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

Calorie restriction (CR) is a well-established weight loss strategy, albeit with variation in response. Using genetically heterogeneous mice, we sought to identify metabolic predictors of resistance to CR-induced weight loss. Diversity Outbred mice (150 males, 150 females) were fed a high-fat diet for 12 weeks to generate diet-induced obesity (DIO), then underwent CR 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. In response to each dietary intervention, the mice displayed substantial heterogeneity across all outcomes, often with sexual dimorphism. Among the metabolic markers, leptin changed the most in response to each dietary intervention. Logistic regression found that resistance to CR-induced weight loss in obese mice was associated with lower glucose levels in males, and with lower levels of insulin, resistin, homeostatic model assessment for insulin resistance (HOMA-IR), and plasminogen activator inhibitor-1, and higher levels of ghrelin in females. Moreover, lower leptin levels predicted resistance to CR-induced weight loss in obese mice, regardless of sex. These preclinical findings provide proof-of-principle that the genetic and phenotypic heterogeneity of DO mice can be leveraged to identify mechanistic predictors that may enhance the personalization of weight loss interventions.