Endocrine Abstracts

The nicotinamide adenine dinucleotide (NAD+) dependent Poly-(ADP-ribosyl)polymerase 1 (PARP1) generates the post-translational modification ADP-Ribosylation (ADPR). Molecular studies have identified potential for NAD+ consuming enzymes to influence metabolic function. Given that PARP1 determines cellular NAD+ concentrations and ADPR shifts target protein activity, we sought to identify the molecular actions of PARP1 within skeletal muscle. Analysis of C2C12 lysates demonstrate...

The glucocorticoid receptor is constitutively expressed and fundamental to life. Activity of GR is partially governed by interacting partners whose actions skew the frequency with which GR produces meaningful transcriptional outcomes. Moreover, the tissue-specific actions of GR are themselves defined, with binding patterns being distinct in various tissue types. These features mean full molecular understanding of this steroid hormone receptor remains incomplete. As glucocortic...

Appreciation of hormonal control over mitochondrial function has increased over recent decades. Mitochondria adapt to the cellular environment through a variety of mechanisms; mitochondrial dynamics (fusion, fission, transfer) or through the signalling of a variety of proteins to induce mitophagy, depending on the cell stressor. In parallel, nuclear receptors and the production of their steroid hormone ligands within mitochondria have been a reoccurring incidental measurement....

Ligand binding of the glucocorticoid receptor (GR) initiates recruitment to GR Response Elements (GRREs). GR transcriptional activation of genes manifests many of the pleiotropic actions attributed to glucocorticoids. However, excessive exposure to GCs produces detrimental impacts, shifting GR behaviour and driving dysregulated metabolic states. Moreover, GR, its interacting partners, and influencing proteins remain ambiguous. Poly-(ADP-ribosyl) polymerase 1 (PARP1) is a chrom...

Metabolic dysfunction in skeletal muscle disturbs both the critical vascular network and fundamental muscle fibre architecture. However, the molecular drivers during metabolic stress responsible for transmitting these events remain poorly defined. To reveal these we mapped changes in the spatial proteome occurring as a result of impaired metabolic health. We exposed male and female mice (C57/BL6J) to high fat diets and conducted digital spatial profiling (NanoString GEOMX) on ...

Glycogen storage disease type 1b is a metabolic disorder resulting in an inability to shuttle glucose-6-phosphate across the sarcoplasmic/endoplasmic reticulum (SR/ER) lumen. Mutation of the SoLute Carrier 37a4 (slc37a4) or glucose-6-phosphate transporter (G6PT) gene responsible for the distribution of G-6-P across this membrane leads to, hypoglycemia, hepatic glycogen accumulation, hyperlipidemia, resulting in life-limiting outcomes including growth retardation and neutropeni...

Hexose-6-phosphate dehydrogenase is an important factor in setting the redox status of the endo-/sarcoplasmic reticulum (ER/SR) lumen by generating the NADPH:NADP+ ratio for 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) mediated glucocorticoid (GC) activation. H6PDH knockout mice (H6KO) clearly demonstrate the obligate nature of 11β-HSD1 for H6PDH, and display a vacuolating of type IIb fiber myopathy, elevated glycogen storage and type II to type...

In the endo/sarcoplasmic reticulum (ER/SR), hexose-6-phosphate dehydrogenase (H6PDH) generates an NADPH/ NADP ratio sufficient to drive 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1)-mediated glucocorticoid (GC) activation (11-DHC to corticosterone). In H6PDH knockout (H6PDKO) mice a reduced NADPH/NADP ratio leads to reversed 11β-HSD1 activity (corticosterone to 11-DHC), and GC insensitivity. They also display skeletal myopathy driven by activation of the un...

Obesity, a complex metabolic disorder characterised by excessive adipose tissue accumulation, is associated with numerous health complications. This study aimed to investigate the molecular mechanisms underlying obesity, focusing on the role of hypoxia-inducible factor 1 alpha (HIF1α). Our findings establish a novel link between HIF1α and the pathogenesis of obesity-related conditions. We uncovered a connection between HIF1α and diabetic neuropathy, a prevalent ...

Glucocorticoids (GCs) have potent immunomodulatory and anti-inflammatory effects and are widely used in the treatment of inflammatory diseases. Unfortunately, their long term administration causes serious systemic metabolic side effects including osteoporosis, muscle wasting and insulin resistance. 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) is responsible for the local conversion of inactive GCs to their active counterparts. It has been shown that many of the...