Endocrinology最新文献

Progesterone receptor membrane components 1 and 2 (PGRMC1 and PGRMC2) are single-pass proteins that function as multi-ligand regulators. They integrate signals from progesterone (P4), heme, and cytochrome P450 enzymes (CYPs). Accumulating evidence implicates PGRMCs in non-genomic progesterone signaling in cell, cancer and reproductive biology. Heme binding (through their heme binding domain) and cytochrome P450 enzymes (CYPs) binding provide distinct functional roles for PGRMCs in various cells under specific cellular environment. In reproductive tissues, multiple functional roles have been reported for both PGRMC1 and PGRMC2 in both maternal and fetal organs. Ambiguity still exists about their independent functional role and contributions in pregnancy maintenance or initiation of parturition. Collectively, PGRMC1 and PGRMC2 act in complementary ways to regulate heme biology, metabolism, and P4-responsive signaling in gestational tissues. With the growing interest in PGRMC's role in pregnancy associated tissues, we provide a comprehensive narrative of PGRMCs through this review to facilitate future research and stimulate continued discussions.

Dysregulation of hepatokines has been observed in patients with metabolic dysfunction-associated steatotic liver disease (MASLD), suggesting their involvement in disease progression. In this study, we aimed to investigate the role of α1-acid glycoprotein (AGP), a hepatokine, in the progression of MASLD, and to evaluate its potential therapeutic utility. Reanalysis of hepatic RNA-seq datasets from patients with fatty liver disease showed that expression of the hepatic AGP gene decreased with disease progression. A high-fat diet (HFD)-induced mouse model of MASLD also showed decreased plasma and hepatic AGP levels. Whole-body AGP-knockout (AGP-KO) mice were fed a HFD for 12 weeks. Compared to wild-type mice, AGP-KO mice fed a HFD displayed further exacerbated hepatic steatosis, obesity, adipose tissue inflammation and impaired glucose tolerance, suggesting a protective role for endogenous AGP against MASLD. Morphological abnormalities of hepatic mitochondria were observed in AGP-KO mice. Human-derived AGP (hAGP) was isolated and purified from plasma fraction V supernatant derived from human blood donations using ion-exchange column chromatography. hAGP exerted a protective effect against palmitate-induced lipotoxicity in hepatocytes, adipocytes and macrophages. Exogenous administration of hAGP to MASLD mice attenuated disease progression by reducing hepatic mitochondrial dysfunction and adipose tissue inflammation. In conclusion, decreased endogenous AGP levels may contribute to the disease progression of MASLD. AGP has the potential to serve as a novel therapeutic agent against MASLD by targeting both liver and adipose tissue.

Type 2 diabetes (T2D) is a heterogenous metabolic condition characterized by varying degrees of insulin resistance and β-cell dysfunction. Preclinical mouse models are essential tools to investigate the mechanisms of T2D pathogenesis and develop therapeutic targets, yet researchers often fail to specify which aspects of the spectrum of human T2D phenotypes are being modelled. In this mini-review, we critically examine mouse models of T2D and categorize them into recently redefined T2D subtypes according to key pathophysiological features. We focus on models that exhibit i) insulin deficiency, ii) insulin resistance independent of weight gain, or iii) insulin resistance associated with weight gain. Onset, severity, and progression of metabolic phenotypes are described and discussed in context with clinical presentation in humans. While we find current T2D mouse models do not fully capture the heterogeneity of T2D, strategic model combinations and longer-term phenotyping could help better mimic clinical progression. Existing phenotyping data are often incomplete and largely available only for young male mice. We highlight the urgent need for thorough and standardized phenotyping of both sexes in all models. We also encourage the field to move toward using age-appropriate mice to better reflect human T2D pathophysiology and to advance precision medicine efforts in diabetes research.

Septic shock urgently requires new treatments. We reported that low circulating concentrations of the native glucocorticoid carrier, corticosteroid-binding globulin (CBG), predict a three-fold increase in human septic shock mortality. To explore this, we used our murine model of high-grade polymicrobial sepsis (cecal ligation and puncture, CLP) to test CBG therapy. We pre-fitted adult male C57BL/6 mice (n=106) with wireless arterial telemetry, then induced high-grade CLP. Mice were randomised with or without intravenous CBG therapy at 6 hr (3.5 mg/kg) and 30 hr (2.5 mg/kg). Terminal bloods, collected on humane endpoints or at 96 hr, were assessed for inflammation and organ damage; PET imaging was used to assess [124I]I-CBG biodistribution. CLP mice developed septic shock leading to multi-organ failure and 58% mortality. CBG therapy reduced mortality to 17% (a relative decrease of 72%), reduced hypotension duration by 75%, and lowered organ damage markers. CBG transiently suppressed the pro-inflammatory cytokine peak at 12 hr (45-59%) and markedly augmented anti-inflammatory IL-10 and IFN-β1 (2-fold to 96 hr). The decrease in corticosterone alongside this profile suggests an intrinsic anti-inflammatory response. Combined with PET-confirmed [124I]I-CBG targeting to the injury site, these data suggest CBG survival benefits are due to targeted delivery or direct immunomodulation. While host responses involve a complex interplay of neuroendocrine and metabolic factors, our findings demonstrate marked improvements in disease progression and mortality with CBG therapy in murine modelled septic shock. These results provide a strong impetus for a study of CBG therapy in patients with septic shock.

The mineralocorticoid receptor (MR), classically known for its role in electrolyte homeostasis, has emerged since the early 2000s as a key regulator of adipocyte biology. MR activation induces oxidative stress and inflammation, promotes white adipogenesis, and suppresses brown fat differentiation, potentially contributing to obesity and metabolic syndrome (MetS). In mice, MR antagonists (MRAs) have shown beneficial metabolic effects by reversing adipose tissue dysfunctions, counteracting excessive expansion of fat depots and enhancing brown adipose tissue (BAT) thermogenesis. Clinical translation remains limited, with inconsistent outcomes in individuals with overweight or obesity, and concerns about side effects of steroidal MRAs (sMRAs), particularly hyperkalemia. Nevertheless, recent data showed that MRAs are able to activate BAT in healthy subjects and in patients with familial partial lipodystrophy type 2 (FPLD2). Nonsteroidal MR antagonists (nsMRAs), such as finerenone, exhibit anti-inflammatory and anti-fibrotic properties in the kidney and heart, with improved safety profiles compared to steroidal MR antagonists (sMRAs), and are currently explored in metabolic disorders beyond cardiorenal disease. This review summarizes novel insights into MR function in adipose tissue and critically evaluates whether MR can still be considered a valid target to treat obesity and associated metabolic disorders.

Thyroid hormone (TH) is essential for cardiovascular function, and women are disproportionately affected by TH disorders and experience worse outcomes following myocardial infarction (MI). However, the role of sex-specific TH regulation in post-MI cardiac recovery remains poorly understood. We investigated TH homeostasis and type 3 deiodinase (D3) activity, an enzyme that inactivates TH, in male and female C57BL/6 mice following MI. Using cardiomyocyte-specific D3-deficient (Dio3ΔHeart) mice, we investigated how impaired TH inactivation influences cardiac function and mitochondrial respiration. We also examined DIO3 messenger RNA expression, which encodes the D3 enzyme, in left ventricular (LV) tissue from human donors with nonfailing (NF) hearts or ischemic cardiomyopathy (ICM). Four weeks post MI, wild-type female mice exhibited sustained cardiac D3 activity, which effectively limited 3,5,3'-triiodothyronine (T3) levels in the LV. In contrast, Dio3ΔHeart females, lacking cardiomyocyte D3, showed impaired systolic recovery, elevated LV thyroxine and T3 levels, and reduced fatty acid-supported mitochondrial respiration, effects not observed in Dio3ΔHeart males. Similarly, DIO3 expression was selectively upregulated in LV tissue from women with ICM, but not in men. These findings identify DIO3 as a key protective mechanism in females that limits T3-induced metabolic stress and preserves mitochondrial function after MI, revealing a sex-dependent pathway with therapeutic relevance for cardiac recovery.

Glucose homeostasis is tightly controlled by hormones secreted from pancreatic islets. The most abundant cell type in islets is the β-cell, which secretes insulin in response to nutritional stimuli. We previously reported that the adverse metabolic effects of high-dose dioxin exposure in mice are regulated by the aryl hydrocarbon receptor (AHR) specifically in β-cells. Additionally, fetal exposure to low-dose dioxin reduced β-cell area in female mice at birth; however, the role of AHR in β-cell development has not been explored. To characterize the AHR pathway in developing human β-cells, we differentiated human embryonic stem cells (hESCs) into "islet-like" cell clusters (SC-islets) in vitro and treated cells with vehicle or dioxin for 24-hours at key stages of differentiation. Dioxin exposure robustly upregulated AHR gene targets (CYP1A1, AHRR) at all stages of differentiation but only had modest effects on markers of islet development and maturity. We next generated an AHR knock-out (KO) hESC line and found that basal CYP1A1 expression was profoundly suppressed in AHR-KO cells compared to parental cells at all stages of differentiation. Key markers of developing and mature pancreatic islets were largely unaffected by AHR deletion; however, G6PC2 was consistently downregulated in SC-islets from AHR-KO cells compared to parental cells. Interestingly, AHR-KO SC-islets also showed modestly increased insulin secretion relative to the parental line, suggesting a role for AHR in islet development. This novel AHR-KO cell line will allow for deeper investigation into the impact of AHR on development of human islets and other cell lineages.

Mutations in the SOX2 gene have been previously linked to a syndromic form of isolated hypogonadotropic hypogonadism, with additional ocular and neurodevelopmental phenotypes. Recently, we reported a functional role for SOX2 in hypothalamic kisspeptin-expressing neurons and established a mechanistic relationship between SOX2 heterozygous variants and isolated hypogonadotropic hypogonadism. To further test the role of Sox2 in the hypothalamic-pituitary-gonadal axis, we generated mice with a whole-body heterozygous knockout of Sox2 (Sox2WT/KO). We found that heterozygous loss of Sox2 significantly delayed pubertal onset in both male and female Sox2WT/KO mice compared to wild-ype (WT) controls. In females, fertility was also compromised, with fewer estrous cycles and a significant delay in time to first litter of Sox2WT/KO dams compared to WT controls. Circulating levels of gonadotropins were normal in both male and female Sox2WT/KO mice, suggesting a functional pituitary. Finally, we assessed the number of kisspeptin and GnRH neurons and found that Sox2WT/KO mice do not differ from controls in the number of kisspeptin neurons but have significantly fewer GnRH neurons. This deficit occurs before birth, as by embryonic day 15.5, there are already fewer GnRH neurons in the Sox2WT/KO mice. Using luciferase assays, we determined that Sox2 increases expression of GnRH in vitro; thus, the decrease in GnRH-expressing neurons in vivo is likely the result of Sox2 haploinsufficiency. Together, these data further substantiate a critical role for SOX2 in the hypothalamic-pituitary-gonadal axis via effects on GnRH neuron development and, therefore, pubertal timing and reproductive function.

In diabetes, glucagon is typically oversecreted during hyperglycemia but under secreted during hypoglycemia. Administration of a somatostatin receptor antagonist (SSTR2a) increases glucagon counterregulation during hypoglycemia in rodent models of type 1 diabetes (T1D) but less is known about its impact on glucagon in T2D. Using a rodent model of insulin-requiring diabetes, we evaluated the effects of daily SSTR2a administration with insulin dosing (Study A: 8 days) and repeated exposures to hypoglycemia (Study B: 4x over 11 days) on glucagon and glycemia. In study A, 8 days of SSTR2a treatment at 3.0 mg/kg transiently increased glucagon levels after dosing but did not significantly impact the glycemic response to basal or bolus insulin. In study B, with daily low-dose SSTR2a treatment (0.3 mg/kg/d), the glucagon counterregulatory response to insulin-induced hypoglycemia was increased while time to hypoglycemic onset was delayed on challenge days 1 and 2. SSTR2a treatment did not affect food intake, body mass or C-peptide levels, but was associated with a lower HbA1c level at the end of the study relative to controls (4.3 ± 0.9 vs 5.3 ± 0.8%, p<0.05). In summary, in a rat model of insulin-treated T2D, daily SSTR2a administration increased glucagon counterregulation to hypoglycemia without worsening overall insulin sensitivity or glycemic control.

Label-free quantification (LFQ) proteomics is growing in popularity and becoming increasingly more accessible to researchers, empowering them to compare proteome-wide changes between different treatment conditions. However, it remains difficult to leverage the full potential of LFQ data when the researcher has limited experience in proteomics and/or bioinformatics due to the complexity of data analysis. Here, we present MetaboMiNR, an easy-to-use web application for the analysis of LFQ data with a focus on metabolism and nuclear receptors (NRs). MetaboMiNR guides users through an intuitive process with clear instructions and minimal user input to conduct statistical analysis and produce publication ready plots. Users may input a MaxQuant-generated output file and perform standard global analysis and data quality control with the click of a button. The application offers 3 additional unique features: 1) Metabolism Miner extracts a user-selected Reactome pathway from the dataset, 2) Nuclear Receptor Miner extracts the target genes of a user-selected NR, and 3) Individual Plotter produces publication-ready bar plots for a selected protein. The utility of this application was demonstrated by analyzing a previously published dataset from mice treated with LDT409, a synthetic peroxisome proliferator-activated receptor agonist. MetaboMiNR can be accessed freely at https://cumminslab.shinyapps.io/MetaboMiNR/.