Glucocorticoids are released after hypothalamus-pituitary-adrenal axis stimulation by stress and act both in the periphery and in the brain to bring about adaptive responses that are essential for life. Dysregulation of the stress response can precipitate psychiatric diseases, in particular depression. Recent genetic studies have suggested that the glucocorticoid carrier transcortin, also called corticosteroid-binding globulin (CBG), may have an important role in stress response. We have investigated the effect of partial or total transcortin deficiency using transcortin knockout mice on hypothalamus-pituitary-adrenal axis functioning and regulation as well as on behaviors linked to anxiety and depression traits in animals. We show that CBG deficiency in mice results in markedly reduced total circulating corticosterone at rest and in response to stress. Interestingly, free corticosterone concentrations are normal at rest but present a reduced surge after stress in transcortin-deficient mice. No differences were detected between transcortin-deficient mice for anxiety-related traits. However, transcortin-deficient mice display increased immobility in the forced-swimming test and markedly enhanced learned helplessness after prolonged uncontrollable stress. The latter is associated with an approximately 30% decrease in circulating levels of free corticosterone as well as reduced Egr-1 mRNA expression in hippocampus in CBG-deficient mice. Additionally, transcortin-deficient mice show no sensitization to cocaine-induced locomotor responses, a well described corticosterone-dependent test. Thus, transcortin deficiency leads to insufficient glucocorticoid signaling and altered behavioral responses after stress. These findings uncover the critical role of plasma transcortin in providing an adequate endocrine and behavioral response to stress.

Our aim was to explore the nutritional consequences of functional variations in the hypothalamic-pituitary-adrenocortical (HPA) axis in rats. We first aimed to compare the HPA axis activity and reactivity to stress between Fischer 344 (F344) and LOU/C (LOU) strains that differ in food behavior and metabolism. When compared with F344 rats, LOU rats showed lower corticosterone (Cort) levels across the circadian cycle and after restraint stress. Then, we compared the effects of adrenalectomized (ADX) and Cort substitution after ADX on food intake, body weight gain, body composition, and biochemical parameters related to metabolism and HPA axis function between 1) the F344 rat strain, a model of HPA axis hyperactivity and hyperreactivity to stress, and characterized by a large fat mass; 2) the LOU strain, shown to exhibit hypoactive/hyporeactive HPA axis, reduced fat mass, and resistance to diet-induced obesity; and 3) the Lewis (LEW) strain, a third condition of fat deposition (high) related to HPA axis function (low activity/reactivity). The F344 and LEW strains exhibited classical responses to ADX and Cort. On the contrary, LOU rats showed an apparent insensitivity to ADX. Despite the highest effects of Cort related to glucocorticoid receptor (on thymus weight, corticotropinreleasing factor, or corticosteroid-binding globulin), the LOU strain was insensitive to Cort effects on body weight, liver, and abdominal fat mass. These characteristics could be involved in the leanness, insensitivity to diet-induced obesity, and healthy aging in LOU. Our study shows the relevance of comparing the F344, LOU, and LEW strains to cover the complexity of interactions between metabolism and HPA axis function.

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With the aim to reveal common genomic regions influencing phenotypes related to HPA axis function and metabolism, we did a quantitative trait loci (QTL) study in a F2 population obtained from the cross-breeding between 2 contrasted rat strains, LOU/C and Fischer 344. QTL determining phenotypes related first to corticotropic function were searched: plasma corticosterone (Cort) in control and stress conditions, after a dexamethasone suppression treatment (glucocorticoid receptor related-effect), and mineralocorticoid receptor-mediated urinary response to aldosterone. Then, phenotypes related to metabolism were studied on the same animals: body composition, basal and post-insulin plasma glucose, plasma free fatty acids, leptin, and insulin. Finally, we analyzed the overlapping regions between these QTL and looked for candidate genes within these regions. The gene NR3C1 encoding the glucocorticoid receptor was confirmed to be central in the link between hypothalamic-pituitary-adrenal (HPA) axis function and fat deposition, and its metabolic consequences. Among the other candidate genes detected, most contain a glucocorticoid responsive element, strengthening our hypothesis of common genetic determinism between HPA axis and metabolism.