Hypoxia stress exerts responses involving the HPA and HPT axes.

<p>Under hypoxia, the potential neuro-endocrine-immune/metabolism networks contribute to the regulation of moderate inflammation and the maintenance of energy balance. Hypoxia may inhibit the hypothalamic-pituitary-adrenal (HPA) axis and induce the expression of ET-1/ADM, and the latter then promote the expression of IL-6/TNF-α and form a positive feedback loop with them. On the other hand, the ET-1/ADM and IL-6/TNF-α may in turn activate the HPA axis, and the latter subsequently induces glucocorticoids and generates a negative feedback to inhibit <i>ET-1/ADM</i> and <i>IL-6/TNF-α</i> expression to reduce the inflammatory responses in brain. Therefore a HPA axis-ET-1/ADM-IL-6/TNF-α feedback regulatory loop is outlined here. Besides, both SOCS-1 and SOCS-3 may have complementary roles in down-regulating <i>IL-6</i> and <i>TNF-α</i>, and both IL-6 and TNF-α have reciprocal functions to induce <i>SOCS-1</i> and <i>SOCS-3</i> expression, thus constituting a SOCS-1/3-dependent feedback regulation to modify cerebral inflammation. The hypothalamic-pituitary-thyroid (HPT) axis was inhibited in <i>L</i>. <i>crocea</i> brains during the early period of hypoxia, thus leading to a decrease in thyroid hormone (T3 and T4) production. Decrease of HPT axis-thyroid hormones subsequently may inhibit protein synthesis by the PI3K-Akt-mTOR-S6K signaling pathway, which contributes to the reduction in energy consumption during hypoxia stress. Meanwhile, down-regulation of HPT axis-thyroid hormones also represses the tricarboxylic acid (TCA) cycle and accelerates the anaerobic glycolytic pathway, which facilitates O₂-independent ATP production under hypoxia. Therefore the HPT axis-mediated effects may play roles in response to hypoxia by reorganizing energy consumption and generation. Genes related to the neuro-endocrine system (orange), immunity (red), and metabolic system and protein synthesis (blue) are indicated. The outer border indicates the brain of <i>L</i>. <i>crocea</i>. The arrow represents promotion, and the interrupted line represents inhibition. Solid lines indicate direct relationships between genes. Dashed lines indicate that more than one step is involved in the process.