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The Metabolic Benefits of Short Cycles of Very Low Caloric Intake are Dependent on Diet Composition in Middle-Aged Mice

ABSTRACT: Diet composition, calories, and fasting times contribute to maintenance of health. Here, middle-aged mice were maintained for 5 months on 4:10 feeding cycles, consisting of 4 days of very low-calorie intake (VLCI) achieved with either standard laboratory chow (SD) or a fasting mimicking diet (FMD), followed by 10 days of ad libitum access to SD. Fat and lean mass loss was accompanied with improved performance, glucoregulation, and metabolic flexibility independent of diet composition. However, only the 4:10/SD cycles elicited a long-lasting metabolomic reprograming in serum and liver that was preserved six days after refeeding. Challenged with an obesogenic diet, cycles of VLCI achieved with either high-fat diet (HFD) or FMD during the low-calorie period did not prevent diet-induced obesity nor did they elicited a long-lasting metabolic memory, despite achieving modest metabolic flexibility. Our results highlight the importance of diet composition in mediating the metabolic benefits of short cycles of VLCI.

ORGANISM(S): Mouse Mus Musculus

TISSUE(S): Blood

SUBMITTER: Rafael de Cabo

PROVIDER: ST001809 | MetabolomicsWorkbench | Thu May 27 00:00:00 BST 2021

REPOSITORIES: MetabolomicsWorkbench

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Project description:The long-term effects of neonatal intermittent hypoxia (IH), an accepted model of apnea-induced hypoxia, are unclear. We have previously shown lasting âprogrammingâ effects on the HPA axis in adult rats exposed to neonatal IH. We hypothesized that neonatal rat exposure to IH will subsequently result in a heightened inflammatory state in the adult. Rat pups were exposed to normoxia (control) or six cycles of 5% IH or 10% IH over one hour daily from postnatal day 2 â 6. Plasma samples from blood obtained at 114 days of age were analyzed by assessing the capacity to induce transcription in a healthy peripheral blood mononuclear cell (PBMC) population and read using a high-density microarray. The analysis of plasma from adult rats previously exposed to neonatal 5% IH vs. 10% IH resulted in 2,579 significantly regulated genes including increased expression of Cxcl1, Cxcl2, Ccl3, Il1a, and Il1b. We conclude that neonatal exposure to intermittent hypoxia elicits a long-lasting programming effect in the adult resulting in an upregulation of inflammatory-related genes. Apnea is the most common cause of neonatal hypoxia affecting about 50% of preterm births (30 Ã¢ÂÂ 31 weeks), usually due to immature respiratory development. Upregulation of inflammatory genes and pathways in children 7 Ã¢ÂÂ 10 years of age has been shown, and there is a known increased risk of insulin resistance in adulthood when the fetus is exposed to maternal hypoxia, but the mechanism is unclear. The long-term metabolic, endocrine, and immunological effects of neonatal intermittent hypoxia (IH) exposure, an accepted model of apnea-induced hypoxia, have not been thoroughly evaluated. Recent studies in rats have shown that perinatal IH exposure can result in oxidative stress, causing a permanent immune response subsequently resulting in features of diabetes mellitus. We have previously examined adult rats exposed to neonatal intermittent hypoxia and perinatal continuous hypoxia, and have found lasting Ã¢ÂÂprogrammingÃ¢ÂÂ effects on the HPA axis. We now assess the long term effects of an accepted model of apnea-induced hypoxia using a validated transcriptional bioassay to study the extracellular milieu of adult rats exposed to neonatal intermittent hypoxia. We hypothesize that exposure to neonatal intermittent hypoxia will result in an increased inflammatory state in the adult as a result of long-lasting programming. Sprague-Dawley (SD) rat pups were treated with neonatal normoxia (21% O2, control), 5% intermittent hypoxia (IH), or 10% IH on postnatal days (PD) 2-6, daily over 1 hr. They were reared normally by birth dams and weaned at PD22. Males were allowed to mature and sacrificed at age PD114 after an overnight fast. Whole blood collected by decapitation into tubes with EDTA, and plasma saved for further analysis. Two adult (~180 day) male Brown Norway (BN) rats served as PBMC donors. Cells were incubated with 20% plasma that was either autologous BN (self-control), or one of 3 pools: a) SD normoxic N=8, b) SD 5% IH treated N=5, and c) SD 10% IH N=3.

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The Metabolic Benefits of Short Cycles of Very Low Caloric Intake are Dependent on Diet Composition in Middle-Aged Mice

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