MAP Kinases Couple Hindbrain-Derived Catecholamine Signals to Hypothalamic Adrenocortical Control Mechanisms during Glycemia-Related Challenges

Abstract

Physiological responses to hypoglycemia, hyperinsulinemia, or hyperglycemia include a critical adrenocortical component that is initiated by hypothalamic control of the anterior pituitary and adrenal cortex. These adrenocortical responses ensure appropriate long-term glucocorticoid-mediated modifications to metabolism. Despite the importance of these mechanisms to disease processes, how hypothalamic afferent pathways engage the intracellular mechanisms that initiate adrenocortical responses to glycemia-related challenges are unknown. This study explores these mechanisms using network- and cellular-level interventions in in vivo and ex vivo rat preparations. Results show that a hindbrain-originating catecholamine afferent system selectively engages a MAP kinase pathway in rat paraventricular hypothalamic CRH neuroendocrine neurons shortly after vascular insulin and 2-deoxyglucose challenges in vivo. In turn, this MAP kinase pathway can control both neuroendocrine neuronal firing rate and the state of CREB phosphorylation in a reduced ex vivo paraventricular hypothalamic preparation, making this signaling pathway an ideal candidate for coordinating CRH synthesis and release. These results establish the first clear structural and functional relationships linking neurons in known nutrient-sensing regions with intracellular mechanisms in hypothalamic CRH neuroendocrine neurons that initiate the adrenocortical response to various glycemia-related challenges.

Stimulation of feeding by three different glucose-sensing mechanisms requires hindbrain catecholamine neurons

“…First, the blockade of GcA-induced feeding by U0126 suggests that the postsynaptic effects of catecholamine neurons required for GcA-induced feeding, like those required for secretion of corticotrophin-releasing hormone in response to 2DG and hypoglycemia (19), may be transduced by the MEK/ ERK1/2 signaling cascade. Second, differential dependence of 5TG, GcA and Phl on MEK signaling for the feeding effect may indicate that these substances exert their effects on different catecholaminergic cell populations, as discussed above.…”

“…Since both lateral and fourth ventricle (LV and 4V, respectively) injections of GcA, Phl, and 5TG have been demonstrated to increase food intake (11,34,44,45), suggesting the possibility that these drugs may act at multiple sites to produce their glucoregulatory actions, we tested both LV and 4V injections of these agents in this study. Finally, we examined the dependence of GcA-, Phl-, and 5TG-induced feeding on the mitogen-activated protein kinase (MAPK)/ERK1/2 signaling cascade, which has been shown to be essential for transducing NE-mediated corticotropin-releasing hormone transcription and release in response to glucoprivation (19).…”

CRH: The link between hormonal-, metabolic- and behavioral responses to stress

“…CRH promoter contains cis-acting elements among those the cAMP-response element (CRE) is of the highest significance in stress-initiated CRH transcription (Kovacs & Sawchenko 1996b, Seasholtz et al 1991, Seasholtz et al 1988 . This site integrates cAMP-PKA (Majzoub et al 1993), MAPK -ERK 1/2 (Khan et al 2011, Khan et al 2007, PKC (Majzoub et al 1993) and intracellular Ca 2+ signaling via phosphorylation of CREB (Khan et al 2011, Kovacs & Sawchenko 1996a). This relatively simple scenario of CRH regulation is complicated by several factors.…”

Molecular Regulation of Corticotropin-Releasing Hormone Gene Expression in Parvocellular Neurons of the Hypothalamic Paraventricular Nucleus

“…Activation of the CRH neuron during stress is associated with induction of a number of immediate early genes, such as c-fos, Fra-2, zif-268/Egr-1, the Nr4a family factors, Nur-77 and Nor-1, NGF1B, as well as nuclear translocation of phopho-CREB and the MAP kinase, ERK, in CRH neurons [32]. Although all of these transcription factors are potentially involved in transcriptional regulation of CRH, with the exception of CREB, the exact interaction of these factors with response elements in the CRH promoter remains unknown.…”