Journal of the Endocrine Society最新文献

Nuclear receptors are important in normal physiology and disease. Physicians and scientists who study nuclear receptors organize and attend conferences and symposia devoted to foundational and translational nuclear receptor research, but the field lacks a platform for early-stage investigators and aspiring leaders. In 2019, Zeynep Madak-Erdogan, Rebecca Riggins, and Matthew Sikora founded Nuclear Receptor (NR) Interdisciplinary Meeting for Progress And Collaboration Together (IMPACT, https://nrimpact.com), a collaborative group designed for early- and mid-career faculty who study nuclear receptors in any context or organism [1]. NR IMPACT addresses challenges for early- and mid-career faculty. Here, we review the progress of NR IMPACT and discuss how our peer-mentoring cohort is removing hurdles for new faculty and advancing nuclear receptor biology.

Context: Evidence for a beneficial role of vitamin D on blood pressure (BP) outcomes is inconclusive.

Objective: This work aimed to investigate the effect of 2 doses of cholecalciferol (vitamin D₃) supplementation coadministered with calcium on systolic blood pressure (SBP) and diastolic blood pressure (DBP).

Methods: Exploratory analyses were conducted from a 1-year, multicenter, double-blind, randomized controlled trial (RCT). Total of 221 ambulatory older overweight individuals received calcium dose and oral vitamin D₃, at the equivalent of 600 IU/day or 3750 IU/day.

Results: SBP and DBP decreased significantly in the overall group, and in the high-dose group at 6 and 12 months. Similar trends were observed in the low-dose group, but did not achieve statistical significance. In participants with a body mass index (BMI) greater than 30, SBP decreased significantly in both treatment groups whereas DBP significantly decreased in the high-dose group only. In the subgroups of hypertensive participants (N = 143), there was a decrease in SBP and DBP at 6 and 12 months, with both vitamin D doses and independently of BMI levels. Using multivariate linear mixed models with random effects in the overall group of participants, SBP at 6 and 12 months was significantly predicted by BMI (β = .29; P = .05) and by baseline SBP (β = .16; P < .001), but not by vitamin D treatment dose.

Conclusion: Vitamin D and calcium decrease SBP and DBP in overweight older individuals, but more is not necessarily better. This effect is seen in individuals with BMI greater than 30, in hypertensive patients, and seems to be largely independent of dose.

Context: The efficacy of tocilizumab (TCZ) in treating Graves orbitopathy (GO) remains uncertain due to the small sample sizes of earlier studies, and there is a lack of research on the drug for juvenile GO.

Objective: To evaluate the effectiveness of TCZ in treating GO that is resistant to conventional therapy.

Design: This observational study at a tertiary care center included 79 Chinese GO patients, 15 of whom were pediatric patients, with 52 of these patients having moderate to severe active GO (all adult patients having steroid-resistant GO). Intravenous infusion of TCZ 8 mg/kg was given every 28 days for 4 months. Changes from baseline in visual acuity (VA), intraocular pressure (IOP), proptosis, clinical activity score (CAS), and thyrotropin receptor antibody (TRAb) levels throughout TCZ therapy were assessed at baseline (T0), the fifth month (T4), and follow-up (T5). Additionally, improvements in CAS by at least 2 points and CAS < 4 points at T4 and T5 were evaluated.

Results: Significant improvements were found in VA, IOP, proptosis, CAS, and TRAb levels in the adult group, and proptosis in the pediatric group at T5 (P < .05). Additionally, significant improvements were identified in TRAb levels and CAS (active GO at T0) in the pediatric group at T4 (P < .05). In the adult and pediatric group with active GO at T5, 71.4% and 60% experienced a decrease in CAS by ≥ 2 points, respectively; 89.3% and 60% achieved the response criterion of low activity disease (CAS < 4 points), respectively.

Conclusion: TCZ emerged as a valuable therapeutic option for Chinese patients with active, corticosteroid-resistant, moderate to severe GO.

Context: Excessive eating and intake of a Western diet negatively affect the intestinal immune system, resulting in compromised glucose homeostasis and lower gut bacterial diversity. The G protein-coupled receptor GPR183 regulates immune cell migration and intestinal immune response and has been associated with tuberculosis, type 1 diabetes, and inflammatory bowel diseases.

Objective: We hypothesized that with these implications, GPR183 has an important immunometabolic role and investigated this using a global Gpr183 knockout mouse model.

Methods: Wild-type (WT) and Gpr183-deficient (Gpr183^-/-) mice were fed a high-fat, high-sucrose diet (HFSD) for 15 weeks. We investigated changes in weight, body composition, fecal immunoglobulin A (IgA) levels, fecal microbiome, and glucose tolerance before and after the diet. Macrophage infiltration into visceral fat was determined by flow cytometry, and hepatic gene expression was measured.

Results: A sexual dimorphism was discovered, whereby female Gpr183^-/- mice showed adverse metabolic outcomes compared to WT counterparts with inferior glucose tolerance, lower fecal IgA levels, and increased macrophage infiltration in visceral fat. In contrast, male Gpr183^-/- mice had significantly lower fasting blood glucose after diet than male WT mice. Liver gene expression showed reduced inflammation and macrophage markers in Gpr183^-/- livers, regardless of sex, while the pancreatic islet area did not differ between the groups. No conclusive differences were found after microbiome sequencing.

Conclusion: Gpr183 maintains metabolic homeostasis in female but not in male mice independent of diet. If confirmed in humans, future therapy targeting GPR183 should consider this sexual dimorphism.

Tributyltin (TBT) is a synthetic chemical widely used in industrial and commercial applications. TBT exposure has been proven to elicit obesogenic effects. Gestational exposure led to increased white adipose tissue depot size in exposed (F1, F2) animals and in unexposed generations (F3, F4), an example of transgenerational inheritance. TBT exerts these effects in part by increasing the number and size of white adipocytes, altering the fate of multipotent mesenchymal stromal stem cells to favor the adipocyte lineage, altering adipokine secretion, and modulating chromatin structure. Adipose tissue resident macrophages are critical regulators in adipose tissue; however, the effects of TBT on adipose tissue macrophages remained unclear. Here we investigated the effects of TBT on macrophages and consequent impacts on adipocyte function. TBT significantly enhanced palmitate-induced inflammatory gene expression in mouse bone marrow derived macrophages and this effect was attenuated by the antagonizing action of the nuclear receptor peroxisome proliferator activated receptor gamma. TBT-treated macrophages decreased lipid accumulation in white adipocytes differentiated from mesenchymal stromal stem cells accompanied by increased expression of lipolysis genes. Lastly, ancestral TBT exposure increased Tnf expression in adipose tissue resident macrophages in both exposed (F2) and unexposed (F3) generations, suggesting that TBT exposure led to an inherited predisposition toward inflammatory adipose tissue macrophages that can manipulate adipose tissue function. These findings provide new insights into the interplay between adipocytes and adipose tissue macrophages in obesity, further establishing a role for obesogens such as TBT in the development of obesity-related metabolic disorders.

Objective: To examine the real-world clinical and healthcare resource burden of familial hypophosphatemia (FH).

Methods: In a retrospective, observational cohort study using MarketScan claims data from 2017 to 2021, clinical characteristics and healthcare resource utilization (HCRU) and costs were compared between burosumab-naïve pediatric and adult patients with ≥ 1 FH diagnosis code and matched controls without FH. Patient characteristics were evaluated at baseline, and disease characteristics, HCRU, and costs were evaluated over a 12-month follow-up period. Outcomes were analyzed descriptively. Costs were additionally analyzed using multivariate regression models.

Results: Overall, 570 patients with FH and 1710 non-FH matched controls were included. Approximately 10% of study participants were aged < 18 years. Patients with FH had 7.8-fold higher mean baseline comorbidity (Charlson Comorbidity Index). The prevalence of morbidities over the 12-month follow-up period was higher in patients with FH than controls, including renal disease (33% vs 3%), arthralgia (25% vs 10%), osteoarthritis (17% vs 6%), and delayed growth/walking difficulty (16% vs 2%; all P < .001). All-cause HCRU was significantly greater for patients with FH than controls over follow-up, including the proportion of patients with at least one inpatient admission (60% vs 4%), outpatient emergency room visit (52% vs 16%), and outpatient pharmacy prescription (96% vs 71%; all P < .001). The mean annual total healthcare cost per patient was also 22.6-fold higher for patients with FH than controls (adjusted cost difference = $129 643; P < .001). Differences were apparent across all age groups.

Conclusion: Compared with non-FH matched controls, burosumab-naïve patients with FH experienced multiple morbidities and had substantially higher HCRU and costs.

Context: Ghrelin circulates in acylated (AG) and deacylated (DAG) forms, which are known to affect appetite. Although acute exercise has been shown to modulate ghrelin levels, data on the impact of exercise intensity on AG and DAG levels and their effects on appetite are sparse and primarily limited to males.

Objective: To investigate the effect of exercise intensity and sex on ghrelin levels and appetite in untrained humans.

Methods: Eight males (age: 43.1 ± 10.9 years; body mass index [BMI]: 22.2 ± 1.7 kg/m²; peak oxygen consumption [VO_2peak]: 36.3 ± 6.4 mL/kg/min) and 6 females (age: 32.2 ± 11.1 years; BMI: 22.7 ± 1.0 kg/m²; VO_2peak: 29.2 ± 4.0 mL/kg/min) completed a maximal graded cycle ergometer lactate threshold (LT)/VO_2peak test. These data were used to determine the exercise intensity on 3 subsequent randomized control or calorically matched cycle exercise bouts: (1) CON, no exercise; (2) MOD, the power output at LT; (3) HIGH, the power output associated with 75% of the difference between LT and VO_2peak. Perception of appetite was analyzed using visual analog scales.

Results: Females had higher levels of total ghrelin (TG) (P = .03) and DAG (P = .01) at baseline than males. Both groups exhibited reduced DAG levels in HIGH compared with MOD and CON (P < .0001-.004); however, only females had significantly reduced AG in HIGH (P < .0001). Hunger scores were higher in MOD than in CON (P < .01).

Conclusion: High-intensity may be superior to moderate-intensity exercise for reducing ghrelin levels and modifying hunger, and sex may impact this response.

Background: Steroidogenic Factor 1/Nuclear Receptor Subfamily 5 Group A Member 1 (SF-1/NR5A1) is critical for the development and function of sex organs, influencing steroidogenesis and reproduction. While rare deleterious NR5A1/SF-1 variants have been identified in individuals with various differences of sex development (DSD), primary ovarian insufficiency, and infertility, their impact on the general population remains unclear.

Methods: We analyzed health records and exome sequencing data from up to 420 162 individuals (227 858 women) from the UK Biobank study to assess the impact of rare (frequency < 0.1%) predicted deleterious NR5A1/SF-1 variants on age at menopause and 26 other traits.

Results: No carriers of rare protein truncating variants in NR5A1/SF-1 were identified. We found that the previously reported association of rare deleterious missense NR5A1/SF-1 variants with earlier age at menopause is driven by variants in the DNA binding domain (DBD) and ligand binding domain (LBD) (combined test: beta = -2.36 years/allele, [95% CI: 3.21, -1.51], N = 107 carriers, P = 4.6 × 10^-8). Carriers also had a higher risk of adult obesity (OR = 1.061, [95% CI: 1.003, 1.104], N = 344, P = .015), particularly among women (OR = 1.095 [95% CI: 1.034, 1.163, P = 3.87 × 10^-3], N = 176), but not men (OR = 1.019, [95% CI: 0.955, 1.088], P = .57, N = 168).

Conclusion: Deleterious missense variants in the DBD and LBD likely disrupt NR5A1/SF-1 function. This study broadens the relevance of deleterious NR5A1/SF-1 variants beyond rare DSDs, suggesting the need for extended phenotyping and monitoring of affected individuals.

In June 2024, the Endocrine Feedback Loop podcast recorded its fiftieth episode at the annual meeting of the Endocrine Society. Launched in May 2020, the podcast serves as a way for listeners to hear a critical analysis of recent and impactful research studies published in clinical journals of the Endocrine Society. The podcast follows methods proven effective in traditional journal clubs and adapts them to reach a wide audience with different levels of expertise in endocrinology. This Perspective outlines the history of the podcast, the process of producing a monthly episode, and the topics covered, as well as an assessment of the experience of producing the podcast and future plans for the Endocrine Feedback Loop.