity Outbred mice, we sought to identify metabolic predictors of responsiveness to CR-induced weight loss. Methods Diversity Outbred mice (n=150 males n=150 females) were given high-fat diet for 12 weeks, resulting in diet-induced obesity (DIO), then administered a CR diet regimen for 8 weeks. Body weight and composition, blood glucose, and plasma levels of 9 metabolic hormones were assessed at baseline, following DIO, and following CR. Data from obese mice in the lower and upper quartiles of CR-induced weight loss were compared using multinomial regression and principal component analyses to identify predictors of responsiveness to CR. Results At baseline and following each dietary intervention, mice of each sex displayed substantial heterogeneity in weight, body composition, and circulating levels of glucose and metabolic hormones. Lower leptin and adiponectin levels, taken individually or collectively with resistin in a panel, significantly distinguished CR nonresponders from responders in both males and females. Conclusions Circulating leptin, adiponectin and resistin levels predict responsiveness to CR-induced weight loss in a population of genetically, phenotypically, and metabolically heterogeneous obese mice.