Journal of Endocrinology最新文献

Previous research showed that a maternal high-fat (HF) diet during the perinatal period impairs skeletal muscle metabolism in offspring. Supplementing the HF diet with fish oil (FO), a source of n-3 polyunsaturated fatty acids, during gestation partially mitigates these adverse effects at weaning. This study investigated whether maternal HF diet, with or without FO supplementation during gestation, alters the expression of muscle-secreted molecules (myokines) in female and male offspring at weaning. Female Wistar rats were fed a control (9% lipids) or HF diet (29% lipids) for 8 weeks before mating and throughout gestation and lactation. A subset of HF-fed dams received a 3% FO-supplemented HF diet (HFFO) during gestation. In glycolytic extensor digitorum longus (EDL) muscle, FO tended to decrease Nmb (neuromedin B) mRNA in females and increased Erfe (myonectin) mRNA in males, compared to sex-matched HF groups. HFFO males also exhibited elevated expression of genes involved in fatty acid uptake and oxidation, suggesting enhanced lipid metabolism. However, FO did not reverse the HF-induced downregulation of Igf1r in EDL or Igf1 in the oxidative soleus muscle of male offspring, and muscle fiber size remained unchanged across groups. In the soleus muscle, FO increased Il6 mRNA in females, while in males, FO induced FNDC5 (the irisin precursor), accompanied by increased uncoupling protein-1 in subcutaneous white adipose tissue, suggesting increased thermogenic activity. Gestational FO supplementation induces sex- and muscle-specific alterations in myokine expression in weanling offspring exposed to a maternal HF diet, potentially shaping early muscle metabolism and contributing to sex-dependent metabolic programming.

Graves' disease (GD) is an important risk factor for secondary osteoporosis (OP). Thyrotropin-receptor stimulating antibody (TSAb) is a pathogenic antibody detected in patients with GD. However, few studies have examined the effects of TSAb on bone. Consequently, this study aimed to explore the effect of TSAb on osteoblast differentiation and its possible mechanisms. MC3T3-E1 cells were treated with different concentrations of TSAb. The relative survival rate of cells was assessed using the cell counting kit-8 (CCK-8) assay. Osteoblast differentiation markers were determined using western blotting and immunofluorescence assays. To further evaluate the roles of TSAb in osteogenesis in vivo, a GD-induced OP mouse model was generated by Ad-TSHR289 immunization followed by intragastric administration of methimazole (MMI). Femurs were collected for micro-CT scanning and histomorphometry analysis. The viability of MC3T3-E1 cells did not significantly change with increasing TSAb concentrations. The protein levels of osteoblast differentiation markers (OCN, Col1a1, Runx2, and OPN) in MC3T3-E1 cells treated with 1 and 10 ng/mL TSAb were significantly reduced. Furthermore, TSAb significantly promoted the AKT/mTOR pathway. Moreover, inhibition of this signaling pathway attenuated the phosphorylation of AKT and mTOR enhanced by TSAb and reversed osteoblast differentiation. GD mice treated with MMI exhibited reduced bone mass and degraded bone formation. TSAb exacerbates bone loss in GD mice. These findings demonstrated that TSAb inhibits osteoblast differentiation by activating the AKT/mTOR pathway. This study revealed a novel function of TSAb in regulating osteoblast activity.

Disturbances in calciotropic hormones: parathyroid hormone (PTH), vitamin D, fibroblast growth factor-23 (FGF-23)/Klotho, and mineral homeostasis are often seen in chronic kidney disease (CKD) and are key factors driving vascular calcification (VC). Importantly, the role of these hormones in VC is poorly understood. Therefore, we investigated how the dysregulation of calciotropic hormones and mineral metabolism determines the dynamics of the VC process in adenine-induced CKD in rats. Male rats were fed a diet containing 0.3% adenine for 4, 6, and 8 weeks to establish CKD. Classical markers of renal function, mineral homeostasis, and progression of VC were determined. In the earlier stages of CKD, in conditions of low 1,25-dihydroxyvitamin-D3 (1,25(OH)2D3) and Klotho deficiency, PTH exhibited an effective phosphaturic effect, and the PTH/FGF-23/Klotho axis seems to have a protective function against VC. In the later stage of the disease, the predominance of PTH led to the activation of 1,25(OH)2D3 synthesis, which resulted in the rebuilding of Klotho resources and allowed FGF-23 to take over a phosphaturic role. As a result, PTH/1,25(OH)2D3/Klotho signaling seems to exert a procalcifying effect. Moreover, VC was directly and inversely associated with the minerals excreted in the urine, and receiver operating characteristic analysis revealed a high diagnostic potential of calcium excretion in VC prediction. The present study shows that measuring serum panel of calciotropic hormones and urine tests assessing the excretion of minerals performed in a laboratory routine may be helpful tools for predicting VC progression at different CKD stages.

Insulin resistance (IR) is described as an impaired response to insulin stimulation of target cells. The present study was designed to investigate the impact of the dexamethasone-induced IR model on self-care behaviors and brain-derived neurotrophic factor (BDNF). Sixteen adult Wistar albino rats were divided into control and IR groups (n = 8). Dexamethasone was administered intraperitoneally at 1 mg/kg/day for 5 days to induce the IR model. Open field and splash tests were performed to evaluate locomotor activity and self-care depression-like behaviors, respectively. BDNF was analyzed by enzyme-linked immunosorbent assay in the striatum and prefrontal cortex (PFC). Shapiro-Wilk, Student's t-test, and Fisher's exact test were used as statistical tests. Furthermore, the relationship among homeostasis model assessment of insulin resistance (HOMA-IR), BDNF, and total grooming behavior was analyzed using the Pearson correlation test. Total distance traveled, grooming frequency, and grooming time decreased in the IR group compared to the control group. Serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), glucose, insulin, and HOMA-IR values increased in the dexamethasone-applied group (P < 0.05). BDNF decreased in the prefrontal cortex in the IR group (P < 0.05). The striatum BDNF level decreased slightly but was insignificant (P > 0.05). Degeneration of the islets of Langerhans in the pancreas, tubular degeneration in the kidney, degeneration of hepatocytes, and mononuclear cell infiltration in the liver increased in the IR group compared to the control group (P < 0.05). PFC BDNF levels, total grooming, and HOMA-IR values displayed a significant correlation (P < 0.05). The PFC was found to be more vulnerable to IR. Our results suggest that IR deteriorates self-care behaviors and the BDNF level of the prefrontal cortex.

Adipose tissue (AT) releases adipokines and inflammatory cytokines, which may have an adverse impact on the mother and fetus during pregnancy. Mothers with gestational diabetes mellitus (GDM) differentially express adipokines and cytokines compared to normal glucose tolerant (NGT) mothers, but the mechanisms are unknown. The purpose of this study was to identify molecular mechanisms in subcutaneous (SQAT) and visceral AT (VAT) which may help characterize GDM and pinpoint those that contribute to its pathology. SQAT and VAT samples were collected from 22 NGT and six GDM pregnant women undergoing a C-section. A panel of inflammatory, mitochondrial, and metabolic genes and proteins (via q-rtPCR and Western blot) was measured. Blood was assessed for concentrations of adiponectin, brain neurotrophic factor, C-reactive protein, and non-esterified fatty acids (via ELISA). In GDM, VAT protein content was lower for oxidative phosphorylation complexes CI-CIII, adiponectin, and adipose triglyceride lipase. Gene expression of adiponectin, estrogen receptor β, uncoupling protein 1, and peroxisome proliferator-activated receptor gamma was also lower in GDM mothers, while gene expression of an anti-inflammatory macrophage marker was higher. No differences in the measured blood markers were found. Mothers with GDM differentially express AT adipokines and genes associated with inflammation, insulin resistance, and altered lipid metabolism relative to mothers with NGT.

Cardiogenic shock (CS) is a life-threatening complication of acute myocardial infarction (AMI) with high mortality. Hormonal alterations during CS may offer prognostic insights. While growth hormone (GH) dynamics have been studied in heart failure, the role of insulin-like growth factor-1 (IGF-1) in CS remains unclear. IGF-1 exerts cardioprotective effects, including reducing myocardial apoptosis after ischemia-reperfusion injury. This study examines temporal changes in GH and IGF-1 levels in CS and their prognostic value. The Halle-Cardiogenic Shock Registry included 41 AMI patients with CS. GH and IGF-1 levels were measured at admission and on day 1, 2 and 4 post-percutaneous coronary intervention. Differences were analyzed between survivors and non-survivors, as well as by age (<70 vs ≥70 years) and sex. We found that at admission, GH levels (2.86 ± 0.78 μg/L) were within the normal range in 75.6% of patients and showed no significant differences between survivors and non-survivors. IGF-1 levels (76.23 ± 5.67 μg/L) were at the lower end of normal and declined to 66.8 μg/L at 48-72 h (P = 0.14). Non-survivors had a more rapid IGF-1 decline, while survivors maintained stable levels. IGF-1 was higher in younger and male patients, while older and female patients showed a greater decline. We conclude that GH levels remained stable and lacked prognostic value, while IGF-1 decline correlated with disease severity and possible hepatic dysfunction. IGF-1 may serve as a biomarker for risk stratification and a therapeutic target for metabolic regulation and recovery in CS, warranting further investigation.

Neurosteroids synthesized within the central nervous system play essential roles in modulating neurotransmission, providing neuroprotection, regulating immune responses, influencing behavior and cognition and mediating stress physiology. Despite their broad significance, the specific brain cell types capable of de novo steroid synthesis from cholesterol remain poorly defined. In this study, we analyzed single-cell transcriptomic data to map steroidogenic gene expression across cell populations in the murine brain, focusing on the de novo production of the neurosteroid pregnenolone. Our findings reveal that de novo steroidogenesis, as marked by Cyp11a1 expression, is predominantly confined to specific neuronal subtypes, particularly glutamatergic neurons of the intra- and extra-telencephalic regions and the corticothalamic layer. In contrast, Star expression, which is essential for mitochondrial cholesterol import, was more broadly distributed, occurring in both neuronal and non-neuronal cells (including oligodendrocytes, astrocytes, immune cells and vascular cells). In these non-neuronal populations, Star was notably co-expressed with mitochondrial Cyp27a1, indicative of bile acid synthesis rather than neurosteroidogenesis. This distinction highlights that Star expression alone is not a reliable marker of de novo neurosteroidogenic capacity in the brain, as its functional significance depends on the broader enzymatic context in which it occurs. The resulting single-cell map of de novo neurosteroid biosynthetic capacity across brain regions, including modest sex-associated differences, provides a foundational framework for understanding neurosteroid signaling in distinct cell types and its relevance to brain physiology and pathophysiology.

Neurosteroids synthesized within the central nervous system modulate neurotransmission, enhance neuroprotection, regulate immune responses and influence cognitive and behavioral processes. Beyond de novo synthesis of pregnenolone (PREG) from cholesterol, the brain also engages in intermediary synthesis, converting local or circulating precursors into active neurosteroids. However, the specific cell types and brain regions involved remain poorly defined. In this study, we used single-cell transcriptomic data to map the expression of steroidogenic genes and identify cell populations in the murine brain responsible for intermediary neurosteroid biosynthesis. Our findings reveal that the synthesis of bioactive steroids downstream of PREG is not streamlined but selectively compartmentalized. Notably, cells involved in de novo neurosteroid biosynthesis are largely disjointed from intermediary steps, indicating reliance on regional diffusion and/or systemic sources. Capacity for synthesis of androgens and corticosteroids anew are practically absent. While sterol sulfotransferases are expressed, sterol sulfatase required for desulfation is absent, indicating irreversible sulfonation of PREG and dehydroepiandrosterone (DHEA). Other enzymes involved in bioconversions of pregnanes and androstanes, when expressed, showed cell type- and region-specific ramifications. Although certain limitations exist in fully deciphering these results due to certain gaps in enzyme substrate specificity and isoform catalytic preferences, our study reveals valuable insights into the brain's intermediary neurosteroid pathways. The distinct compartmentalization of these processes suggests precise control over steroid regulation, which could have far-reaching functional implications. By mapping the neurosteroidogenic potential in the murine brain and sex-associated variations, this study sets the stage for future investigations into the roles of neurosteroids in brain function and their therapeutic potential in neurological disorders.

Regulation of steroid hormone biosynthesis is principally mediated by the steroidogenic acute regulatory (StAR) protein and involves endocrine, autocrine and paracrine signaling in a variety of classical and non-classical tissues. Cholesterol is the precursor of all steroid hormones. The StAR protein, by mobilizing the transport of intramitochondrial cholesterol, regulates the biosynthesis of steroid hormones which play pivotal roles in diverse processes. Steroid biosynthesis is primarily mediated by mechanisms that enhance transcription, translation, or activation of StAR. These processes are primarily regulated by the cAMP/protein kinase A (PKA) pathway, in which a plethora of signaling plays permissible roles. Whereas gain-of-function of StAR, involving phosphorylation and/or acetylation, enhances the activity of StAR in optimal steroid biosynthesis; its loss-of-function, connecting mutations, markedly decreases the biosynthesis of steroid hormones. Deterioration in the steroidogenic machinery, including hormonal homeostasis, modulates immunosenescence and results in the development of various health complications and diseases. Recent advances provide evidence that aberrant expression of StAR-driven estrogen, especially 17β-estradiol (E2), biosynthesis promotes breast tumorigenesis, in which StAR is uncovered as an acetylated protein. Moreover, age-associated progressive suppression of StAR-governed sex neurosteroids influences the most prevalent neurological disorder, Alzheimer's disease, in both women and men. This review summarizes significant findings and the current understanding of the regulation of StAR in a variety of steroid-coupled events, ranging from organogenesis to carcinogenesis to neurodegeneration, and helps unravel the mechanistic insights into relevant physiological and pathophysiological implications.

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Abstract: 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): i) HFD without intervention (HFNI), ii) 6 weeks of exercise followed by ND for 10 weeks (HFEX-S), iii) 16 weeks of continuous exercise (HFEX-L), iv) 40% CR for 6 weeks followed by a ND ad libitum for 10 weeks (HFCR-S), and v) 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.