Journal of Endocrinology最新文献

The role that vascular smooth muscle cell (VSMC)-derived foam cells play as drivers of atherosclerosis has been a growing focus of recent research interest. Toll-like receptor 4 (TLR4) has been identified as a regulator of the formation of VSMC foam cells, while vitamin D can reportedly suppress macrophage-derived foam cell development. Our aim is to investigate Whether vitamin D can similarly suppress the formation of VSMC foam cells, as does the role that TLR4 plays in this pathogenic context.The impact of vitamin D on VSMC-derived foam cell and atherosclerotic plaque formation was assessed, and the expression of cholesterol transport-related genes and TLR4 was assessed in ApoE-/- mice. The impact of 1,25(OH)2D3 on the ox-LDL-mediated formation of foam cells and the underlying molecular mechanisms were also examined in VSMCs cultured in vitro. Supplemental vitamin D administration resulted in a pronounced reduction in aortic atherosclerotic plaque formation and the development of SMA-a-positive foam cells. Vitamin D further suppressed TLR4, CD36, and SR-A in atherosclerotic plaque lesions while promoting ABCA1, ABCG1, and LXR-α upregulation. 1, 25 (OH)2 D3 significantly reduced Dil-ox-LDL uptake and increased NBD-LDL efflux in VSMCs, in addition to suppressing TLR4, CD36, and SR-A expression, while upregulating ABCA1, ABCG1, and LXR-α. Knocking down TLR4 impaired VSMC foam cell formation, while 1,25(OH)2D3-induced JNK activation suppressed TLR4 signaling and promoted VSMC foam cell development. Our study reveals that Vitamin D can reduce VSMC foam cell formation and protect against atherosclerotic progression through the JNK-TLR4 signaling pathway.

Fragility fractures are frequently observed among the elderly population with osteoporosis, and the fundamental process of fractured recovery relies on the differentiation of osteoblasts. LINC01094 was a crucial lncRNA in the regulation of the progression of diseases, but its role in osteoporotic fracture remained unclear. This study was to investigate alterations in the expression of LINC01094 in patients with osteoporotic fracture, evaluate its potential role as a diagnostic biomarker, and explore its effects on osteoblast differentiation. The circulating LINC01094 was tested using serum from 60 healthy individuals, 60 patients with osteoporosis, and 74 patients with osteoporotic fractures by RT-qPCR. The receiver operating characteristics curve was conducted to evaluate its diagnostic performance. The function of LINC01094 was measured in both MC3T3-E1 and BMSC cells. ALP activity detection and ELISA assay were performed to measure the osteogenesis markers, including OCN, and Runx2 expression. Dual-luciferase reporter assay was utilized to validate the downstream miR-362-3p of LINC01094 in cells. The expression of circulating LINC01094 was increased in osteoporotic patients with/without fracture than in healthy controls. LINC01094 can differentiate osteoporotic patients from healthy ones and distinguish osteoporotic fracture patients from those without fractures. LINC01094 levels were decreased in osteogenically induced MC3T3-E1 and BMSC cells. miR-362-3p was a direct target of LINC01094 and miR-362-3p partially reversed the effect of LINC01094 in cell viability and differentiation processes. Silencing LINC01094 is crucial for facilitating bone formation and has the potential to serve as both a diagnostic indicator and a treatment target for osteoporosis.

Glucagon-like peptide-1 receptor (GLP-1R) and neuropeptide Y receptors (NPYRs) are expressed in reproductive tissues contributing to the regulation of gonadal function. This exploratory study examines the potential impact of their modulation by assessing the effects of exendin-4 (Ex-4) and peptide YY (PYY) (3-36) on endocrine ovaries and adrenals in high-fat diet (HFD) mice. Ex-4 and PYY(3-36) reduced blood glucose and energy intake, with no effects on body weight. While HFD did not impact the estrous cycle, Ex-4 increased metestrus frequency and decreased diestrus frequency resulting in 0% mice experiencing repeated diestrus or becoming acyclic. Luteinizing hormone levels were significantly higher in the Ex-4 and PYY(3-36) groups compared to the normal diet and HFD controls. In the adrenals, reduced capsule and zona glomerulosa thickness caused by HFD was reversed after peptide treatments. Within the ovaries, HFD increased the number of atretic follicles, an effect that disappeared after Ex-4 and PYY(3-36) treatments. Ex-4 also increased the number of corpora lutea owing to the prolonged metestrus phase. Gene expression analysis within the adrenals revealed the upregulation of Insr and the downregulation of Prgtr in HFD mice, while Ex-4 downregulated the expression of Gipr. The ovarian gene expression of Gipr, Npy1r and Prgtr was downregulated by Ex-4 treatment, while PYY(3-36) significantly downregulated the Prgtr expression compared to HFD mice. These data indicate that manipulating GLP-1R and NPY2R leads to changes in the reproductive physiology of mice. In addition, the observed alterations in the morphology and gene expression in the adrenals and ovaries imply a direct impact of these peptides on female reproductive function.

Systemic glucocorticoid excess causes several adverse metabolic conditions, most notably Cushing's syndrome. These effects are amplified by the intracellular enzyme 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1). Here, we determined the less well-characterised effects of glucocorticoid excess, and the contribution of 11β-HSD1 amplification on metabolic rate in mice. Male and female C57BL/6J (wild type, WT) and 11β-HSD1 knockout (11β-HSD1 KO) mice were treated with high-dose corticosterone or a vehicle control for 3 weeks. Indirect calorimetry was conducted during the final week of treatment, with or without fasting, to determine the impact on metabolic rate. We found that corticosterone treatment elevated metabolic rate and promoted carbohydrate utilisation primarily in female WT mice, with effects more pronounced during the light phase. Corticosterone treatment also resulted in greater fat accumulation in female WT mice. Corticosterone induced hyperphagia was identified as a likely causal factor altering the respiratory exchange ratio (RER) but not energy expenditure (EE). Male and female 11β-HSD1 KO mice were protected against these effects. We identify novel metabolic consequences of sustained glucocorticoid excess, identify a key mechanism of hyperphagia, and demonstrate that 11β-HSD1 is required to manifest the full metabolic derangement.

Cardiovascular outcome trials (CVOTs) in people living with type 2 diabetes mellitus and obesity have confirmed the cardiovascular benefits of glucagon-like peptide 1 receptor agonists (GLP-1RAs), including reduced cardiovascular mortality, lower rates of myocardial infarction, and lower rates of stroke. The cardiovascular benefits observed following GLP-1RA treatment could be secondary to improvements in glycemia, blood pressure, postprandial lipidemia, and inflammation. Yet, the GLP-1R is also expressed in the heart and vasculature, suggesting that GLP-1R agonism may impact the cardiovascular system. The emergence of GLP-1RAs combined with glucose-dependent insulinotropic polypeptide and glucagon receptor agonists has shown promising results as new weight loss medications. Dual-agonist and tri-agonist therapies have demonstrated superior outcomes in weight loss, lowered blood sugar and lipid levels, restoration of tissue function, and enhancement of overall substrate metabolism compared to using GLP-1R agonists alone. However, the precise mechanisms underlying their cardiovascular benefits remain to be fully elucidated. This review aims to summarize the findings from CVOTs of GLP-1RAs, explore the latest data on dual and tri-agonist therapies, and delve into potential mechanisms contributing to their cardioprotective effects. It also addresses current gaps in understanding and areas for further research.

Aldosterone is a mineralocorticoid hormone involved in controlling electrolyte balance, blood pressure, and cellular signaling. It plays a pivotal role in cardiovascular and metabolic physiology. Excess aldosterone activates mineralocorticoid receptors, leading to subsequent inflammatory responses, increased oxidative stress, and tissue remodeling. Various mechanisms have been reported to link aldosterone with cardiovascular and metabolic diseases. However, mitochondria, responsible for energy generation through oxidative phosphorylation, have received less attention regarding their potential role in aldosterone-related pathogenesis. Excess aldosterone leads to mitochondrial dysfunction, and this may play a role in the development of cardiovascular and metabolic diseases. Aldosterone has the potential to affect mitochondrial structure, function, and dynamic processes, such as mitochondrial fusion and fission. In addition, aldosterone has been associated with the suppression of mitochondrial DNA, mitochondria-specific proteins, and ATP production in the myocardium through mineralocorticoid receptor, nicotinamide adenine dinucleotide phosphate oxidase, and reactive oxygen species pathways. In this review, we explore the mechanisms underlying aldosterone-induced cardiovascular and metabolic mitochondrial dysfunction, including mineralocorticoid receptor activation and subsequent inflammatory responses, as well as increased oxidative stress. Furthermore, we review potential therapeutic targets aimed at restoring mitochondrial function in the context of aldosterone-associated pathologies. Understanding these mechanisms is vital, as it offers insights into novel therapeutic strategies to mitigate the impact of aldosterone-induced mitochondrial dysfunction, thereby potentially improving the outcomes of individuals affected by cardiovascular and metabolic disorders.

LEAP2, a liver-derived antagonist for the ghrelin receptor, GHSR1a, counteracts effects of ghrelin on appetite and energy balance. Less is known about its impact on blood glucose-regulating hormones from pancreatic islets. Here we investigate whether acyl-ghrelin (AG) and LEAP2 regulate islet hormone release in a cell type- and sex-specific manner. Hormone content from secretion experiments with isolated islets from male and female mice was measured by radioimmunoassay and mRNA expression by qPCR. LEAP2 enhanced insulin secretion in islets from males (p<0.01) but not females (p<0.2), whilst AG-stimulated somatostatin release was significantly reversed by LEAP2 in males (p<0.001) but not females (p<0.2). Glucagon release was not significantly affected by AG and LEAP2. Ghsr1a, Ghrelin, Leap2, Mrap2, Mboat4 and Sstr3 islet mRNA expression did not differ between sexes. In control male islets maintained without 17-beta oestradiol (E2), AG exerted an insulinostatic effect (p<0.05), with a trend towards reversal by LEAP2 (p=0.06). Both were abolished by 72h E2 pre-treatment (10 nmol/l, p<0.2). AG-stimulated somatostatin release was inhibited by LEAP2 from control (p<0.001) but not E2-treated islets (p<0.2). LEAP2 and AG did not modulate insulin secretion from MIN6 beta cells and Mrap2 was downregulated (P<0.05) and Ghsr1a upregulated (P<0.0001) in islets from Sst^-/- mice. Our findings show that AG and LEAP2 regulate insulin and somatostatin release in an opposing and sex-dependent manner, which in males can be modulated by E2. We suggest that regulation of SST release is a key starting point for understanding the role of GHSR1a in islet function and glucose metabolism.

The mineralocorticoid system, comprising the renin-angiotensin-aldosterone system (RAAS) and associated receptors, is traditionally viewed as a regulator of sodium and fluid balance and blood pressure (BP), with the main mineralocorticoid hormone aldosterone acting via the mineralocorticoid receptor (MR) in distal renal tubules. Over the past few decades, there has been a wider understanding of the role of the mineralocorticoid system in regulating both classical BP-dependent and non-BP-dependent systemic effects. Mounting evidence indicates the novel role of the mineralocorticoid system in cardiometabolic health with excess mineralocorticoid system activity being associated with adiposity, diabetes, insulin resistance and cardiovascular diseases independent of its effect on BP, and RAAS blockade and MR antagonists offering protection against cardiometabolic dysfunction. The metabolic manifestations of mineralocorticoid system overactivation are mainly mediated by their interactions with adipose tissue which orchestrates energy, lipids and glucose homeostasis via effects on the functions of brown and white adipocytes and immune cells. Adipose tissue can in turn influence mineralocorticoid system activity by harbouring its own RAAS system and by releasing mineralocorticoid-secretory factors/adipokines, with resultant further progression of cardiometabolic dysfunction. This article discusses the interplay between the mineralocorticoid system and adipose tissue in the pathophysiology of cardiometabolic diseases.

Glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like-peptide-1 (GLP-1) are incretin hormones that stimulate insulin secretion and improve glycemic control in individuals with type 2 diabetes (T2D). Data from several cardiovascular outcome trials for GLP-1 receptor (GLP-1R) agonists have demonstrated significant reductions in the occurrence of major adverse cardiovascular events in individuals with T2D. Although the cardiovascular actions attributed to GLP-1R agonism have been extensively studied, little is known regarding the cardiovascular consequences attributed to GIP receptor (GIPR) agonism. As there is now an increasing focus on the development of incretin-based co-agonist therapies that activate both the GLP-1R and GIPR, it is imperative that we understand the mechanism(s) through which these incretins impact cardiovascular function. This is especially important considering that cardiovascular disease represents the leading cause of death in individuals with T2D. With increasing evidence that perturbations in cardiac energy metabolism are a major contributor to the pathology of diabetes-related cardiovascular disease, this may represent a key component through which GLP-1R and GIPR agonism influence cardiovascular outcomes. Not only do GIP and GLP-1 increase the secretion of insulin, they may also modify glucagon secretion, both of which have potent actions on cardiac substrate utilization. Herein we will discuss the potential direct and indirect actions through which GLP-1R and GIPR agonism impact cardiac energy metabolism while interrogating the evidence to support whether such actions may account for incretin-mediated cardioprotection in T2D.