Biology subjects

Nixon, M.

Publications and source records attributed to Nixon, M..

5 recordsLinked to original sources

bioRxiv2026

Rapid turnover of corticosterone in humans: the role of a second glucocorticoid hormone

BACKGROUNDAdrenal insufficiency is primarily treated with replacement of cortisol, which is the predominant circulating glucocorticoid. Human adrenals also secrete corticosterone and emerging evidence suggests this may be a safer glucocorticoid replacement therapy. However, little is known about corticosterone in humans, particularly related to its metabolism. METHODSTo investigate the secretion and metabolism of corticosterone in comparison with cortisol, we: 1) investigated the diurnal rhythm of circulating cortisol/ corticosterone in 7 healthy volunteers; 2) quantified A-ring reduction of both hormones in human hepatic cytosol and 3) measured glucocorticoid metabolites in vivo in 24 healthy men; 4) determined the pharmacokinetics of corticosterone via intravenous infusion of 2,2,4,6,6,17,21,21-[2H]8-corticosterone; 5) assessed the response of corticosterone and cortisol to 1mcg ACTH in 279 healthy volunteers. RESULTSThe natural diurnal rhythm of corticosterone closely mirrored that of cortisol, and accounted for [~]3% of total circulating glucocorticoid concentrations. Daily corticosterone production, as measured through urinary steroid profiling, was approximately 10-fold lower than cortisol, and corticosterone demonstrated substantially greater metabolism by both 5- and 5{beta}-reductase than cortisol. In keeping with greater metabolism, the half-life of corticosterone was 28.5 {+/-} 3.3 minutes. Finally, corticosterone demonstrated a greater relative rise in response to ACTH than cortisol, particularly in men, revealing sex-specific differences. CONCLUSIONSCorticosterone is a dynamic glucocorticoid with faster metabolism and greater response to stimulation than cortisol in humans. These data raise the possibility of distinct roles for these two glucocorticoids and highlight important pharmacokinetic differences with implications for the therapeutic potential of corticosterone replacement in humans.

pharmacology and toxicology↗

bioRxiv2024

ATP-Binding Cassette Family C member 1 constrains metabolic responses to high-fat diet in male mice

Glucocorticoids modulate glucose homeostasis, acting on metabolically active tissues such as liver, skeletal muscle, and adipose tissue. Intra-cellular regulation of glucocorticoid action in adipose tissue impacts metabolic responses to obesity. ATP-Binding Cassette Family C member 1 (ABCC1) is a transmembrane glucocorticoid transporter known to limit the accumulation of exogenously administered corticosterone in adipose tissue. However, the role of ABCC1 in the regulation of endogenous glucocorticoid action and its impact on fuel metabolism has not been studied. Here, we investigate the impact of Abcc1 deficiency on glucocorticoid action and high fat-diet (HFD)-induced obesity. In lean mice, deficiency of Abcc1 increased endogenous corticosterone levels in skeletal muscle and adipose tissue but did not impact insulin sensitivity. In contrast, Abcc1-deficient mice on HFD displayed impaired glucose and insulin tolerance, and fasting hyperinsulinemia, without alterations in tissue corticosterone levels. Proteomics and bulk RNA sequencing in adipose tissue and skeletal muscle revealed that Abcc1 deficiency amplified the transcriptional response to an obesogenic diet in adipose tissue. Moreover, the Abcc1 deficiency impairs key signalling pathways related to glucose metabolism in both skeletal muscle and adipose tissue, in particular those related to OXPHOS machinery and Glut4. Together, our results highlight a role for ABCC1 in regulating glucose homeostasis, demonstrating diet-dependent effects that are not associated with altered tissue glucocorticoid concentrations.

physiology↗

bioRxiv2022

High salt intake activates the hypothalamic-pituitary-adrenal axis, amplifies the stress response, and alters tissue glucocorticoid exposure in mice

High salt intake is common and contributes to poor cardiovascular health. Sustained cortisol excess also induces an adverse cardiovascular profile. Urinary cortisol excretion positively correlates with urinary sodium excretion. We hypothesised that this was due to hypothalamic-pituitary-adrenal axis activation by high salt intake. In male C57BL6/J mice, 2 weeks of high salt intake increased Crh and Pomc mRNA abundance in the hypothalamus and anterior pituitary, respectively and caused a sustained rise in plasma corticosterone. Plasma copeptin and anterior pituitary V1b receptor mRNA expression was elevated, which may contribute to basal HPA axis activation. Additionally, high salt intake amplified glucocorticoid response to restraint stress, indicative of enhanced HPA axis sensitivity. In the periphery, high salt intake reduced the binding capacity of corticosteroid-binding globulin, enhancing glucocorticoid bioavailability. Within several tissues, the expression of glucocorticoid-regenerating enzyme, 11{beta}-hydroxysteroid dehydrogenase type 1, was increased and the glucocorticoid receptor downregulated. Overall, high salt intake increased glucocorticoid exposure in the hippocampus, anterior pituitary and liver. Chronic high salt intake amplifies basal and stress-induced glucocorticoid levels and resets glucocorticoid biology centrally, peripherally and within cells. This shows direct connectivity between salt homeostasis and HPA axis function. The cumulative effect is likely maladaptive and may contribute to the long-term health consequences of a high salt diet.

physiology↗

bioRxiv2019

Neutrophils mediate the capture of peritoneal contaminants by fat-associated lymphoid clusters of the omentum

The omentum is a visceral adipose tissue rich in fat-associated lymphoid clusters (FALCs), which collects peritoneal contaminants and provides a first layer of immunological defence within the abdomen. Using single-cell RNA sequencing and spatial analysis of omental stromal cells, we reveal that the surface of FALCs are covered with specialised mesothelial cells, which we name FALC cover cells. We demonstrate that CXCL1 is expressed by FALC cover cells and that CXCL1 is critical for the retention and accumulation of neutrophils within FALCs during peritonitis. We show that protein arginine deiminase 4 mediates the formation of dense neutrophil aggregates, which are required for the neutralisation of particles present in the peritoneal cavity. Finally, we provide confirmatory evidence in humans with acute appendicitis, that the omentum is also a site of neutrophil recruitment and bacterial capture, and is thus an important component of the immunological defence against the propagation of peritoneal contaminants.

immunology↗

bioRxiv2019

Smartphone screening for neonatal jaundice via ambient-subtracted sclera chromaticity: neoSCB app pilot study

Jaundice is a major cause of mortality and morbidity in the newborn. Globally, early identification and home monitoring are significant challenges in reducing the incidence of jaundice-related neurological damage. Smartphone cameras are promising as colour-based screening tools as they are low-cost, objective and ubiquitous. We propose a novel smartphone method and app called neoSCB to screen for neonatal jaundice by imaging the sclera. It does not rely on colour calibration cards or accessories, which may facilitate its adoption at scale and in less economically developed regions. Our approach is to explicitly address three confounding factors in relating colour to jaundice: (1) skin pigmentation, (2) ambient light, and (3) camera spectral response. (1) The variation in skin pigmentation is avoided by imaging the sclera. (2) With the smartphone screen acting as an illuminating flash, a flash/ no-flash image pair is captured using the front-facing camera. The contribution of ambient light is subtracted. (3) This permits a device-and ambient-independent measure of sclera chromaticity following a one-time calibration. We introduce the concept of Scleral-Conjunctival Bilirubin (SCB), in analogy with Transcutaneous Bilirubin (TcB). The scleral chromaticity is mapped to an SCB value. A pilot study was conducted in the UCL Hospital Neonatal Care Unit. 51 neonates were imaged using the neoSCB app and had a blood test for total serum bilirubin (TSB). The better of two models for SCB based on ambient-subtracted sclera chromaticity achieved r = 0.75 (p<0.01) correlation with TSB. Ambient subtraction improved chromaticity estimates in laboratory tests and screening performance within our study sample. Using an SCB decision threshold of 190mol/L, the sensitivity was 100% (specificity 61%) in identifying newborns with TSB>250mol/L (area under receiver operating characteristic curve, AUROC, 0.86), and 92% (specificity 67%) in identifying newborns with TSB>205mol/L (AUROC 0.85). These results are comparable to modern transcutaneous bilirubinometers.

bioengineering↗