Elucidating Molecular Networks That Either Affect or Respond to Plasma Cortisol Concentration in Target Tissues of Liver and Muscle

Abstract

Cortisol is a steroid hormone with important roles in regulating immune and metabolic functions and organismal responses to external stimuli are mediated by the glucocorticoid system. Dysregulation of the afferent and efferent axis of glucocorticoid signaling have adverse effects on growth, health status, and well-being. Glucocorticoid secretion and signaling show large interindividual variation that has a considerable genetic component; however, little is known about the underlying genetic variants. Here, we used trait-correlated expression analysis, screening for expression quantitative trait loci (eQTL), genome-wide association (GWA) studies, and causality modeling to identify candidate genes in porcine liver and muscle that affect or respond to plasma cortisol levels. Through trait-correlated expression, we characterized transcript activities in many biological functions in liver and muscle. Candidates from the list of trait-correlated expressed genes were narrowed using only those genes with an eQTL, and these were further prioritized by determining whether their expression was predicted to be related to variation in plasma cortisol levels. Using network edge orienting (NEO), a causality modeling algorithm, 26 of 990 candidates in liver were predicted to affect and 70 to respond to plasma cortisol levels. Of 593 candidates in muscle that were correlated with cortisol levels and were regulated by eQTL, 2 and 25 were predicted as effective and responsive, respectively, to plasma cortisol levels. Comprehensive data integration has helped to elucidate the complex molecular networks contributing to cortisol levels and thus its subsequent metabolic effects. The discrimination of up-and downstream effects of transcripts affecting or responding to plasma cortisol concentrations improves the understanding of the biology of complex traits related to growth, health, and well-being. C ORTISOL, a steroid hormone released in response to stress and a low level of blood glucocorticoids, acts to increase blood sugar through gluconeogenesis; suppress the immune system; and aid in fat, protein, and carbohydrate metabolism. Produced in the adrenal cortex under the control of the hypothalamic-pituitary-adrenal axis and the sympatho-adrenomedullar (SAM) system, cortisol is most important during times of stress, when it modulates many of the acute responses to illness and "resets" metabolism in favor of providing substrates for oxidative metabolism (Andrews and Walker 1999). Stress factors can unbalance metabolic homeostasis, directing the demand for nutrients and energy for essential physiological processes away from growth (Heetkamp et al. 1995). Individual cortisol concentration is variable and depends on sensitivity to stress, which is highly genetically determined (e.g., heritability estimates of 0.40-0.70 in pigs) (Geverink et al. 2002; Kadarmideen and Janss 2009). According to the function of cortisol in the maintenance of basal and stress-related homeostasis the adrenocortical steroidogenesis is sensitive to exo...

Biochemical and proteomic analyses of the physiological response induced by individual housing in gilts provide new potential stress markers

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Emerging Role of Corticosteroid-Binding Globulin in Glucocorticoid-Driven Metabolic Disorders

“…The cDNA sequence analysis of parental strains revealed a Met276Ile mutation in WKY rat identical to that found in the Biobreeding rat strain that exhibits decreased CBG binding affinity for corticosterone (14). More recently, a series of studies conducted in different pig lines confirmed the genetic linkage or genetic association between SerpinA6/CBG locus and basal cortisol levels in pig (15–18). Finally, in humans, a very significant association between the SERPINA6/SERPINA1 locus and morning plasma cortisol concentrations was reported in a genome-wide association meta-analysis using ~2.5 M SNPs in 12,597 Caucasian subjects, replicated in 2,795 participants (19).…”

Transcript variants of the porcine glucocorticoid receptor gene (NR3C1)

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