Nutritional Reprogramming of Hepatic Metabolism by Feeding a Diet Containing Large, Phospholipid-Coated Lipid Droplets in Early Life Protects against Western Style Diet-Induced Insulin Resistance in Adult Mice

Early life nutrition possibly influences long-term metabolic outcomes. Previous studies in mice showed that adult obesity and energy metabolism can be improved by early life exposure to an infant milk formula (IMF) with large (3-5μm), (milk)-phospholipid coated lipid droplets (Concept diet, Nuturis®). This study examined the effects of the Concept diet on (adult) fasting insulin sensitivity and hepatic mitochondrial capacity. From postnatal day (PN) 16 to PN42, male C57BL/6j mice were exposed to a semisynthetic rodent diet containing Concept or Control (CTRL)-IMF. Subsequently, mice were fed either Western-style (WSD) or standard rodent diet (AIN) from PN42 to PN98 and sacrificed after 3 hours fasting, at PN98. Homeostasis model assessment insulin resistance index (HOMA-IR) was calculated from fasting insulin and glucose levels. Mitochondrial function was assessed by high-resolution respirometry in liver tissue at PN98 using substrates stimulating β-oxidation (β-OX) and tricarboxylic acid cycle (TCA) flux. Plasma thiobarbituric acid reactive substances (TBARS), a marker of lipid peroxidation, were measured fluorometrically. At PN98, WSD induced insulin resistance in CTRL, but not in Concept fed mice (p<0.05). Furthermore, Concept mice on WSD had a lower liver weight (p<0.05) and 69% higher maximal β-OX compared to CTRL (p<0.05). Liver fat content increased with WSD independent of initial diet (p<0.05) and was not different between CTRL and Concept groups. Yet, plasma TBARS were 23% lower in Concept compared to CTRL mice fed WSD (p<0.05). In conclusion, early life feeding of the Concept diet improved hepatic oxidative capacity and protected adult mice against diet-induced insulin resistance. These results suggest that early postnatal metabolic priming may decrease systemic oxidative damage which can help to maintain liver health in an obesogenic environment. Disclosure T. Jelenik: Employee; Self; Boehringer Ingelheim Pharmaceuticals, Inc. A. Kodde: Employee; Self; Danone Nutricia Research. D. Pesta: None. E. Rohbeck: None. B. Dewidar: None. E. Phielix: None. A. Oosting: Employee; Self; Danone Nutricia Research. E.M. van der Beek: Employee; Self; Danone Nutricia Research. M. Roden: Advisory Panel; Self; Servier. Board Member; Self; Poxel SA. Consultant; Self; Eli Lilly and Company, Gilead Sciences, Inc., ProSciento, TARGET PharmaSolutions. Research Support; Self; Boehringer Ingelheim International GmbH, Novartis Pharma K.K., Sanofi US. Speaker’s Bureau; Self; Novo Nordisk A/S. Funding Danone Nutricia Research