Identification of blood cell transcriptome‐based biomarkers in adulthood predictive of increased risk to develop metabolic disorders using early life intervention rat models

• Published in: The FASEB journal 2020-07, Vol.34 (7), p.9003-9017
• Main Authors: Szostaczuk, Nara, Schothorst, Evert M., Sánchez, Juana, Priego, Teresa, Palou, Mariona, Bekkenkamp‐Grovenstein, Melissa, Faustmann, Gernot, Obermayer‐Pietsch, Barbara, Tiran, Beate, Roob, Johannes M., Winklhofer‐Roob, Brigitte M., Keijer, Jaap, Palou, Andreu, Picó, Catalina
• Format: Article
• Language: English
• Subjects: Animals; Biomarkers - blood; Caloric Restriction; Disease Models, Animal; Female; Gene Expression Regulation, Developmental; gestational calorie restriction; Leukocytes, Mononuclear - metabolism; Male; Metabolic Diseases - diagnosis; Metabolic Diseases - etiology; Metabolic Diseases - metabolism; metabolic health; metabolic programing; NPC1; PBMCs; predictive biomarkers; Pregnancy; Prenatal Exposure Delayed Effects - physiopathology; Rats; Rats, Wistar; Transcriptome
• ISSN: 0892-6638; 1530-6860
• DOI: 10.1096/fj.202000071RR

Calorie restriction during gestation in rats has long‐lasting adverse effects in the offspring. It induces metabolic syndrome‐related alterations, which are partially reversed by leptin supplementation during lactation. We employed these conditions to identify transcript‐based nutrient sensitive biomarkers in peripheral blood mononuclear cells (PBMCs) predictive of later adverse metabolic health. The best candidate was validated in humans. Transcriptome analysis of PBMCs from adult male Wistar rats of three experimental groups was performed: offspring of control dams (CON), and offspring of 20% calorie‐restricted dams during gestation without (CR) and with leptin supplementation throughout lactation (CR‐LEP). The expression of 401 genes was affected by gestational calorie restriction and reversed by leptin. The changes preceded metabolic syndrome‐related phenotypic alterations. Of these genes, Npc1 mRNA levels were lower in CR vs CON, and normalized to CON in CR‐LEP. In humans, NPC1 mRNA levels in peripheral blood cells (PBCs) were decreased in subjects with mildly impaired metabolic health compared to healthy subjects. Therefore, a set of potential transcript‐based biomarkers indicative of a predisposition to metabolic syndrome‐related alterations were identified, including NPC1, which was validated in humans. Low NPC1 transcript levels in PBCs are a candidate biomarker of increased risk for impaired metabolic health in humans.