Journal of Endocrinology最新文献

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.

Tirzepatide is a first-in-class dual agonist at receptors for glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) for the treatment of T2D and obesity, with unprecedented efficacy for glycaemic control, reductions in body weight and improvements in blood pressure and lipid profile compared with placebo and GLP-1 receptor agonists. To date, clinical trials of tirzepatide have fulfilled the requirement by regulatory authorities of demonstrated cardiovascular safety in high-risk patients. Whether cardiovascular benefits will be found with dual GLP-1/GIP receptor agonists remains uncertain, and the contribution of GIP receptor activation to cardiovascular risk has not been established. Several ongoing large-scale cardiovascular outcome trials for tirzepatide will provide a clearer understanding of where tirzepatide should be positioned in the treatment of established atherosclerotic cardiovascular disease or in people at high risk, in relation to current standard-of-care cardioprotective agents and approaches.

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.