Daily Endocrinology Research Analysis

AIMS/HYPOTHESIS: Exercise elicits a spectrum of metabolic and inflammatory responses that are crucial for skeletal muscle adaptation and overall health, particularly in the context of metabolic diseases, yet the contribution of prostanoid signalling to these processes remains unclear. We hypothesised that exercise-induced thromboxane production enhances skeletal muscle glucose uptake and improves whole-body glucose control. METHODS: Plasma prostanoids were quantified in men and women with normal glucose tolerance or type 2 diabetes before, immediately after and 3 h after a single bout of exercise. Cyclooxygenase (COX-2) transcript levels were evaluated in human skeletal muscle, whole blood, peripheral blood mononuclear cells and skeletal muscle-resident immune cells. Metabolic and transcriptomic effects of thromboxane receptor activation were analysed in mouse C2C12, rat L6 and human primary skeletal muscle cells. Glucose tolerance in vivo was assessed following i.p. administration of the thromboxane receptor agonist I-BOP in male and female mice. Tissue-specific glucose uptake was quantified by measuring radiolabelled 2-deoxyglucose incorporation during an IVGTT. RESULTS: Acute exercise increased plasma thromboxane B₂ concentrations and skeletal muscle mRNA levels of PTGS2 (encoding COX-2) selectively in monocyte/macrophage populations. In skeletal muscle cells, the thromboxane receptor agonist I-BOP increased glucose uptake in a dose-dependent manner up to 2.5-fold within 4 h and enhanced glycogen synthesis by 430%. Transcriptomic and signalling analysis revealed activation of protein kinase A and cytoskeletal remodelling pathways linked to GLUT4 trafficking. In vivo, I-BOP improved glucose tolerance in male mice in a dose-dependent manner, without altering insulin levels. Thromboxane receptor stimulation increased glucose uptake in extensor digitorum longus muscle by 43%. Importantly, thromboxane receptor activation preserved its glucose-lowering efficacy in diet-induced obese male mice. CONCLUSIONS/INTERPRETATION: Exercise induces skeletal muscle-derived thromboxane production through macrophage-specific COX-2 activation. Thromboxane receptor stimulation enhances glucose uptake and glycogen storage via cytoskeletal remodelling, partially mimicking the acute exercise transcriptomic response. In vivo, thromboxane receptor activation improves glucose tolerance and skeletal muscle glucose uptake, with preserved efficacy in obesity. These findings identify thromboxane signalling as a previously unrecognised immunometabolic axis linking inflammation to glucose regulation and highlight the thromboxane receptor as a potential therapeutic target for metabolic disease.

Activin-class ligands of the transforming growth factor β family induce follicle-stimulating hormone (FSH) production by pituitary gonadotrope cells in mice via the actions of the transcription factors SMAD3, SMAD4, and FOXL2, which bind to cis-elements in the FSHβ subunit (Fshb) promoter. An enhancer region for murine Fshb transcription was identified in vitro. However, deletion of the region using CRISPR-Cas9 did not affect FSH synthesis or secretion in mice. Using single-nucleus ATAC-seq of whole murine pituitaries, we identified three additional open chromatin regions upstream of Fshb exclusively in gonadotropes. These regions, as well as the Fshb gene, were fully or partially closed in gonadotropes of FSH-deficient mice with genetically or pharmacologically inactivated activin type II receptors. The initially characterized enhancer region did not significantly alter basal or activin-stimulated murine Fshb promoter-reporter activity in homologous LβT2 cells. In contrast, the other three open chromatin regions enhanced basal and activin A-stimulated Fshb promoter-reporter activity in LβT2 cells, with the two most distal showing the greatest effects. These two regions were open, exhibited enrichment of the enhancer mark H3K27ac, and were bound by SMAD2/3 and FOXL2 in response to activin A in LβT2 cells. The most distal enhancer exhibited strong FOXL2 and weak SMAD4 binding in gel shift assays. SMAD4, but not FOXL2, directly bound the other distal enhancer. Mutation of defined FOXL2 and SMAD4 cis-elements diminished enhancer activity in reporter assays in LβT2 cells. Collectively, the data indicate that there may be as many as four activin-sensitive enhancers upstream of murine Fshb.

OBJECTIVE: Weight loss in older men with obesity and hypogonadism accelerates musculoskeletal decline, yet the underlying metabolic mechanisms remain unclear. Testosterone replacement therapy (TRT), when added to lifestyle therapy (LT), mitigates this decline, but its metabolic basis has not been defined. We examined skeletal muscle metabolomic adaptations to LT with or without TRT, focusing on glycolysis, the pentose phosphate pathway (PPP), the tricarboxylic acid (TCA) cycle, and carnitine metabolism to identify dominant pathways of metabolic adaptation. DESIGN: Randomized, double-blind, placebo-controlled trial (LITROS). METHODS: Eighty-three men aged 65 years or older with obesity (BMI ≥30 kg/m RESULTS: Among the pathways examined, only glycolysis showed a consistent and significant response to LT+TRT versus LT+Pbo (between-group CONCLUSIONS: TRT during LT selectively enhances skeletal muscle glycolysis, identifying glycolic activation as the dominant metabolic adaptation in this mechanistic study. By increasing glycolytic flux under calorie restriction, TRT may produce efficient ATP generation while conserving amino acids, supporting muscle and bone preservation and improving aerobic and cardiometabolic function in older men with obesity and hypogonadism.