In addition to their well-known function as dietary lipid detergents, bile acids have emerged as important signalling molecules that regulate energy homeostasis. Recent studies have highlighted that disrupted bile acid metabolism is associated with metabolism disorders such as dyslipidaemia, intestinal chronic inflammatory diseases and obesity. In particular, type 2 diabetes (T2D) is associated with quantitative and qualitative modifications in bile acid metabolism. Bile acids bind and modulate the activity of transmembrane and nuclear receptors (NR). Among these receptors, the G-protein-coupled bile acid receptor 1 (TGR5) and the NR farnesoid X receptor (FXR) are implicated in the regulation of bile acid, lipid, glucose and energy homeostasis. The role of these receptors in the intestine in energy metabolism regulation has been recently highlighted. More precisely, recent studies have shown that FXR is important for glucose homeostasis in particular in metabolic disorders such as T2D and obesity. This review highlights the growing importance of the bile acid receptors TGR5 and FXR in the intestine as key regulators of glucose metabolism and their potential as therapeutic targets.

A fundamental question in stress research is when the glucocorticoid stress hormone (cortisol in man) stops being neuroprotective and becomes harmful to the brain with negative consequences for cognition and mood. To address this question Section 1 focuses on the action mechanism of glucocorticoids. These hormones act via high and low affinity nuclear receptors, which regulate gene transcription in a coordinate manner. The receptors are expressed abundantly in hippocampus, amygdala and frontal cortex involved in cognitive processes. In Section 2 hypercortisolism is considered a potential disease factor for about 50% of the patients suffering from major depression. Recent data show that these patients recover within a few days when excess cortisol action is blocked with high doses of an antiglucocorticoid. Section 3 concerns animal models with ‘depression-like’ features of hypercorticism generated by manipulation of gene X environment inputs. Using gene expression profiling technology in the hippocampal transcriptome of these animals we identified about 700 potential targets for antidepressants out of 30 000 detectable gene products. One of our models is based on early life programming of the stress system. Rats exposed as pups to maternal deprivation display at senescence an enhanced individual difference in cognitive performance. The maternally deprived senescent animals age either successfully or become senile, at the expense of the average performance of non-deprived controls. The essay is concluded with the notion that the new generation of antidepressants ameliorates specific psychic dysfunctions (e.g. cognitive performance) linked to aberrant stress hormone action in discrete brain regions.

ATP-binding cassette (ABC) transporters play a pivotal role in human physiology, and mutations in these genes often result in severe hereditary diseases. ABC transporters are expressed in the bovine mammary gland but their physiological role in this organ remains elusive. Based on findings in the context of human disorders we speculated that candidate ABC transporters are implicated in lipid and cholesterol transport in the mammary gland. Therefore we investigated the expression pattern of selected genes that are associated with sterol transport in lactating and nonlactating mammary glands of dairy cows. mRNA levels from mammary gland biopsies taken during lactation and in the first and second week of the dry period were analysed using quantitative PCR. Five ABC transporter genes, namely ABCA1, ABCA7, ABCG1, ABCG2 and ABCG5, their regulating genes LXRα, PPARγ, SREBP1 and the milk proteins lactoferrin and α-lactalbumin were assessed. A significantly enhanced expression in the dry period was observed for ABCA1 while a significant decrease of expression in this period was detected for ABCA7, ABCG2, SREBP1 and α-lactalbumin. ABCG1, ABCG5, LXRα, PPARγ and lactoferrin expression was not altered between lactation and dry period. These results indicate that candidate ABC transporters involved in lipid and cholesterol transport show differential mRNA expression between lactation and the dry period. This may be due to physiological changes in the mammary gland such as immigration of macrophages or the accumulation of fat due to the loss of liquid in the involuting mammary gland. The current mRNA expression analysis of transporters in the mammary gland is the prerequisite for elucidating novel molecular mechanisms underlying cholesterol and lipid transfer into milk.

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. By contrast, nuclear receptors for lipid-soluble molecules such as glucocorticoids (GC) and thyroid hormones (TH) directly regulate transcription via DNA binding and chromatin remodelling. Nuclear hormone receptors are members of a large superfamily of transcriptional regulators with the ability to activate or repress many genes involved in development and disease. Nutrition influences not only hormone synthesis and metabolism but also hormone receptors, and regulation is mediated either by specific nutrients or by energy status. Recent studies on the role of early environment on development have implicated GC and their receptors in the programming of adult disease. Intrauterine growth restriction and postnatal undernutrition also induce striking differences in TH-receptor isoforms in functionally-distinct muscles, with critical implications for gene transcription of myosin isoforms, glucose transporters, uncoupling proteins and cation pumps. Such findings highlight a mechanism by which nutritional status can influence normal development, and modify nutrient utilization, thermogenesis, peripheral sensitivity to insulin and optimal cardiac function. Diet and stage of development will also influence the transcriptional activity of drugs acting as ligands for nuclear receptors. Potential interactions between nuclear receptors, including those for retinoic acid and vitamin D, should not be overlooked in intervention programmes using I or vitamin A supplementation of young and adult human populations.

The peroxisome proliferator-activated receptor gamma (PPARγ) is nuclear receptor that controls the expression of a large number of genes involved in adipocyte differentiation, lipid storage and insulin sensitization. PPARγ is bound and activated by fatty acid derivatives and prostaglandin J2. In addition, thiazolidinediones, non-steroidal anti-inflammatory drugs are synthetic ligands and agonists of this receptor. This review addresses the role of PPARγ in obesity and diabetes.

The thyroid hormones are very hydrophobic and those that exhibit biological activity are 3′,5′,3,5-L-tetraiodothyronine (T4), 3′,5,3-L-triiodothyronine (T3), 3′,5′,3-L-triiodothyronine (rT3) and 3,5,-L-diiodothyronine (3,5-T2). At physiological pH, dissociation of the phenolic −OH group of these iodothyronines is an important determinant of their physical chemistry that impacts on their biological effects. When non-ionized these iodothyronines are strongly amphipathic. It is proposed that iodothyronines are normal constituents of biological membranes in vertebrates. In plasma of adult vertebrates, unbound T4 and T3 are regulated in the picomolar range whilst protein-bound T4 and T3 are maintained in the nanomolar range. The function of thyroid-hormone-binding plasma proteins is to ensure an even distribution throughout the body. Various iodothyronines are produced by three types of membrane-bound cellular deiodinase enzyme systems in vertebrates. The distribution of deiodinases varies between tissues and each has a distinct developmental profile. Thyroid hormones have many effects in vertebrates. It is proposed that there are several modes of action of these hormones. (1) The nuclear receptor mode is especially important in the thyroid hormone axis that controls plasma and cellular levels of these hormones. (2) These hormones are strongly associated with membranes in tissues and normally rigidify these membranes. (3) They also affect the acyl composition of membrane bilayers and it is suggested that this is due to the cells responding to thyroid-hormone-induced membrane rigidification. Both their immediate effects on the physical state of membranes and the consequent changes in membrane composition result in several other thyroid hormone effects. Effects on metabolism may be due primarily to membrane acyl changes. There are other actions of thyroid hormones involving membrane receptors and influences on cellular interactions with the extracellular matrix. The effects of thyroid hormones are reviewed and appear to be combinations of these various modes of action. During development, vertebrates show a surge in T4 and other thyroid hormones, as well as distinctive profiles in the appearance of the deiodinase enzymes and nuclear receptors. Evidence from the use of analogues supports multiple modes of action. Re-examination of data from the early 1960s supports a membrane action. Findings from receptor ‘knockout’ mice supports an important role for receptors in the development of the thyroid axis. These iodothyronines may be better thought of as ‘vitamone’-like molecules than traditional hormonal messengers.

The properties of nuclear receptors belonging to the superfamily of receptors acting as transcription factors are modulated by nutritional and hormonal conditions. We showed recently that retinoic acid (RA) restored to normal the expression of receptors attenuated by hypothyroidism. The present study was designed to find out whether dietary vitamin A (as retinol) had the same effect. Propylthiouracil in drinking water induced both hypothyroidism and a vitamin A-deficient status in rats. The maximum binding capacity (Cmax) of triiodothyronine nuclear receptors (TR) was unchanged, while that of nuclear RA receptors (RAR) and nuclear glucocorticoid hormone receptors (GRn) was reduced in the liver of these hypothyroid rats. The reduced Cmax of RAR stemmed from a lower level of RAR mRNA, while the reduced Cmax of GRn was assumed to be due to reduced translocation of the receptor from the cytosol to the nucleus. Feeding the hypothyroid rats with a vitamin A-rich diet did not restore the Cmax of either RAR or GRn to normal. The lack of effect of dietary retinol on RAR expression may be attributed to either genomic (unoccupied TR block the expression of RAR genes) and/or extragenomic (hypothyroidism decreases the availability of retinol and/or its metabolism to RA) mechanisms. Triiodothyronine is thought to favour the translocation of glucocorticoid hormone receptors from cytosol to nucleus. These findings provide more information on the relationship between vitamin A and hormonal status, showing that a vitamin A-rich diet is without apparent effect on the expression of nuclear receptors in hypothyroid rats.