Journal of Endocrinology最新文献

Polycystic ovary syndrome (PCOS), a reproductive endocrine disorder with quintessential features of metabolic dysfunction, affects millions of women worldwide. Hyperinsulinemia (i.e., elevated insulin without hypoglycemia) is a common metabolic feature of PCOS that worsens its reproductive symptoms by exacerbating pituitary hormone imbalances and increasing levels of bioactive androgens. Hyperinsulinemia in PCOS is often attributed to insulin resistance, based on the concept that impaired insulin-mediated glucose disposal would induce compensatory insulin hypersecretion. However, it is challenging to define the sequential relationship between insulin sensitivity and insulin secretion, as they are tightly interlinked, and evidence suggests that hyperinsulinemia can alternatively precede insulin resistance. Notably, other drivers of hyperinsulinemia (outside of insulin resistance) may be highly relevant in the context of PCOS. For instance, high androgen levels can augment both hyperinsulinemia and insulin resistance, generating a self-perpetuating cycle of reproductive and metabolic dysfunction. In this review, we evaluate the cause-and-effect relationships between insulin resistance and hyperinsulinemia in PCOS. We examine evidence for the prevailing theory of insulin resistance as the primary defect that causes secondary compensatory hyperinsulinemia, and an alternative framework of hyperinsulinemia as the earlier defect that perpetuates reproductive and metabolic features of PCOS. Considering the heterogeneous nature of PCOS, it is improbable that its metabolic characteristics always follow the same progression. Comprehensively examining all mechanistic regulators of hyperinsulinemia and insulin resistance in PCOS might thereby lead to improved prevention and management strategies, and address critical knowledge gaps in the progression of PCOS pathogenesis.

The role that vascular smooth muscle cell (VSMC)-derived foam cells play as drivers of atherosclerosis has been an increasing 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 well as the role of TLR4 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-α-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)2D3 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. TLR4 knockdown 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.

Maternal diet has long-term effects on offspring brain development and behavior. Sucrose (table sugar) intake is high in modern diets, but it is not clear how a maternal high-sucrose diet (HSD) affects offspring. In rats, a maternal HSD (26% of calories from sucrose, which is human-relevant) alters maternal metabolism and brain and also alters adult offspring endocrinology and behavior in a sex-specific manner. Maternal sucrose intake increases corticosterone levels in adult female offspring and increases motivation for a sugar reward in adult male offspring. Here, to identify possible underlying mechanisms, we examined how a maternal HSD affects steroids in the dam, placenta and fetus at embryonic day 19.5 using liquid chromatography-tandem mass spectrometry. Maternal sucrose intake increased glucocorticoids (11-deoxycorticosterone and 11-dehydrocorticosterone) and tended to increase the mineralocorticoid aldosterone in maternal serum. In the placenta, maternal sucrose intake decreased androstenedione and testosterone. Maternal HSD increased aldosterone in the fetal blood. Similarly, in the fetal brain, maternal high sucrose intake increased aldosterone in the medial prefrontal cortex and nucleus accumbens, decreased testosterone in the nucleus accumbens and decreased corticosterone in the orbital cortex. In addition, the 11-dehydrocorticosterone/corticosterone and aldosterone/corticosterone ratios were increased in most examined brain regions. Finally, maternal HSD increased 11-dehydrocorticosterone and aldosterone in the amniotic fluid. In summary, we found dramatic and widespread changes in maternal, placental and fetal steroids that might mediate the long-term effects of maternal sucrose consumption on adult offspring neuroendocrinology and behavior.

Adropin, a peptide hormone encoded by the energy homeostasis-associated gene, is expressed in various tissues, including the brain. Accumulating evidence from in vivo and in vitro studies highlights adropin's pivotal role in modulating carbohydrate and lipid metabolism. Notably, circulating adropin levels are lower in overweight and obese humans, and experimental interventions involving adropin overexpression or synthetic administration demonstrate promising outcomes in mitigating obesity-related metabolic abnormalities and preventing weight gain. This review comprehensively summarizes the current understanding of adropin's potential implications in diverse types of diabetes. Specifically, it explores adropin's utility as a biomarker for different types of diabetes and elucidates its significance as a potential predictor of diabetic adverse outcomes. Furthermore, the review delves into the beneficial effects of adropin treatment in animal models of experimentally induced diabetes, shedding light on its mechanisms of action in modulating glucose metabolism. In this comprehensive overview, we aim to provide a nuanced understanding of multifaceted role of adropin in diabetes pathogenesis and its therapeutic potential in combating this global health challenge.

Endocrine dysfunction and diabetes can develop secondary to fibrotic diseases within the pancreas, including cystic fibrosis (CF). A phenotypic shift within epithelial cells has been recognised in association with pro-fibrotic signalling. We sought evidence of endocrine cell epithelial-to-mesenchymal transition in CF and non-CF pancreas. Post-mortem pancreatic sections from 24 people with CF and 10 organ donors without CF or diabetes were stained for insulin/glucagon/vimentin and Sirius red/fast green with collagen distribution assessed semi-quantitatively (CF) and quantitatively (non-CF). Analysis of existing single-cell RNA-sequencing datasets (three adult donors without diabetes and nine with chronic pancreatitis) for α-cell vimentin expression was performed. Cells co-expressing glucagon/vimentin were detected in a proportion (32(4,61)% (median (Q1,Q3))) of islets in all CF pancreata except donors dying perinatally. CF histopathology was characterised by peri-islet fibrosis, and 60(45,80)% of islets were surrounded by collagen strands. A positive correlation between islet fibrosis and vimentin-expressing α-cells was seen in non-CF donors <31 years (r = 0.972; P = 0.006). A possible association with donor age was seen in all donors (r = 0.343; P = 0.047). Single-cell RNA-sequencing analysis of isolated islets from non-diabetic donors and donors with chronic pancreatitis confirmed the presence of vimentin-positive and vimentin-negative α-cells. Differentiated α-cell function-associated gene expression was maintained. Differentially upregulated processes in co-expressing cells included pathways associated with extracellular matrix organisation, cell-cell adhesion, migratory capability and self-renewal. We have identified and characterised an intermediate epithelial/mesenchymal state in a sub-population of α-cells present throughout post-natal life, which may play a role in their response to extrinsic stressors, including fibrosis and ageing.

Leptin increases focal inflammation and osteolysis induced by polyethylene particles in leptin-deficient ob/ob mice, suggesting that this adipokine, an important immune modulator, contributes to orthopedic implant failure. Focal inflammation leads to bone loss at distant skeletal sites, and it is plausible that leptin also contributes to this response. We tested this possibility in 6-week-old female ob/ob mice (6-8/group) by evaluating bone architecture, turnover and gene expression 12 days following the surgical placement of polyethylene particles over the calvaria. Particle treatment had minimal effect on bone mass, density or cancellous bone architecture in the femur and 5th lumbar vertebra (LV). However, compared to controls, particle treatment altered tibial expression levels of 32/84 genes related to bone metabolism. Subcutaneous infusion of leptin (6 μg/d) to mice following the placement of polyethylene particles over the calvaria (combination treatment) resulted in cancellous bone loss in the distal femur metaphysis and LV and in the differential expression of 34/84 genes, 15 of which overlapped with particle treatment. Notably, combination treatment, but not particle treatment, resulted in increased expression of genes strongly associated with bone turnover and response to inflammation. Leptin treatment alone (0.1-10 μg/day) did not result in bone loss in the femur or LV in the ob/ob mice. These findings suggest that leptin exaggerates the detrimental effects of particle-induced inflammation on bone turnover balance, leading to systemic bone loss.

The importance of steroidogenesis is underscored by its vital and conserved functions from higher to lower vertebrate species, such as stress, immune and inflammatory responses, sexual development and reproduction, osmoregulation and even the ability to adapt to the environment and environmental changes. Correspondingly, the rate-limiting step of steroidogenesis mediated by the steroidogenic acute regulatory protein is an ongoing target for scientific investigation. An expanding collection of studies has now reported key similarities, as well as some differences, in the transcriptional and translational regulation of steroidogenic acute regulatory protein across species. This review will discuss the current understanding of steroidogenic acute regulatory protein in fish, as these lower vertebrate models uniquely rely on steroid hormones for osmotic balance, reproductive functions, responses to environmental stimuli and much more.

The current understanding of the biology, biochemistry and genetics of the steroidogenic acute regulatory protein (StAR) and its deficiency state (lipoid congenital adrenal hyperplasia, lipoid CAH) involves the complex interplay of four areas of study: the acute regulation of steroidogenesis, clinical phenomena in lipoid CAH, the enzymatic conversion of cholesterol to pregnenolone in steroidogenic mitochondria, and the cell biology of StAR. This review traces the origins of these areas of study, describes how they have been woven into an increasingly coherent fabric and tries to explore some remaining loose ends in this ongoing field of endocrine research. Extensive research from multiple laboratories has established that StAR is required for the rapid, abundant steroidal responses of the adrenals and gonads, but all steroidogenic cells, especially the placenta, also have StAR-independent steroidogenesis, whose basis remains under investigation. Lipoid CAH is the StAR knockout of nature whose complex (and unexpected) clinical features are explained by the 'two-hit model', in which StAR-dependent steroidogenesis and StAR-independent steroidogenesis are lost sequentially. StAR is targeted to mitochondria and acts on the outer mitochondrial membrane before being imported via the 'translocase of outer membrane' system and is then inactivated by mitochondrial proteases. A role for the 'translocator protein' (TSPO) has long been proposed, but an essential role for TSPO is excluded by recent transgenic mouse experiments. Crystal structures show that a StAR molecule can bind one cholesterol but does not explain how each StAR molecule triggers the import of hundreds of cholesterol molecules; this is the most pressing area for future research.

Glucocorticoids and androgens affect each other in several ways. In metabolic organs, such as adipose tissue and the liver, androgens enhance glucocorticoid-induced insulin resistance and promote fat accumulation in male mice. However, the direct contribution of the androgen receptor (AR) to these effects is unknown. Furthermore, it is unclear whether the potentiating effect of androgens on glucocorticoid signaling in fat extends to other tissues, such as skeletal muscle and bone. In this study, we used two complementary models for androgen deprivation (orchidectomy and chemical castration) to investigate the effects of dihydrotestosterone (DHT) on corticosterone (CORT). We found that after 2 weeks of intervention, DHT alone did not affect fat mass but increased lean mass, while CORT increased fat mass and decreased lean mass. Co-supplementation with DHT counteracted the CORT effect on lean mass but enhanced its effect on adiposity. Glucocorticoid induction of Gilz, Fkbp5 and Mt2a in gonadal white adipose tissue depended on the presence of androgens, while in interscapular brown adipose tissue, these genes responded to glucocorticoids also without androgens. To directly assess the impact of the AR on the glucocorticoid response, male global AR knock-out mice were exposed to CORT and compared to WT littermates. CORT exposure resulted in an increase in fat mass and a decrease in lean mass in both genotypes. In conclusion, functional AR signaling is dispensable for the metabolic response to glucocorticoids. However, androgen signaling in WT mice modulates glucocorticoid response in a tissue-dependent manner, by counteracting lean mass and potentiating fat mass effects.

Glucagon-like peptide 1 (GLP-1) receptor agonists (GLP-1 RAs) are widely used as antidiabetic and anti-obesity agents. Although conventional GLP-1 RAs, such as liraglutide and semaglutide, are acylated with fatty acids to delay their degradation by dipeptidyl peptidase-4, the manufacturing process is challenging. We previously developed selectively lipidated GLP-1 peptides at their only tryptophan residue (peptide A having one 8-amino-3,6-dioxaoctanoic acid (miniPEG) linker and peptide B having three miniPEG linkers). In this study, we evaluated their effects on the GLP-1 receptor in vitro and in vivo. Both novel peptides were shown to increase cyclic adenosine monophosphate production and insulin secretion similarly to that by GLP-1(7-37) and liraglutide in vitro. In addition, these novel peptides lowered blood glucose levels by increasing insulin levels after oral administration of glucose and they suppressed gastrointestinal motility as effectively as liraglutide. The effects of peptide A on activation of satiety-promoting neurons in the arcuate nucleus and the consequent suppression of food intake and body weight were also similar to those of liraglutide, while the effects of peptide B were less than those of liraglutide. Under high-fat diet feeding, both long-term administration of peptide A and peptide B improved glucose tolerance and insulin sensitivity similarly to liraglutide. Thus, tryptophan-selective lipidated GLP-1 peptides are as effective as conventional GLP-1 RAs in reducing plasma glucose levels and body weight and may represent a less demanding method of manufacture of GLP-1 RAs.