Endocrinology最新文献

Blood-brain barrier (BBB) breakdown plays a key role in cognitive impairment in diabetic encephalopathy (DE). This study aimed to investigate whether myeloid-derived growth factor (MYDGF) can prevent BBB injury and cognitive impairment in DE. Circulating MYDGF levels were measured in patients with diabetes. In vivo experiments, both loss- and gain-of-function strategies, were used to evaluate the effect of MYDGF on BBB injury and cognitive impairment in diabetic mice. We used multiple low-dose streptozotocin-treated Mydgf knockout and wild-type (WT) mice on high-fat diets to induce diabetes. Then, cognitive function and BBB permeability were examined in diabetic mice that were subjected to adeno-associated virus-mediated Mydgf gene transfer. In vitro experiments, primary human brain microvascular endothelial cells (HBMECs) were treated with high glucose (HG) to mimic diabetic conditions. The effects of MYDGF on transendothelial permeability were investigated. The results indicated that circulating MYDGF levels were decreased in patients with DE and diabetic mice with cognitive impairment. Compared with WT mice, MYDGF deficiency presented more severe impaired cognitive performance, BBB leakage, and cerebrovascular inflammation in diabetic mice. Inversely, MYDGF restoration alleviated cognitive decline, BBB breakdown, and cerebrovascular inflammation in diabetic mice. In HG-treated HBMECs, MYDGF restoration attenuated the transendothelial permeability and junction protein downregulation and protected against endothelial inflammation and apoptosis. Mechanistically, the protective effect of MYDGF was attributed to mitogen-activated protein kinase kinase kinase kinase 4/nuclear factor-kappa B signaling pathway inhibition. This study demonstrated that MYDGF protects against BBB injury and prevents the progression of cognitive decline in DE, suggesting that MYDGF may be an effective therapeutic strategy for DE.

Background: The global obesity epidemic necessitates the identification of novel therapeutic targets. Although central administration of α-Klotho improves metabolic function in rodents, its precise mechanisms of action remain unclear. Since α-Klotho signals through fibroblast growth factor receptors (FGFRs), we hypothesized that FGFR1 within specific hypothalamic neuronal populations is critical for maintaining metabolic homeostasis.

Methods: We investigated the metabolic role of FGFR1 in the arcuate nucleus of adult mice using an adeno-associated virus (AAV)-mediated CRISPR/Cas9 system, in conjunction with transgenic models, to achieve cell-type-specific knockout of FGFR1 in mature glutamatergic, gamma-aminobutyric acid (GABA)ergic, and agouti-related peptide (AgRP) neurons.

Results: We found that FGFR1 governs distinct metabolic functions in different neuronal populations. Conditional deletion of FGFR1 in glutamatergic neurons impaired glucose tolerance. In contrast, its ablation in GABAergic neurons induced a severe energy imbalance, resulting in obesity characterized by significant weight gain and adiposity. Notably, AgRP neuron-specific deletion of FGFR1 recapitulated this obese phenotype. Furthermore, the loss of FGFR1 in AgRP neurons disrupted α-Klotho signaling, preventing its ability to modulate AgRP neuron activity and abolishing its beneficial effects on glucose and energy metabolism.

Conclusion: Our results establish FGFR1 in hypothalamic neurons as an essential component of the pathway through which α-Klotho regulates systemic energy balance. These findings identify hypothalamic FGFR1 as a critical molecular target for developing anti-obesity therapies.

Aromatase inhibitors (AI) are first-line therapy for postmenopausal women with estrogen receptor-expressing (ER+) breast cancer (BC). AI therapy effectively reduces recurrence and extends lifespan for patients with ER+ BC through long-term estrogen deprivation (LTED) resulting from inhibition of the enzyme aromatase that converts androgens to estrogens. However, up to 50% of ER+ BC recurs as AI-resistant metastatic disease within 10 years of diagnosis. AI-resistant BC upregulates androgen receptors (AR) and mitochondrial oxidative phosphorylation (OXPHOS) and requires OXPHOS and fatty acid oxidation (FAO). The liver and lung, common ER+ BC metastatic sites, have high abundance of the saturated fatty acid palmitate. We asked whether AR signaling regulates OXPHOS in the context of LTED. Using mutant ER-expressing MCF7 and T47D BC cell lines with AR antagonism via the anti-androgen enzalutamide and with shRNA knockdown, we demonstrate that AR supports cell growth, OXPHOS, FAO, and resistance to palmitate lipotoxicity. We identify AR as a positive regulator of the carnitine acyltransferase family enzyme CRAT that promotes OXPHOS capacity. These studies identify AR as pro-tumor in the LTED setting and as a therapeutic target for ER-mutant BC that develops under the selective pressure of AI therapy.

Fibrosis, excessive extracellular matrix deposition, disrupts normal tissue function. It has been observed in select tissues of individuals with acromegaly and in transgenic mouse models of acromegaly, suggesting a role of GH and/or IGF-1. However, analysis across multiple tissues and ages has not been reported. This study evaluated fibrosis in 6 tissues -lung, kidney, liver, spleen, quadriceps, and heart-from young (3 months) and aged (12-15 months) bovine GH transgenic and wild-type mice of both sexes. Fibrosis was assessed using hydroxyproline content, picrosirius red (PSR) staining, and serum biomarkers of collagen turnover (PINP, ICTP, and FAP). Hydroxyproline assays showed collagen content significantly increased with age across all tissues and both sexes. Compared to wild-type, aged male bGH mice had elevated hydroxyproline in the lung, kidney, liver, and quadriceps; aged female bGH mice showed increases in kidney, liver, and quadriceps. PSR staining showed minimal differences in young mice. In aged bGH mice, males exhibited increased PSR staining in all tissues except lung; females showed increases in all tissues except lung and heart. Serum biomarkers showed sex- and age-specific patterns: PINP decreased with age in both sexes; ICTP increased with age in both sexes; FAP was lower in bGH mice and decreased with age in females. In conclusion, excess GH promotes fibrosis in most tissues studied and becomes more pronounced with advancing age, suggesting fibrosis is a common outcome of excess GH. Whether fibrosis is directly caused by GH/IGF-1 or secondary to poor health of bGH mice requires further investigation.

White adipose tissue (WAT) performs vital metabolic and endocrine functions, but roles in female reproduction remain understudied and poorly understood. Here, we report that female mice experiencing progressive lipoatrophy after knockout of Ubc9 in adipocytes (Ubc9fKO) displayed disrupted estrous cycles, reduced ovarian reserve, and subfertility. During aging, female Ubc9fKO mice lose subcutaneous WAT more quickly than their male counterparts and weigh less than littermate controls. Subcutaneous WAT excised from female Ubc9fKO mice strongly enriched for thermogenesis genes generally associated with metabolic benefits. Female Ubc9fKO mice exhibited hypermetabolism and accumulated thermogenic, Uncoupling Protein 1-expressing beige fat cells in residual subcutaneous WAT depots in a sex-dependent manner. However, remnant beige fat appearance occurred at the expense of fertility in Ubc9fKO female mice. A high-fat diet diminished the appearance of beige fat cells and restored estrous cycle regularity among Ubc9fKO mice compared to littermate controls, despite the presence of profound insulin resistance. Together, these results reveal sexual dimorphism in a mouse model of lipoatrophy and the importance of WAT for sustaining reproduction in female mice. These findings also provide evidence that beige adipocytes compensate for fat loss at the expense of fecundity in female mice and identify pathways to improve fertility in very lean and lipodystrophic women.

Glucagon is a 29-amino acid hormone synthesized and secreted by the pancreatic alpha cell in the islets of Langerhans. It is the primary glucose counter-regulatory hormone, secreted by the alpha cell to maintain euglycemia by stimulating hepatic gluconeogenesis and glycogenolysis. In addition to glucose, the alpha cell senses and responds to a number of inputs, such as paracrine factors, neurotransmitters, and other nutrients, including amino acids, to regulate the secretion of glucagon. Disruption of this fine regulation results in excessive glucagon secretion (hyperglucagonemia) and contributes to the pathogenesis of diabetes. In this mini-review, we summarize the current understanding of glucagon biosynthesis and intracellular trafficking, and we discuss emerging concepts in amino acid sensing and signaling that underpin the biology of the alpha cell and that may provide clues to the control of the hyperglucagonemia of diabetes.

Nuclear receptors (NRs) orchestrate transcriptional programs that regulate cell fate decisions, and when these processes are disrupted, they can drive hormone-dependent cancers. This review summarizes mechanisms by which NRs function collectively, or crosstalk, to bring about the complex transcriptional control of cell fate decisions and indicate where these processes can act as cancer drivers. These crosstalk mechanisms include the exchange of coregulators between NRs and as well as genomic convergence of NRs. Evidence is also discussed for how NRs potentially pass through a continuum of interactions as part of a biological ratchet mechanism to regulate gene transcription. In this continuum, pioneer factors drive chromatin competence for NRs and, along with mammalian SWI/SNF complexes, facilitate transient assisted loading between NRs, as well as more stable crosstalk in the form of mitotic bookmarking, which allows inheritance of transcriptional control. NR crosstalk is also sustained through the function of larger and perhaps more stable interactions, such as through the megatrans complex. Also considered to explain NR crosstalk is the established and emerging understanding of the grammar of motif selection, and this is placed in the context of NR network approaches, for example in breast cancer. Finally, a systems-level framework, called NuRome, is discussed that combines high-dimensional data at the cistrome, transcriptome, and proteome levels to provide a predictive understanding of NR crosstalk and transcription in cancer.

Preliminary studies suggest a link between shortened telomeres, infertility, and poorer in vitro fertilization (IVF) outcomes. Infertility patients often experience high levels of psychological stress during treatment. Whether there is a link between stress and telomere length in infertility patients has not previously been studied; thus our goal was to examine differences in telomere length in infertile vs noninfertile women and to determine if telomere length correlates with psychological stress and IVF laboratory outcomes. We conducted a case-control study comparing nulliparous women aged 35 to 42 years with unexplained infertility or diminished ovarian reserve undergoing IVF to noninfertile age-matched controls. Average telomere length was measured in peripheral blood mononuclear cells. Psychological stress was measured by the Perceived Stress Scale and the Center for Epidemiologic Studies Depression Scale. The infertile cases had significantly shorter telomeres than the fertile controls; stress did not account for this difference. Associations were observed between telomere length, ovarian reserve measures, and quantitative IVF outcomes independent of age, suggesting that telomere attrition in somatic cells may relate to the underlying pathophysiology of low ovarian reserve and fertility status.

Primary aldosteronism (PA) is characterized by autonomous aldosterone (Aldo) production, resulting in blood volume/electrolyte imbalance and hypertension. Intracellular calcium (Ca2+) is the principal signal driving Aldo synthesis in adrenal zona glomerulosa (zG) cells, and mutations in ion transport genes that regulate Ca2+ are frequently mediators of PA. When organized in intact rosette structures, zG cells are voltage oscillators; stimulation by angiotensin II (AngII) or loss of TWIK-related acid-sensitive potassium (TASK) channel function evokes stereotypic Ca2+ oscillations with bursting activity proportional to increased steroidogenesis. Here, we delineate the role of the osmolar-volume regulatory axis in the control of Ca2+ and Aldo production in adrenal slices. Strikingly, in both pharmacological and genetic models of PA, extracellular osmolarity (OSMEC) potently and reversibly regulated Aldo secretion and Ca2+ signaling. Elevated OSMEC progressively suppressed Aldo production from AngII-stimulated adrenal slices and strongly inhibited autonomous production in both zG-specific TASK knockout slices and wild-type slices incubated with TASK inhibitors (TIs). To determine if the effects of OSMEC on Ca2+ dynamics were causative, we imaged adrenal slices expressing zG-specific GCaMP6f incubated in variable osmotic media with TIs or AngII. Consistent with Aldo suppression, increasing osmolarity proportionally reduced the number of active cells and the Ca2+ activity of bursting cells evoked by TASK loss of function or AngII stimulation. Collectively, our findings identify OSMEC as a broad regulator of zG excitability and adrenal steroidogenesis, and suggest that targeting volume-regulatory mechanisms such as the Na+-K+-2Cl- cotransporter may offer a novel strategy to suppress Aldo autonomy in PA.

Polycystic ovary syndrome (PCOS) is a complex endocrine disorder affecting women worldwide. For decades, the "chronic inflammation hypothesis" has guided research into the role of the immune system in PCOS pathogenesis. However, this review challenges this paradigm by pointing out discrepancies in current literature on systemic immune markers in PCOS. We highlight the limitations of relying solely on systemic inflammatory markers and emphasize the importance and diversity of tissue-specific immune responses. Evidence from human and animal studies reveals distinct immune responses across various tissues affected by PCOS or inflammation, including the hypothalamus, pituitary, ovaries, endometrium, and adipose tissue. These findings suggest that PCOS is not characterized by systemic low-grade inflammation, but rather by discrete tissue-specific immune interaction with endocrine cells. Finally, we discuss how advanced single-cell technologies and computational tools are enhancing our understanding of immune cell signaling to endocrine cells in PCOS. Moving forward, we propose that research should focus on elucidating causal relationships between local immune responses and endocrine dysfunction in PCOS. This shift in perspective from systemic to tissue-specific immune responses is critical for developing targeted immunotherapies for PCOS.