Shipston, M. J. | Search bioRxiv

bioRxiv2022

LKB1 is the gatekeeper of carotid body chemo-sensing and the hypoxic ventilatory response

The hypoxic ventilatory response (HVR) is critical to breathing and thus oxygen supply to the body and is primarily mediated by the carotid bodies. Here we reveal that carotid body afferent discharge during hypoxia and hypercapnia is determined by the expression of Liver Kinase B1 (LKB1), the principal kinase that activates the AMP-activated protein kinase (AMPK) during metabolic stresses. Conversely, conditional deletion in catecholaminergic cells of AMPK had no effect on carotid body responses to hypoxia or hypercapnia. By contrast, the HVR was attenuated by LKB1 and AMPK deletion. However, in LKB1 knockouts hypoxia evoked hypoventilation, apnoea and Cheyne-Stokes-like breathing, while only hypoventilation and apnoea were observed after AMPK deletion. We therefore identify LKB1 as an essential regulator of carotid body chemosensing and uncover a divergence in dependency on LKB1 and AMPK between the carotid body on one hand and the HVR on the other.

physiology↗

bioRxiv2020

Dissection of the corticotroph transcriptome in a mouse model of glucocorticoid-induced suppression of the HPA axis

Glucocorticoids (GC) are prescribed for periods >3 months to 1-3% of the UK population; 10-50% of these patients develop hypothalamus-pituitary-adrenal (HPA) axis suppression, which may last over 6 months and is associated with morbidity and mortality. Recovery of higher nodes of the axis is necessary for recovery of adrenal function. We developed a mouse model of Dexamethasone (DEX)-induced HPA axis dysfunction in order to further explore recovery in the pituitary. Adult male C57BL6/J or those crossed with Pomc-eGFP mice were randomly assigned to receive DEX (~0.4 mg/kg bodyweight/day) or vehicle via drinking water for 4 weeks following which treatment was withdrawn. Tissues were harvested at 0, 1, and 4 weeks following withdrawal of treatment. Corticotrophs were isolated from Pomc-eGFP pituitaries using FACS, and RNA extracted for RNA-seq. DEX treatment suppressed corticosterone production, which remained partially suppressed at least 1 week following DEX withdrawal. In the adrenal, at time 0, Hsd3b2, Cyp11a1, and Mc2r mRNA levels were significantly reduced, with Mc2r and Cyp11a1 remaining reduced 1 week following DEX withdrawal. The corticotroph transcriptome was modified by DEX treatment with some differences between groups persisting 4 weeks following withdrawal. No genes supressed by DEX exhibited ongoing attenuation 1 and 4 weeks following withdrawal, whilst only 2 genes were upregulated and remained so following withdrawal. A pattern of rebound at 1 and 4 weeks was observed in 14 genes that increased following suppression, and 6 genes that were reduced by DEX and then increased. Chronic GC treatment may induce persistent changes in the pituitary that may influence future response to GC treatment or stress.

physiology↗