Biology subjects

Stimson, R. H.

Publications and source records attributed to Stimson, R. H..

6 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↗

bioRxiv2025

Human brown adipose tissue demonstrates substantial 18F-fluorocholine uptake at room temperature for phosphatidylcholine synthesis

ObjectiveBrown Adipose Tissue (BAT) is composed of mitochondrial-rich, multilocular adipocytes, which dissipate energy to produce heat. Quantification of BAT mass is most commonly performed by 18F-fluorodeoxyglucose positron emission tomography (PET), which requires antecedent cold exposure. We hypothesized that 18F-fluorocholine PET could detect human BAT due to its requirement for considerable phosphatidylcholine synthesis, secondary to brown adipocytes high mitochondrial density and multiple lipid droplets. Methods1) Six healthy men with detectable 18F-fluorodeoxyglucose uptake by BAT were recruited to a randomised crossover study investigating 18F-fluorocholine uptake by BAT during warm and cold exposure. 2) 18F-fluorocholine uptake by supraclavicular adipose tissue was quantified in 76 patients who had undergone 18F-fluorocholine PET/CT scanning. 3) Choline transporter expression was quantified in human BAT and white adipose tissue (WAT), and in brown and white adipocytes. 4) Lipidomics was performed on human brown adipocytes incubated with 15N-choline to determine phospholipid synthesis. Results1) 18F-Fluorocholine uptake by BAT was substantially greater than by WAT during both warm and cold exposure. 2) 18F-Fluorocholine uptake by supraclavicular adipose tissue was higher in the colder seasons, inversely associated with body mass index, and positively associated with tissue radiodensity. 3) Expression of the choline transporter SLC44A3 was higher in human supraclavicular BAT than WAT, while SLC44A2 was expressed more highly in human brown than white adipocytes. 4) 15N-choline tracing in human brown adipocytes identified incorporation into >30 phosphatidylcholine species. Conclusions18F-fluorocholine PET may be a novel method to quantify human BAT at room temperature. HighlightsO_LI18F-Fluorocholine (FCH) PET can detect human BAT without the need for cold exposure. C_LIO_LI18F-FCH uptake by supraclavicular AT is inversely associated with body mass index. C_LIO_LIThe choline transporter SLC44A3 is more highly expressed in BAT than WAT. C_LIO_LIHuman brown adipocytes utilise choline for phosphatidylcholine synthesis. C_LI O_FIG O_LINKSMALLFIG WIDTH=168 HEIGHT=200 SRC="FIGDIR/small/671970v1_ufig1.gif" ALT="Figure 1"> View larger version (50K): org.highwire.dtl.DTLVardef@11e85forg.highwire.dtl.DTLVardef@1aec87forg.highwire.dtl.DTLVardef@1ed3bf3org.highwire.dtl.DTLVardef@1fadbd1_HPS_FORMAT_FIGEXP M_FIG GRAPHICAL ABSTRACT C_FIG

physiology↗

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

The effects of caloric restriction on adipose tissue and metabolic health are sex- and age-dependent

Caloric restriction (CR) is a nutritional intervention that reduces the risk of age-related diseases in numerous species, including humans. CRs metabolic effects, including decreased fat mass and improved insulin sensitivity, play an important role in its broader health benefits. However, the extent and basis of sex differences in CRs health benefits are unknown. We found that 30% CR in young (3-month-old) male mice decreased fat mass and improved glucose tolerance and insulin sensitivity, whereas these effects were blunted or absent in young female mice. Females resistance to fat and weight loss was associated with decreased lipolysis, lower systemic energy expenditure and fatty acid oxidation, and increased postprandial lipogenesis compared to males. Positron emission tomography-computed tomography (PET/CT) with 18F-fluorodeoxyglucose (18F-FDG) showed that peripheral glucose uptake was comparable between sexes. Instead, the sex differences in glucose homeostasis were associated with altered hepatic ceramide content and substrate metabolism: compared to CR males, CR females had lower TCA cycle activity but higher blood ketone concentrations, a marker of hepatic acetyl-CoA content. This suggests that males use hepatic acetyl-CoA for the TCA cycle whereas in females it accumulates, thereby stimulating gluconeogenesis and limiting hypoglycaemia during CR. In aged mice (18-months old), when females are anoestrus, CR decreased fat mass and improved glucose homeostasis to a similar extent in both sexes. Finally, in a cohort of overweight and obese humans CR-induced fat loss was also sex- and age-dependent: younger females (<45 years) resisted fat loss compared to younger males while in older subjects (>45 years) this sex difference was absent. Collectively, these studies identify age-dependent sex differences in the metabolic effects of CR and highlight adipose tissue, the liver and oestrogen as key determinants of CRs metabolic benefits. These findings have important implications for understanding the interplay between diet and health and for maximising the benefits of CR in humans. HIGHLIGHTSO_LICaloric restriction (CR) decreases fat mass and improves glucose homeostasis in young male mice, but young females resist these effects. C_LIO_LICR females resist lipolysis, decrease energy expenditure and increase postprandial lipogenesis more than CR males, explaining how females resist fat loss. C_LIO_LISex differences in glucose homeostasis are associated with altered hepatic metabolism and gluconeogenesis, without marked differences in peripheral glucose uptake. C_LIO_LICRs effects on fat loss and glucose homeostasis are comparable in aged male and female mice, implicating oestrogen as the driver of the sexually dimorphic effects in young mice. C_LIO_LIIn humans, females resist CR-induced fat loss in an age-dependent manner, further supporting the role of oestrogen in the sexually dimorphic effects of CR. C_LI

physiology↗

bioRxiv2021

A systems-level analysis of dynamic total-body PET data reveals complex skeletal energy metabolism networks in vivo

Bone is now regarded to be a key regulator of a number of metabolic processes, in addition to the regulation of mineral metabolism. However, our understanding of complex bone metabolic interactions at a systems level remains rudimentary, limiting our ability to assess systemic mechanisms underlying diseases and develop novel therapeutics. In vitro molecular biology and bioinformatics approaches have frequently been used to understand the mechanistic changes underlying disease at the cell level, however, these approaches lack the capability to interrogate dynamic multi-bone metabolic interactions in vivo. Here we present a novel and integrative approach to understand complex bone metabolic interactions in vivo using total-body positron emission tomography (PET) network analysis of murine 18F-FDG scans, as a biomarker of glucose metabolism signature in bones. In this report we show that different bones within the skeleton have a unique glucose metabolism and form a complex metabolic network. These data could have important therapeutic implications in the management of the metabolic syndrome and skeletal disease. The application of our approach to clinical and preclinical total-body PET studies promises to reveal further physiological and pathological tissue interactions, which simplistic PET standard uptake values analysis fail to interrogate, extending beyond skeletal metabolism, due to the diversity of PET radiotracers available and under development as well as the advent of clinical total-body PET systems. One Sentence SummaryBones form a complex metabolic network.

physiology↗

bioRxiv2019

Bone marrow adipose tissue is a unique adipose subtype with distinct roles in systemic glucose homeostasis

Bone marrow adipose tissue (BMAT) represents >10% of total adipose mass, yet unlike white or brown adipose tissues (WAT or BAT), its role in systemic metabolism remains unclear. Using transcriptomics, we reveal that BMAT is molecularly distinct to WAT but is not enriched for brown or beige adipocyte markers. Instead, pathway analysis indicated altered glucose metabolism and decreased insulin responsiveness in BMAT. We therefore tested these functions in mice and humans using positron emission tomography-computed tomography (PET/CT) with 18F-fluorodeoxyglucose, including establishing a new method for BMAT identification from clinical CT scans. This revealed that BMAT resists insulin- and cold-stimulated glucose uptake and is thus functionally distinct to WAT and BAT. However, BMAT displayed greater basal glucose uptake than axial bones or subcutaneous WAT, underscoring its potential to influence systemic glucose homeostasis. These PET/CT studies are the first to characterise BMAT function in vivo and identify BMAT as a distinct, major subtype of adipose tissue.\n\nHIGHLIGHTSO_LIBone marrow adipose tissue (BMAT) is molecularly distinct to other adipose subtypes.\nC_LIO_LIBMAT is less insulin responsive than WAT and, unlike BAT, is not cold-responsive.\nC_LIO_LIHuman BMAT has greater basal glucose uptake than axial bone or subcutaneous WAT.\nC_LIO_LIWe establish a PET/CT method for BMAT localisation and functional analysis in vivo.\nC_LI

physiology↗