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Centre for Discovery Brain Science, University of Edinburgh, Hugh Robson Building, Edinburgh, UK
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Clinical & Translational Research Institute, Newcastle University, International Centre for Life, Central Parkway, Newcastle upon Tyne, UK
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Mass Spectrometry Core Laboratory, Edinburgh Clinical Research Facility, Queen’s Medical Research Institute, University of Edinburgh, Edinburgh, UK
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11β-Hydroxysteroid dehydrogenase 1 (11βHSD1) is a drug target to attenuate adverse effects of chronic glucocorticoid excess. It catalyses intracellular regeneration of active glucocorticoids in tissues including brain, liver and adipose tissue (coupled to hexose-6-phosphate dehydrogenase, H6PDH). 11βHSD1 activity in individual tissues is thought to contribute significantly to glucocorticoid levels at those sites, but its local contribution vs glucocorticoid delivery via the circulation is unknown. Here, we hypothesised that hepatic 11βHSD1 would contribute significantly to the circulating pool. This was studied in mice with Cre-mediated disruption of Hsd11b1 in liver (Alac-Cre) vs adipose tissue (aP2-Cre) or whole-body disruption of H6pdh. Regeneration of [9,12,12-2H3]-cortisol (d3F) from [9,12,12-2H3]-cortisone (d3E), measuring 11βHSD1 reductase activity was assessed at steady state following infusion of [9,11,12,12-2H4]-cortisol (d4F) in male mice. Concentrations of steroids in plasma and amounts in liver, adipose tissue and brain were measured using mass spectrometry interfaced with matrix-assisted laser desorption ionisation or liquid chromatography. Amounts of d3F were higher in liver, compared with brain and adipose tissue. Rates of appearance of d3F were ~6-fold slower in H6pdh−/− mice, showing the importance for whole-body 11βHSD1 reductase activity. Disruption of liver 11βHSD1 reduced the amounts of d3F in liver (by ~36%), without changes elsewhere. In contrast disruption of 11βHSD1 in adipose tissue reduced rates of appearance of circulating d3F (by ~67%) and also reduced regenerated of d3F in liver and brain (both by ~30%). Thus, the contribution of hepatic 11βHSD1 to circulating glucocorticoid levels and amounts in other tissues is less than that of adipose tissue.
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Gut dysbiosis impairs nonshivering thermogenesis (NST) in obesity. The antiobesogenic effects of exercise training might involve the modulation of gut microbiota and its inflammatory signals to the brown adipose tissue (BAT). This study evaluated whether high-intensity interval training (HIIT) and moderate-intensity continuous training (MICT) prevent overweight through reduced gut-derived inflammatory signals to BAT in high-fat-fed mice. Sixty male C57BL/6 mice (3 months old) comprised six experimental groups: control (C) diet group, C diet + HIIT (C-HIIT) group, C diet + MICT (C-MICT) group, high-fat (HF) diet group, HF diet + HIIT (HF-HIIT) group, and HF diet + MICT (HF-MICT) group. The protocols lasted for 10 weeks. HIIT and MICT restored body mass, mitigated glucose intolerance, and prevented hyperinsulinemia in HF-trained groups. A chronic HF diet caused dysbiosis, but HIIT and MICT prevented gut dysbiosis and preserved tight junction (TJ) gene expression. HF-HIIT and HF-MICT groups exhibited a similar pattern of goblet cell distribution, agreeing with the decreased plasma lipopolysaccharide concentrations and interscapular BAT (iBAT) Lbp-Cd14-Tlr4 expression. The lowered Nlrp3 and Il1β in the HF-HITT and HF-MICT groups complied with iBAT thermogenic capacity maintenance. This study shows reliable evidence that HIIT and MICT prevented overweight by restoring the diversity of the gut microbiota phyla and TJ gene expression, thereby reducing inflammatory signals to brown adipocytes with preserved thermogenic capacity. Both exercise modalities prevented overweight, but HIIT rescued Zo-1 and Jam-a gene expression, exerting more potent anti-inflammatory effects than MICT (reduced LPS concentrations), providing a sustained increase in thermogenesis with 78% less distance traveled.
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Department of Pulmonary and Critical Care Medicine, the First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
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Department of Pulmonary and Critical Care Medicine, the First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
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Department of Pulmonary and Critical Care Medicine, the First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
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Department of Pulmonary and Critical Care Medicine, the First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
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Department of Pulmonary and Critical Care Medicine, the Quzhou Affiliated Hospital of Wenzhou Medical University, Quzhou People's Hospital, Quzhou, China
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Acute lung injury (ALI) is associated with an increased incidence of respiratory diseases, which are devastating clinical disorders with high global mortality and morbidity. Evidence confirms that fibroblast growth factors (FGFs) play key roles in mediating ALI. Mice were treated with LPS (lipopolysaccharide: 5 mg/kg, intratracheally) to establish an in vivo ALI model. Human lung epithelial BEAS-2B cells cultured in a corresponding medium with LPS were used to mimic the ALI model in vitro. In this study, we characterized FGF10 pretreatment (5 mg/kg, intratracheally) which improved LPS-induced ALI, including histopathological changes, and reduced pulmonary edema. At the cellular level, FGF10 pretreatment (10 ng/mL) alleviated LPS-induced ALI accompanied by reduced reactive oxygen species (ROS) accumulation and inflammatory responses, such as IL-1β, IL-6, and IL-10, as well as suppressed excessive autophagy. Additionally, immunoblotting and co-immunoprecipitation showed that FGF10 activated nuclear factor erythroid-2-related factor 2 (Nrf2) signaling pathway via Nrf2 nuclear translocation by promoting the interaction between p62 and keap1, thereby preventing LPS-induced ALI. Nrf2 knockout significantly reversed these protective effects of FGF10. Together, FGF10 protects against LPS-induced ALI by restraining autophagy via p62-Kelch-like ECH-associated protein 1 (Keap1)-Nrf2 signaling pathway, implying that FGF10 could be a novel therapy for ALI.
Gulbali Institute, Charles Sturt University, Wagga Wagga, NSW, Australia
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Gulbali Institute, Charles Sturt University, Wagga Wagga, NSW, Australia
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Gulbali Institute, Charles Sturt University, Wagga Wagga, NSW, Australia
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Our previous studies showed that microinjection into the median eminence of the sheep of glucagon-like peptide- 1 (GLP-1) or its receptor agonist exendin-4 stimulates luteinising hormone (LH) secretion, but it is unknown whether the same effect may be obtained by systemic administration of the same. The present study measured the response in terms of plasma LH concentrations to intravenous (iv) infusion of exendin-4. A preliminary study showed that infusion of 2 mg exendin-4 into ewes produced a greater LH response in the follicular phase of the oestrous cycle than the luteal phase. Accordingly, the main study monitored plasma LH levels in response to either 0.5 mg or 2 mg exendin-4 or vehicle (normal saline) delivered by jugular infusion for 1 h in the follicular phase of the oestrous cycle. Blood samples were collected at 10 min intervals before, during and after infusion. Both doses of exendin-4 increased mean plasma LH concentrations and increased LH peripheral pulse amplitude. There was no effect on inter-pulse interval or timing of the preovulatory LH surge. These doses of exendin-4 did not alter plasma insulin or glucose concentrations. Quantitative PCR of the gastrointestinal tract samples from a population of ewes confirmed the expression of the preproglucagon gene (GCG). Expression increased aborally and was greatest in the rectum. It is concluded that endogenous GLP-1, most likely derived from the hindgut, may act systemically to stimulate LH secretion. The present data suggest that this effect may be obtained with levels of agonist that are lower than those functioning as an incretin.
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Department of Genetics and Molecular Biology, Institute of Biology, University of Magdeburg, Magdeburg, Germany
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Department of Endocrinology, Zhongda Hospital, School of Medicine, Southeast University, Jiangsu, China
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Estrogens regulate synaptic properties and influence hippocampus-related learning and memory via estrogen receptors, which include the G-protein-coupled estrogen receptor 1 (GPER1). Studying mice, in which the GPER1 gene is dysfunctional (GPER1-KO), we here provide evidence for sex-specific roles of GPER1 in these processes. GPER1-KO males showed reduced anxiety in the elevated plus maze, whereas the fear response ('freezing') was specifically increased in GPER1-KO females in a contextual fear conditioning paradigm. In the Morris water maze, spatial learning and memory consolidation was impaired by GPER1 deficiency in both sexes. Notably, in the females, spatial learning deficits and the fear response were more pronounced if mice were in a stage of the estrous cycle, in which E2 serum levels are high (proestrus) or rising (diestrus). On the physiological level, excitability at Schaffer collateral synapses in CA1 increased in GPER1-deficient males and in proestrus/diestrus ('E2 high') females, concordant with an increased hippocampal expression of the AMPA-receptor subunit GluA1 in GPER1-KO males and females as compared to wildtype males. Further changes included an augmented early long-term potentiation (E-LTP) maintenance specifically in GPER1-KO females and an increased hippocampal expression of spinophilin in metestrus/estrus ('E2 low') GPER1-KO females. Our findings suggest modulatory and sex-specific functions of GPER1 in the hippocampal network, which reduce rather than increase neuronal excitability. Dysregulation of these functions may underlie sex-specific cognitive deficits or mood disorders.
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The identification of brown adipose tissue (BAT) as a thermogenic organ in human adults approximately 20 years ago raised the exciting possibility of activating this tissue as a new treatment for obesity and cardiometabolic disease. [18F]Fluoro-2-deoxyglucose (18F-FDG) combined positron emission tomography and computed tomography (PET/CT) scanning is the most commonly used imaging modality to detect and quantify human BAT activity in vivo. This technique exploits the substantial glucose uptake by BAT during thermogenesis as a marker for BAT metabolism. 18F-FDG PET has provided substantial insights into human BAT physiology, including its regulatory pathways and the effect of obesity and cardiometabolic disease on BAT function. The use of alternative PET tracers and the development of novel techniques such as magnetic resonance imaging, supraclavicular skin temperature measurements, contrast-enhanced ultrasound, near-infrared spectroscopy and microdialysis have all added complementary information to improve our understanding of human BAT. However, many questions surrounding BAT physiology remain unanswered, highlighting the need for further research and novel approaches to investigate this tissue. This review critically discusses current techniques to assess human BAT function in vivo, the insights gained from these modalities and their limitations. We also discuss other promising techniques in development that will help dissect the pathways regulating human thermogenesis and determine the therapeutic potential of BAT activation.
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Reproduction in mammals is an extremely energy-intensive process and is therefore tightly controlled by the body's energy status. Changes in the nutritional status of the body cause fluctuations in the levels of peripheral metabolic hormone signals, such as leptin, insulin, and ghrelin, which provide feedback to the hypothalamus and integrate to coordinate metabolism and fertility. Therefore, to link energy and reproduction, energetic information must be centrally transmitted to gonadotropin-releasing hormone (GnRH) neurons that act as reproductive gating. However, GnRH neurons themselves are rarely directly involved in energy information perception. First, as key factors in the control of GnRH neurons, we describe the direct role of Kisspeptin and Arg-Phe amide-related peptide-3 (RFRP-3) neurons in mediating metabolic signaling. Second, we focused on summarizing the roles of metabolic hormone-sensitive neurons in mediating peripheral energy hormone signaling. Some of these hormone-sensitive neurons can directly transmit energy information to GnRH neurons, such as Orexin neurons, while others act indirectly through other neurons such as Kisspeptin, RFRP-3 neuron, and (pituitary adenylate cyclase-activating polypeptide) PACAP neurons. In addition, as another important aspect of the integration of metabolism and reproduction, the impact of reproductive signaling itself on metabolic function was also considered, as exemplified by our examination of the role of Kisspeptin and RFRP-3 in feeding control. This review summarizes the latest research progress in related fields, in order to more fully understand the central neuropeptide network that integrates energy metabolism and reproduction.
Mothers and Babies Research Program, Hunter Medical Research Institute, New Lambton Heights, New South Wales, Australia
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Angiotensin-converting enzyme 2 (ACE2) is not only the viral receptor for the novel coronavirus severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) but is also classically known as a key carboxypeptidase, which through multiple interacting partners plays vital physiological roles in the heart, kidney, lung, and gastrointestinal tract. An accumulating body of evidence has implicated the dysregulation of ACE2 abundance and activity in the pathophysiology of multiple disease states. ACE2 has recently regained attention due to its evolving role in driving the susceptibility and disease severity of coronavirus disease 2019 (COVID-19). This narrative review outlines the current knowledge of the structure and tissue distribution of ACE2, its role in mediating SARS-CoV-2 cellular entry, its interacting partners, and functions. It also highlights how SARS-CoV-2-mediated dysregulation of membrane-bound and circulating soluble ACE2 during infection plays an important role in the pathogenesis of COVID-19. We explore contemporary evidence for the dysregulation of ACE2 in populations that have emerged as most vulnerable to COVID-19 morbidity and mortality, including the elderly, men, and pregnant women, and draw attention to ACE2 dynamics and discrepancies across the mRNA, protein (membrane-bound and circulating), and activity levels. This review highlights the need for improved understanding of the basic biology of ACE2 in populations vulnerable to COVID-19 to best ensure their clinical management and the appropriate prescription of targeted therapeutics.
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There is a growing understanding that the early phases of type 1 diabetes (T1D) are characterised by a deleterious dialogue between the pancreatic beta cells and the immune system. This, combined with the urgent need to better translate this growing knowledge into novel therapies, provided the background for the JDRF–DiabetesUK–INNODIA–nPOD symposium entitled ‘Islet cells in human T1D: from recent advances to novel therapies’, which took place in Stockholm, Sweden, in September 2022. We provide in this article an overview of the main themes addressed in the symposium, pointing to both promising conclusions and key unmet needs that remain to be addressed in order to achieve better approaches to prevent or reverse T1D.
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Division of Diabetes, Endocrinology, & Metabolism, Vanderbilt University Medical Center School of Medicine, Nashville, Tennessee, USA
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Since the discovery of glucagon 100 years ago, the hormone and the pancreatic islet alpha cells that produce it have remained enigmatic relative to insulin-producing beta cells. Canonically, alpha cells have been described in the context of glucagon’s role in glucose metabolism in liver, with glucose as the primary nutrient signal regulating alpha cell function. However, current data reveal a more holistic model of metabolic signalling, involving glucagon-regulated metabolism of multiple nutrients by the liver and other tissues, including amino acids and lipids, providing reciprocal feedback to regulate glucagon secretion and even alpha cell mass. Here we describe how various nutrients are sensed, transported and metabolised in alpha cells, providing an integrative model for the metabolic regulation of glucagon secretion and action. Importantly, we discuss where these nutrient-sensing pathways intersect to regulate alpha cell function and highlight key areas for future research.
