Adult rats sired by obese fathers present learning deficits associated with epigenetic and neurochemical alterations linked to impaired brain glutamatergic signaling.

AIM: Offspring of obese mothers are at high risk of developing metabolic syndrome and cognitive disabilities. Impaired metabolism has also been reported in the offspring of obese fathers. However, whether brain function can also be affected by paternal obesity has barely been examined. This study aimed to characterize the learning deficits resulting from paternal obesity versus those induced by maternal obesity and to identify the underlying mechanisms. METHODS: Founder control and obese female and male Wistar rats were mated to constitute three first-generation (F1) experimental groups: control mother/control father, obese mother/control father, and obese father/control mother. All F1 animals were weaned onto standard chow and underwent a learning test at 4 months of age, after which several markers of glutamate-mediated synaptic plasticity together with the expression of miRNAs targeting glutamate receptors and the concentration of kynurenic and quinolinic acids were quantified in the hippocampus and frontal cortex. RESULTS: Maternal obesity induced a severe learning deficit by impairing memory encoding and memory consolidation. The offspring of obese fathers also showed reduced memory encoding but not impaired long-term memory formation. Memory deficits in offspring of obese fathers and obese mothers were associated with a down-regulation of genes encoding NMDA glutamate receptors subunits and several learning-related genes along with impaired expression of miR-296 and miR-146b and increased concentration of kynurenic acid. CONCLUSION: Paternal and maternal obesity impair offspring's learning abilities by affecting different processes of memory formation. These cognitive deficits are associated with epigenetic and neurochemical alterations leading to impaired glutamate-mediated synaptic plasticity.

Obesity-Induced Memory Deficits in Female Rats Are Oestrous Cycle Dependent and Linked to Impaired Brain Kynurenine Pathway Metabolism.

INTRODUCTION: Obesity is associated with impaired learning, but the mechanisms underlying this cognitive dysfunction are poorly understood. Moreover, whether obesity-induced learning deficits show sexual dimorphism remains controversial. Females are believed to be protected from cognitive decline by oestrogens. These hormones enhance the expression of tryptophan hydroxylase 2, the rate-limiting enzyme in the transformation of tryptophan (Trp) into serotonin which plays a significant role in learning and memory. However, several learning-regulating compounds also arise from Trp metabolism through the kynurenine pathway (KP), including kynurenic acid (KA), xanthurenic acid (XA), and NAD+. The present study aimed to determine the involvement of the KP of Trp metabolism in the regulation of learning in control and obese female rats. METHODS: The learning capabilities of control and obese rats were evaluated using the novel object recognition test. Trp and Trp-derived metabolites were quantified in the hippocampus and frontal cortex by ultra-performance liquid chromatography-tandem mass spectrometry. RESULTS: Control rats in proestrus/oestrous performed better than their control mates in metestrus/dioestrus. Likewise, while control and obese rats in dioestrus/metestrus did not show differences in learning, obese rats in proestrus/oestrous displayed decreased memory capacity along with decreased Trp concentration and reduced KA, XA, and NAD+ production in the hippocampus. These neurochemical alterations were associated with impaired expression of mRNAs coding for key enzymes of the KP. CONCLUSION: The results presented here indicate that the deleterious effects of obesity on learning are closely related to the oestrous cycle and associated with an impairment of the KP of Trp metabolism.

Learning Deficits Induced by High-Calorie Feeding in the Rat are Associated With Impaired Brain Kynurenine Pathway Metabolism.

In addition to be a primary risk factor for type 2 diabetes and cardiovascular disease, obesity is associated with learning disabilities. Here we examined whether a dysregulation of the kynurenine pathway (KP) of tryptophan (Trp) metabolism might underlie the learning deficits exhibited by obese individuals. The KP is initiated by the enzymatic conversion of Trp into kynurenine (KYN) by indoleamine 2,3-dioxygenase (IDO). KYN is further converted to several signaling molecules including quinolinic acid (QA) which has a negative impact on learning. Wistar rats were fed either standard chow or made obese by exposure to a free choice high-fat high-sugar (fcHFHS) diet. Their learning capacities were evaluated using a combination of the novel object recognition and the novel object location tasks, and the concentrations of Trp and KYN-derived metabolites in several brain regions determined by ultra-performance liquid chromatography-tandem mass spectrometry. Male, but not female, obese rats exhibited reduced learning capacity characterized by impaired encoding along with increased hippocampal concentrations of QA, Xanthurenic acid (XA), Nicotinamide (Nam), and oxidized Nicotinamide Adenine Dinucleotide (NAD+). In contrast, no differences were detected in the serum levels of Trp or KP metabolites. Moreover, obesity enhanced the expression in the hippocampus and frontal cortex of kynurenine monooxygenase (KMO), an enzyme involved in the production of QA from kynurenine. QA stimulates the glutamatergic system and its increased production leads to cognitive impairment. These results suggest that the deleterious effects of obesity on cognition are sex dependent and that altered KP metabolism might contribute to obesity-associated learning disabilities.

Adult rats from undernourished dams show sex-dependent impaired expression in taste papillae and hypothalamus of genes responsible for sweet and fat detection and signalling.

AIM: Individuals undernourished in utero or during early life are at high risk of developing obesity and metabolic disorders and show an increased preference for consuming sugary and fatty food. This study aimed at determining whether impaired taste detection and signalling in the lingual epithelium and the brain might contribute to this altered pattern of food intake. METHODS: The preference for feeding fat and sweet food and the expression in circumvallate papillae and hypothalamus of genes coding for sweet and fat receptors and transducing pathways were evaluated in adult rats born to control or calorie-restricted dams. Expression in the hypothalamus and the brain's reward system of genes involved in the homeostatic and hedonic control of food intake was also determined. RESULTS: Male and female undernourished animals exhibited increased expression in taste papillae and hypothalamus of T1R1, T1R2, CD36, gustducin, TRMP5 and PLC-ß2 genes, all of which modulate sweet and fat detection and intracellular signalling. However, the severity of the effect was greater in females than in males. Moreover, male, but not female, undernourished rats consumed more standard and sweetened food than their control counterparts and presented increased hypothalamic AgRP and NPY mRNAs levels together with enhanced dopamine transporter and dopamine receptor D2 expression in the ventral tegmental area. CONCLUSIONS: Maternal undernutrition induces sex-specific changes in food preferences and gene expression in taste papillae, hypothalamus and brain reward regions. The gene expression alterations in the male offspring are in line with their preference for consuming sugary and fatty food.

Maternal DHA Supplementation during Pregnancy and Lactation in the Rat Protects the Offspring against High-Calorie Diet-Induced Hepatic Steatosis.

Maternal supplementation during pregnancy with docosahexaenoic acid (DHA) is internationally recommended to avoid postpartum maternal depression in the mother and improve cognitive and neurological outcomes in the offspring. This study was aimed at determining whether this nutritional intervention, in the rat, protects the offspring against the development of obesity and its associated metabolic disorders. Pregnant Wistar rats received an extract of fish oil enriched in DHA or saline (SAL) as placebo by mouth from the beginning of gestation to the end of lactation. At weaning, pups were fed standard chow or a free-choice, high-fat, high-sugar (fc-HFHS) diet. Compared to animals fed standard chow, rats exposed to the fc-HFHS diet exhibited increased body weight, liver weight, body fat and leptin in serum independently of saline or DHA maternal supplementation. Nevertheless, maternal DHA supplementation prevented both the glucose intolerance and the rise in serum insulin resulting from consumption of the fc-HFHS diet. In addition, animals from the DHA-fc-HFHS diet group showed decreased hepatic triglyceride accumulation compared to SAL-fc-HFHS rats. The beneficial effects on glucose homeostasis declined with age in male rats. Yet, the preventive action against hepatic steatosis was still present in 6-month-old animals of both sexes and was associated with decreased hepatic expression of lipogenic genes. The results of the present work show that maternal DHA supplementation during pregnancy programs a healthy phenotype into the offspring that was protective against the deleterious effects of an obesogenic diet.