Nutrition, the brain and cognitive decline: insights from epigenetics.

Nutrition affects the brain throughout life, with profound implications for cognitive decline and dementia. These effects are mediated by changes in expression of multiple genes, and responses to nutrition are in turn affected by individual genetic variability. An important layer of regulation is provided by the epigenome: nutrition is one of the many epigenetic regulators that modify gene expression without changes in DNA sequence.

Genomic and epigenomic insights into nutrition and brain disorders.

Considerable evidence links many neuropsychiatric, neurodevelopmental and neurodegenerative disorders with multiple complex interactions between genetics and environmental factors such as nutrition. Mental health problems, autism, eating disorders, Alzheimer's disease, schizophrenia, Parkinson's disease and brain tumours are related to individual variability in numerous protein-coding and non-coding regions of the genome. However, genotype does not necessarily determine neurological phenotype because the epigenome modulates gene expression in response to endogenous and exogenous regulators, throughout the life-cycle.

Recent advances in nutrition, genes and brain health.

Molecular mechanisms underlying brain structure and function are affected by nutrition throughout the life cycle, with profound implications for health and disease. Responses to nutrition are in turn influenced by individual differences in multiple target genes. Recent advances in genomics and epigenomics are increasing understanding of mechanisms by which nutrition and genes interact.

New insights into nutrition and cognitive neuroscience.

Nutrition can affect the brain throughout the life cycle, with profound implications for mental health and degenerative disease. Many aspects of nutrition, from entire diets to specific nutrients, affect brain structure and function. The present short review focuses on recent insights into the role of nutrition in cognition and mental health and is divided into four main sections.

Role of the alphaI domain in ligand binding by integrin alphaEbeta7.

The I domain of integrin alphaE was modeled on the crystal structure of that in CD11b and mutated to produce an open (high affinity) or closed (low affinity) conformation. K562 transfectants expressing mutant alphaE and wild-type beta7 were tested for adhesion to E-cadherin-Fc. Downward displacement of the C terminus of the alphaI domain with a disulfide bridge enhanced adhesion and Mn(2+) dependency.

Control of growth hormone receptor and insulin-like growth factor-I expression by cortisol in ovine fetal skeletal muscle.

Insulin-like growth factor (IGF)-I has an important role in myogenesis but its developmental regulation in skeletal muscle before birth remains unknown. In other tissues, cortisol modulates IGF gene expression and is responsible for many of the prepartum maturational changes essential for neonatal survival. Hence, using RNase protection assays and ovine riboprobes, expression of the IGF-I and growth hormone receptor (GHR) genes was examined in ovine skeletal muscle during late gestation and after experimental manipulation of fetal plasma cortisol levels by fetal adrenalectomy and exogenous cortisol infusion.

Differential regulation of porcine hepatic IGF-I mRNA expression and plasma IGF-I concentration by a low lysine diet.

The influence of dietary lysine on hepatic insulin-like growth factor-I (IGF-I) gene expression and plasma IGF-I level was investigated. Two male 6-wk-old pigs from each of six litters were used. Each littermate was assigned to one of two diets, control or low lysine (LL), that were isoenergetic and similar in protein content and provided 14.

Thyroid hormones and the mRNA of the GH receptor and IGFs in skeletal muscle of fetal sheep.

Thyroid hormones are required for the normal development of skeletal muscle in utero, although their mechanism of action is poorly understood. The present study examined the effects of the thyroid hormones on the gene expression of the growth hormone receptor (GHR) and the insulin-like growth factors (IGFs) IGF-I and IGF-II, in skeletal muscle of fetal sheep during late gestation (term 145 +/- 2 days) and after manipulation of plasma thyroid hormone concentration. Thyroidectomy at 105-110 days of gestation suppressed muscle GHR and IGF-I gene expression in fetuses studied at 127-130 and 142-145 days.

Developmental expression analysis of thyroid hormone receptor isoforms reveals new insights into their essential functions in cardiac and skeletal muscles.

Nuclear thyroid hormone (TH) receptors (TR) play a critical role in mediating the diverse actions of TH in development, differentiation, and metabolism of most tissues, but the role of TR isoforms in muscle development and function is unclear. Therefore, we have undertaken a comprehensive expression analysis of TRalpha 1, TRbeta 1, TRbeta 2 (TH binding), and TRalpha 2 (non-TH binding) in functionally distinct porcine muscles during prenatal and postnatal development. Use of a novel and highly sensitive RNase protection assay revealed striking muscle-specific developmental profiles of all four TR isoform mRNAs in cardiac, longissimus, soleus, rhomboideus, and diaphragm.

Nutrition-hormone receptor-gene interactions: implications for development and disease.

Nutrition profoundly alters the phenotypic expression of a given genotype, particularly during fetal and postnatal development. Many hormones act as nutritional signals and their receptors play a key role in mediating the effects of nutrition on numerous genes involved in differentiation, growth and metabolism. Polypeptide hormones act on membrane-bound receptors to trigger gene transcription via complex intracellular signalling pathways.

Postnatal regulation of myosin heavy chain isoform expression and metabolic enzyme activity by nutrition.

Development of muscle is critically dependent on several hormones which in turn are regulated by nutritional status. We therefore determined the impact of mild postnatal undernutrition on key markers of myofibre function: type I slow myosin heavy chain (MyHC) isoform, myosin ATPase, succinate dehydrogenase and alpha-glycerophosphate dehydrogenase. In situ hybridization, immunocytochemistry and enzyme histochemistry were used to assess functionally distinct muscles from 6-week-old pigs which had been fed an optimal (6% (60 g food/kg body weight per d)) or low (2% (20 g food/kg per d)) intake for 3 weeks, and kept at 26 degrees C.

Growth hormone receptor gene expression in porcine skeletal and cardiac muscles is selectively regulated by postnatal undernutrition.

During mild postnatal undernutrition, growth hormone receptor (GHR) mRNA abundance decreases in liver but increases in longissimus dorsi muscle. We tested the following hypotheses: 1) GHR gene expression is related to the metabolic and contractile characteristics of different muscles, and 2) the GHR response to nutrition depends on muscle type. Eight pairs of littermate pigs were weaned at 3 wk and given an optimal [60 g/(kg.

Control of ovine hepatic growth hormone receptor and insulin-like growth factor I by thyroid hormones in utero.

By use of RNase protection assays, hepatic growth hormone receptor (GHR) and insulin-like growth factor I (IGF-I) mRNA abundances were measured in sheep fetuses after experimental manipulation of fetal plasma thyroid hormone concentrations by fetal thyroidectomy (TX) and exogenous infusion of triiodothyronine (T(3)) and cortisol. TX abolished the normal prepartum rise in hepatic GHR abundance but had little effect on hepatic GHR gene expression at 127-130 days (term 145 +/- 2 days). By contrast, it upregulated basal IGF-I expression in immature fetal liver by increasing both Class 1 and Class 2 transcript abundance but had no further effects on IGF-I gene mRNA levels at 142-145 days.

Exogenous growth hormone induces somatotrophic gene expression in neonatal liver and skeletal muscle.

The extent to which the local somatotrophic axis is functional in extrahepatic tissues in the neonate is unclear. We therefore determined the expression of growth hormone (GH) receptor (GHR), and insulin-like growth factors I and II (IGF-I and IGF-II) mRNA in liver and skeletal muscle (longissimus) of neonatal pigs given daily intramuscular injections of either recombinant porcine GH (1 mg/kg body wt; n = 6) or saline (n = 5) for 7 days. Exogenous GH increased plasma concentrations of GH 30-fold and IGF-I threefold.

Sequence-dependent DNA structure: tetranucleotide conformational maps.

A database of X-ray crystal structures of double helical DNA oligomers has been used to analyse the role of the sugar-phosphate backbone in coupling the conformational properties of neighbouring dinucleotide steps. The base step parameters which are most strongly coupled to the backbone degrees of freedom are slide and shift, and these are the two dinucleotide step parameters which show strong correlations along a sequence: the value of slide follows the values in the neighbouring steps, whereas shift tends to alternate. This conformational coupling is mediated by the shared furanose rings at the step junctions: a change in the value of slide causes a change in the mean value of the same strand 3' and 5'-chi torsion angle, and a change in the mean value of the 3' and 5' sugar pseudo-rotation phase angle, P; a change in the value of shift causes a difference between the same strand 3' and 5'-chi in A-DNA and a difference between the 3' and 5'-P in B-DNA.

Sequence-dependent DNA structure: dinucleotide conformational maps.

We have used a computational model to calculate the potential energy surface for dinucleotide steps in double helical DNA as a function of the two principal degrees of freedom, slide and shift. By using a virtual bond to model the constraints imposed by the sugar-phosphate backbone, twist, roll, tilt and rise can be simultaneously optimised for any given values of slide and shift. Thus we have been able to construct complete conformational maps for all step types.

Nutrition and neurodevelopment: mechanisms of developmental dysfunction and disease in later life.

Nutrition plays a central role in linking the fields of developmental neurobiology and cognitive neuroscience. It has a profound impact on the development of brain structure and function and malnutrition can result in developmental dysfunction and disease in later life. A number of diseases, including schizophrenia, may be related to neurodevelopmental insults such as malnutrition, hypoxia, viruses or in utero drug exposure.

Differential expression of thyroid hormone receptor isoforms is strikingly related to cardiac and skeletal muscle phenotype during postnatal development.

The genomic actions of thyroid hormones (THs) are mediated by receptors (TRs) that are encoded by two protooncogenes, c-erbA-alpha and c-erbA-beta. The precise functions of the TR isoforms are unclear and this study focuses on the potential roles of the TRalpha and TRbeta isoforms in mammalian striated muscles postnatally. The porcine TRalpha1, TRalpha2 and TRbeta1 cDNAs were first cloned, sequenced and characterised by Northern blotting.

Suboptimal energy balance selectively up-regulates muscle GLUT gene expression but reduces insulin-dependent glucose uptake during postnatal development.

The major facilitative glucose transporters in muscle, GLUT1 (insulin-independent) and GLUT4 (insulin-dependent), are essential for normal growth and metabolism, but factors controlling their expression during postnatal development are poorly understood. We have therefore determined the role of energy status in regulating muscle GLUT gene expression and function in young, growing pigs on a high (H) or low (L) food intake (H =2L) at 35 degrees C or 26 degrees C. RNase protection assays revealed selective up-regulation of GLUT1 and GLUT4 by mild undernutrition 20-24 h after feeding: mRNA levels were elevated in longissimus dorsi (P<0.

Activation of the adult mode of ovine growth hormone receptor gene expression by cortisol during late fetal development.

The developmental and tissue-specific regulation of growth hormone receptor (GHR) mRNA expression is complex and involves alternate leader exon usage. The transcript composition of hepatic GHR mRNA has therefore been determined in fetal sheep during late gestation and after experimental manipulation of fetal plasma cortisol levels by fetal adrenalectomy and exogenous cortisol infusion, using RNase protection assays and a riboprobe containing exons 1A, 2, and 3 of the ovine GHR gene. Expression of the adult liver-specific GHR mRNA transcript containing exon 1A was not detected earlier than 138 days of gestation (term 145 +/-2 days).

Transcriptional regulation of insulin-like growth factor-II gene expression by cortisol in fetal sheep during late gestation.

The objective of this study was to determine the mechanisms by which cortisol down-regulates hepatic insulin-like growth factor-II (IGF-II) gene expression in late gestation. Leader exons 6 and 7 of the ovine IGF-II gene, with their 5'-flanking regions, were first isolated. Characterization of transcription start sites revealed a unique site for exon 6 and three dispersed sites for exon 7.

Effects of thyroid status on insulin-like growth factor-I, growth hormone and insulin are modified by food intake.

Understanding the interactions between metabolic signals that regulate insulin-like growth factor-I (IGF-I) is crucial to a recognition of mechanisms that control mammalian growth. Thyroid hormones (THs) are essential for normal growth and development, and it has been suggested previously that they can modify circulating IGF-I concentrations. However, the fact that THs influence food intake, which can itself affect plasma IGF-I levels, has been ignored in previous studies.

Transient upregulation of IGF-I gene expression in brown adipose tissue of cold-exposed rats.

The possible involvement of locally produced insulin-like growth factor I (IGF-I) in the cold-induced hyperplasia of interscapular brown adipose tissue (BAT) was investigated in 2-, 4-, and 7-day cold-exposed (CE, 4 degrees C) rats by measuring BAT IGF-I expression at a time when extensive BAT cell proliferation occurs. By comparison with thermoneutral (25 degrees C) controls, plasma IGF-I decreased in CE rats despite an increased food intake, whereas BAT IGF-I peptide increased markedly to peak after 4 days at 4 degrees C. The ratio of class 1 to class 2 IGF-I mRNA was much higher in BAT than in liver.

Postnatal development and differentiation of myofibres in functionally diverse porcine skeletal muscles.

Marked changes in muscle function occur after birth, with the response being dependent on developmental stage. Therefore, postnatal cellular ontogeny of functionally distinct skeletal muscles was investigated in the pig, a large mammal born at a relatively advanced stage of development. Assessment of myofibre contractile (type I slow/type II fast) and metabolic (oxidative/glycolytic) properties at Days 0, 2, 5 and 14 revealed type-specific differences in hypertrophy and differentiation.