Fat Mass Gained Prior to Dietary Intervention Predicts Efficacy of Personalized Dietary Guidance in Mice

OBJECTIVES: In previous studies into effects of carbohydrate restriction, we demonstrated differential responses to American and ketogenic diets in C57BL/6J (B6) and FVB/NJ (FVB) mice during lifetime feeding trials. These preliminary data suggested that both sex and genetic background regulated response to carbohydrate restriction. More recently, we have examined the utility of the ketogenic diet as a dietary intervention in obese B6 and FVB mice. METHODS: Four-to six-week-old B6 and FVB mice were exposed to an American (35% of energy from fat, 50% from carbohydrates) diet for 3 months. After 3 months on the American diet, half of the animals were reversed to a ketogenic dietary intervention for the remainder of the 6-month feeding trial while the other half were left on the American diet. RESULTS: B6 females that received the ketogenic diet as a dietary intervention after 3 months of exposure to the American diet gained less fat mass than B6 females that remained on the American diet for the duration of the feeding trial (B6 female American: 15.94g, +/− 5.00g; B6 female Reversal: 9.67g, +/− 3.98g; p = 0.007, 95% CI: 1.91–10.63g). In contrast, B6 males exposed to the dietary intervention gained more fat mass than B6 males that remained on the American diet for the duration of the feeding trial (B6 male American: 19.69g, +/− 1.42g; B6 male Reversal: 23.86g, +/− 1.28g; P < 0.001, 95% CI: −5.43 – (−2.89) g). As expected, no effect was seen in either FVB males or females. The amount of fat mass gained on the American diet prior to the introduction of the dietary intervention was highly correlated to the amount of fat mass gained at the end of the feeding trial for all strain and diet combinations (r = 0.878, p < 0.001, 95% CI: 0.81- 0.92). CONCLUSIONS: The strong relationship observed between the amount of fat mass gained prior to the introduction of the dietary intervention and the amount of fat mass gained at the end of the feeding trial suggests that there are mechanisms contributing to obesity that are not attenuated by simple dietary intervention, even within genetic backgrounds predicted to respond to carbohydrate restriction. Further studies are under way to investigate temporally controlled windows of opportunity for intervention as well as the effects of surgical removal of accumulated lipid on the plasticity of the obese phenotype. FUNDING SOURCES: National Institutes of Health.