Female and male C57BL/6J offspring exposed to maternal obesogenic diet develop altered hypothalamic energy metabolism in adulthood.

Maternal obesity is exceedingly common and strongly linked to offspring obesity and metabolic disease. Hypothalamic function is critical to obesity development. Hypothalamic mechanisms causing obesity following exposure to maternal obesity have not been elucidated. Therefore, we studied a cohort of C57BL/6J dams, treated with a control or high-fat-high-sugar diet, and their adult offspring to explore potential hypothalamic mechanisms to explain the link between maternal and offspring obesity. Dams treated with obesogenic diet were heavier with mild insulin resistance, which is reflective of the most common metabolic disease in pregnancy. Adult offspring exposed to maternal obesogenic diet had no change in body weight but significant increase in fat mass, decreased glucose tolerance, decreased insulin sensitivity, elevated plasma leptin, and elevated plasma thyroid-stimulating hormone. In addition, offspring exposed to maternal obesity had decreased energy intake and activity without change in basal metabolic rate. Hypothalamic neurochemical profile and transcriptome demonstrated decreased neuronal activity and inhibition of oxidative phosphorylation. Collectively, these results indicate that maternal obesity without diabetes is associated with adiposity and decreased hypothalamic energy production in offspring. We hypothesize that altered hypothalamic function significantly contributes to obesity development. Future studies focused on neuroprotective strategies aimed to improve hypothalamic function may decrease obesity development.NEW & NOTEWORTHY Offspring exposed to maternal diet-induced obesity demonstrate a phenotype consistent with energy excess. Contrary to previous studies, the observed energy phenotype was not associated with hyperphagia or decreased basal metabolic rate but rather decreased hypothalamic neuronal activity and energy production. This was supported by neurochemical changes in the hypothalamus as well as inhibition of hypothalamic oxidative phosphorylation pathway. These results highlight the potential for neuroprotective interventions in the prevention of obesity with fetal origins.

Iron supplementation dose for perinatal iron deficiency differentially alters the neurochemistry of the frontal cortex and hippocampus in adult rats.

BACKGROUND: Long-term prefrontal cortex (PFC)- and hippocampus-based cognitive deficits are the sequelae of perinatal iron deficiency, despite iron supplementation starting in the newborn period. Whether high-dose iron supplementation prevents these deficits is yet to be determined. METHODS: Perinatal iron deficiency was induced in rat pups using a low-iron (3 mg/kg diet) diet during gestation until postnatal day (P)8. Iron was supplemented using a standard (40 mg/kg diet) or a 10-fold higher (400 mg/kg diet) iron-containing diet until P21. PFC and hippocampal neurochemistry was determined using in vivo (1)H nuclear magnetic resonance (NMR) spectroscopy at 9.4 Tesla on P90. RESULTS: Both standard and 10-fold higher iron supplementation doses corrected anemia and brain iron deficiency by P21. The neurochemical profile of the PFC in both supplementation groups was comparable with the control group. In the hippocampus, standard-dose iron supplementation resulted in lower concentrations of N-acetylaspartate (NAA) and phosphoethanolamine (PE) and higher concentrations of N-acetylaspartylglutamate (NAAG) and glycerophosphocholine + phosphocholine (GPC + PC). High-dose iron supplementation resulted in lower PE and higher GPC + PC concentrations. CONCLUSION: The iron supplementation dose for perinatal iron deficiency differentially alters the neurochemical profile of the PFC and hippocampus in adults. The neurochemical changes suggest altered glutamatergic neurotransmission, hypomyelination, and abnormal phospholipid metabolism in the formerly iron-deficient (FID) hippocampus.

Fetal and neonatal iron deficiency causes volume loss and alters the neurochemical profile of the adult rat hippocampus.

OBJECTIVE: Perinatal iron deficiency results in persistent hippocampus-based cognitive deficits in adulthood despite iron supplementation. The objective of the present study was to determine the long-term effects of perinatal iron deficiency and its treatment on hippocampal anatomy and neurochemistry in formerly iron-deficient young adult rats. METHODS: Perinatal iron deficiency was induced using a low-iron diet during gestation and the first postnatal week in male rats. Hippocampal size was determined using volumetric magnetic resonance imaging at 8 weeks of age. Hippocampal neurochemical profile, consisting of 17 metabolites indexing neuronal and glial integrity, energy reserves, amino acids, and myelination, was quantified using high-field in vivo (1)H NMR spectroscopy at 9.4T (N = 11) and compared with iron-sufficient control group (N = 10). RESULTS: The brain iron concentration was 56% lower than the control group at 7 days of age in the iron-deficient group, but had recovered completely at 8 weeks. The cross-sectional area of the hippocampus was decreased by 12% in the formerly iron-deficient group (P = 0.0002). The hippocampal neurochemical profile was altered: relative to the control group, creatine, lactate, N-acetylaspartylglutamate, and taurine concentrations were 6-29% lower, and glutamine concentration 18% higher in the formerly iron-deficient hippocampus (P < 0.05). DISCUSSION: Perinatal iron deficiency was associated with reduced hippocampal size and altered neurochemistry in adulthood, despite correction of brain iron deficiency. The neurochemical changes suggest suppressed energy metabolism, neuronal activity, and plasticity in the formerly iron-deficient hippocampus. These anatomic and neurochemical changes are consistent with previous structural and behavioral studies demonstrating long-term hippocampal dysfunction following perinatal iron deficiency.

Hippocampus specific iron deficiency alters competition and cooperation between developing memory systems.

UNLABELLED: Iron deficiency (ID) is the most common gestational micronutrient deficiency in the world, targets the fetal hippocampus and striatum and results in long-term behavioral abnormalities. These structures primarily mediate spatial and procedural memory, respectively, in the rodent but have interconnections that result in competition or cooperation during cognitive tasks. We determined whether ID-induced impairment of one alters the function of the other by genetically inducing a 40% reduction of hippocampus iron content in late fetal life in mice and measuring dorsal striatal gene expression and metabolism and the behavioral balance between the two memory systems in adulthood. Slc11a2(hipp/hipp) mice had similar striatum iron content, but 18% lower glucose and 44% lower lactate levels, a 30% higher phosphocreatine:creatine ratio, and reduced iron transporter gene expression compared to wild type (WT) littermates, implying reduced striatal metabolic function. Slc11a2(hipp/hipp) mice had longer mean escape times on a cued task paradigm implying impaired procedural memory. Nevertheless, when hippocampal and striatal memory systems were placed in competition using a Morris Water Maze task that alternates spatial navigation and visual cued responses during training, and forces a choice between hippocampal and striatal strategies during probe trials, Slc11a2(hipp/hipp) mice used the hippocampus-dependent response less often (25%) and the visual cued response more often (75%) compared to WT littermates that used both strategies approximately equally. Hippocampal ID not only reduces spatial recognition memory performance but also affects systems that support procedural memory, suggesting an altered balance between memory systems. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1007/s11689-010-9049-0) contains supplementary material, which is available to authorized users.