Journal of Endocrinology最新文献

Unhealthy lifestyles and chronic metabolic stress are key contributors to obesity and the increased risk of osteoporotic fractures, both of which are significant global health concerns. This study aimed to evaluate the time-dependent effects of exercise and caloric restriction (CR) on bone homeostasis and quality in high-fat diet (HFD)-induced obesity. Seven-week-old male Wistar rats were fed either a normal diet (ND; n=6) or an HFD (n=30) for 28 weeks to induce obesity. At week 13, the HFD-fed rats were further divided into five groups (n=6/group): (1) HFD without intervention (HFNI), (2) six weeks of exercise followed by ND for 10 weeks (HFEX-S), (3) 16 weeks of continuous exercise (HFEX-L), (4) 40% CR for six weeks followed by ad libitum ND for 10 weeks (HFCR-S), and (5) 40% CR for 16 weeks (HFCR-L). Metabolic parameters were reassessed, and samples from serum, tibia, and femur were collected for analysis. Compared to ND, HFNI rats exhibited significantly elevated serum CTX-I, TRAP5b, bone malondialdehyde levels, and increased expression of p16, p21, p53, IL1-β, tnfrsf11a, tnfsf11, ctsk, fgf23, and Sost mRNA (p <0.05). Conversely, markers of antioxidant defense (GSH-Px), Wnt signaling (Wnt1, LRP5), and bone strength were reduced (p <0.05). Both exercise and CR improved bone parameters by reducing oxidative stress and inflammatory markers (p <0.05). Notably, long-term exercise provided the greatest benefit by enhancing bone strength, cortical quality, and trabecular microarchitecture (p <0.05). These findings suggest that sustained lifestyle changes, particularly long-term exercise, are effective strategies for mitigating obesity-induced bone fragility.

The role of the GDF15 receptor, GDNF family receptor alpha like (GFRAL), in the metabolic effects of FGF21 was investigated by treating female GFRAL knockout mice with recombinant human FGF21. In contrast to FGF21-treated wildtype mice, which lost 12% body weight relative to vehicle, the absence of GFRAL coincided with a greater compensatory increase in food intake, and accordingly, the weight-lowering effect of FGF21 treatment was blunted. Interestingly, the glycaemic benefits of FGF21 persisted in the absence of GFRAL. Potential crosstalk between FGF21 and GDF15 was further investigated acutely in obese male rats in which a single dose of FGF21 did not increase endogenous circulating GDF15 levels and vice versa. Lastly, overexpression of GDF15 or FGF21 with hydrodynamic gene delivery in obese male mice did not alter the expression of the other's receptor complex in regions of the hypothalamus and hindbrain. Collectively, we demonstrate an impaired weight lowering effect of exogenous FGF21 in female GFRAL knockout mice. Yet, the further examination of the interconnectedness between GDF15 and FGF21 endocrine axes in male rodents imply that they largely operate in parallel and are not extensively intertwined. In future studies, it will be important to investigate the influence of sex, particularly on the role of GDF15-GFRAL signalling in regulating compensatory food intake induced by FGF21 pharmacology.

Non-alcoholic fatty liver disease (NAFLD) can progress to fibrosis and hepatocellular carcinoma, with TGFβ playing a key role. UBAP2L regulates TGFβ expression, but its role in NAFLD remains unclear. While exercise improves NAFLD and cold exposure enhances lipid metabolism, their combined effects on NAFLD-induced fibrosis are unknown. This study examines whether exercise with cold exposure (ECE) attenuates NAFLD-induced fibrosis via UBAP2L-mediated TGFβ/Smad2/3 pathway. Fifty 5-week-old male C57BL/6N mice were assigned to five groups: normal control (C), high-fat diet (H), high-fat diet with cold exposure (HC), high-fat diet with exercise (HE), and high-fat diet with ECE (HCE). After 8 weeks of high-fat diet feeding, the HE and HCE groups underwent treadmill exercise (50 minutes/session, 5 days/week for 8 weeks). HE, Oil Red O, Masson staining, biochemical analyses, proteomics, WB, and RT-qPCR were used to assess fibrosis-related markers. We found that body weight, liver weight, hepatic TG, TC, LDL, Glu, CHO, and AST, ALT were significantly elevated in H group. In HCE group, hepatic TG and BUN decreased, while HDL increased. Proteomics identified UBAP2L as the most upregulated protein in H group, but it was downregulated in HCE group. WB confirmed UBAP2L overexpression in H group and its reduction in HCE group, with decreased α-SMA. RT-qPCR showed elevated TGFβ, α-SMA, Smad2, Smad3, Col1a2 and UBAP2L in H group, which were downregulated by ECE. ECE reduces NAFLD-induced hepatic fibrosis, probably by downregulating UBAP2L and suppressing TGFβ/Smad2 pathway. These suggest ECE may be more effective than exercise at normal temperatures in Mitigating NAFLD-related fibrosis.

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.

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.