Endocrinology最新文献

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.

Over the past 15 years, groundbreaking discoveries have reshaped our understanding of how biomolecules are organized in space and time within cells, revealing that many cellular compartments are separated from their surroundings not by membranes but by physical forces arising from unique interactions among their biomolecular components. These interactions drive the compartmentalization of biomolecules through liquid-liquid phase separation (LLPS) into dynamic droplets, which can further stabilize through liquid-gel phase separation (LGPS). Phase separation plays essential roles across diverse biological systems, including the endocrine system, where it impacts the function on steroid hormone receptors (SHRs). SHRs are a family of nuclear receptors that transduce steroid signals to regulate transcription of thousands of genes, thereby supporting endocrine homeostasis and contributing to diseases when dysregulated. During gene activation, SHRs form high-density clusters at promoters and enhancers. This mini-review summarizes recent literature indicating that these clusters function as transcriptional condensates, where phase separation of SHRs and coregulators mediates chromatin remodeling and enhanced transcription. We also discuss hypotheses suggesting that SHR-driven LLPS at gene loci contributes to hormone therapy resistance, while a transition to LGPS causes reduced hormone responsiveness. Finally, advancements in SHR condensate-modifying drugs to create new therapeutic options for hormone therapy-resistant cancers are highlighted. Overall, emerging evidence on the phase properties of SHR condensates is transforming our understanding of the endocrine regulation and unleashing novel intervention strategies beyond targeting individual proteins.

Neuropeptide FF receptor 2 (NPFFR2) is a key regulator of energy homeostasis, influencing feeding behavior, insulin sensitivity, and lipid metabolism. This study investigates the metabolic consequences of Npffr2 deletion in a mouse model of diet-induced obesity. Wild-type and Npffr2 knockout mice were fed a high-fat, high-sucrose diet to induce obesity, followed by comprehensive metabolic assessments. Npffr2 knockout mice exhibited reduced food intake, accompanied by significant downregulation of hypothalamic orexigenic neuropeptides agouti-related peptide and neuropeptide Y. Enhanced energy expenditure was observed in knockout mice, as evidenced by increased thermogenic capacity, elevated uncoupling protein 1 expression in brown adipose tissue, and improved core temperature maintenance under cold exposure. Lipid metabolism was also improved, with reduced hepatic and adipose lipid accumulation and lower circulating triglyceride and non-esterified fatty acid levels. Molecular analyses revealed increased AKT phosphorylation in the hypothalamus and skeletal muscle, along with downregulation of protein tyrosine phosphatase 1B in the mediobasal hypothalamus, indicating improved central and peripheral insulin signaling. Here, we demonstrated that NPFFR2 plays a critical role in obesity-associated energy regulation, lipid accumulation, and insulin resistance. These findings highlight NPFFR2 as a potential therapeutic target for obesity and related metabolic disorders.

The progesterone receptor (PR) is a critical regulator of hormone signaling in breast tissue, with its 2 primary isoforms, PR-A and PR-B, exhibiting distinct and sometimes opposing functions. These isoforms arise from alternative promoter usage within the PGR gene, resulting in structural differences that influence their transcriptional activity, regulatory interactions, and post-translational modifications. This review explores the historical discovery of PR isoforms, their structural and functional differences, and the molecular mechanisms governing their transcriptional regulation. We also discuss their physiological roles in normal mammary gland development and how their dysregulation contributes to breast cancer progression, endocrine resistance, and cancer stem cell expansion. Understanding the distinct roles of PR isoforms in breast cancer biology holds significant implications for developing targeted therapeutic strategies aimed at modulating isoform-specific PR activity in hormone-driven cancers.

γ-Aminobutyric acid (GABA) and kisspeptin play essential roles in reproduction and metabolism, being expressed in the central nervous system and peripheral organs (ovaries, testes, pancreas, liver, and white adipose tissue [WAT]). While previous research has shed light on their functions, the interaction between GABA and kisspeptin in regulating these processes remains poorly explored. In a recent study, in which we evaluated the action of GABA through GABAB receptors (GABABRs) in Kiss1-expressing cells, we focused on male mice lacking GABABR specifically in Kiss1 cells (Kiss1-GABAB1KO), revealing normal reproductive functions but impaired glucose homeostasis that worsened with age. Here, we explored reproduction and metabolism in Kiss1-GABAB1KO females. Kiss1-GABAB1KO females had increased Kiss1/Tac2 expression in the arcuate nucleus (ARC), while displaying normal estrous cycles and fertility. Metabolically, they showed increased expression of key ARC metabolic genes (Npy/Agrp, Pomc, Lepr), increased WAT weight and leptin secretion, and body weight (BW) gain, not linked to food intake (FI) changes. They exhibited normal glucose levels but heightened insulin secretion and peripheral insulin resistance, potentially due to increased WAT mass. Kisspeptin was specifically increased in KO WAT. Interestingly, BW in older KO females was not different from WTs, yet maintained elevated WAT kisspeptin content, similar to younger females. Our results highlight the effect of GABA, through GABABRs, in the regulation of the WAT kisspeptin system and ARC gene expression in female mice, underscoring that the effect of deletion of GABABRs in Kiss1 cells found in this and our previous study is sex, age, and tissue specific.

Prenatal androgen excess (PNA), an etiologic factor for polycystic ovary syndrome (PCOS), is implicated in programming long-term reproductive deficits in females such as anovulation, subfertility, and hyperandrogenism. Impaired steroid hormone feedback is a key neuroendocrine feature suspected to underpin the development of reproductive dysfunction in both clinical PCOS and in PNA mice exposed to dihydrotestosterone during late gestation. PNA is suspected to act in the brain to program the impaired sensitivity of the GnRH neuronal network to progesterone negative feedback, centrally dysregulating the hypothalamic-pituitary-ovarian axis controlling reproduction. To test the hypothesis that androgen-sensitive neurons mediate PNA programming, we generated PNA female mice with a neuron-specific deletion of androgen receptors (AR) (NeurARKO) using Cre-lox transgenics. Following confirmation of embryonic AR deletion, PNA NeurARKO females were reproductively phenotyped and assessed for changes in progesterone receptor expression in the brain. PNA-induced reproductive traits including delayed pubertal onset, acyclicity, altered ovarian morphology, and subfertility were not different between NeurARKO and wild-type mice. In contrast, downregulation of progesterone receptor expression in PNA wild-type mice was protected against in PNA NeurARKO mice. Together, these findings suggest that although neuronal AR may contribute to PCOS-like impaired sensitivity to progesterone feedback, their deletion alone is insufficient to rescue reproductive dysfunction associated with PCOS.

As a common endocrinopathy of reproductive-aged women, polycystic ovary syndrome (PCOS) is characterized by ovarian hyperandrogenism, insulin resistance, and preferential abdominal fat accumulation. These characteristics in normal-weight women with PCOS are accompanied by subcutaneous abdominal adipose stem cells that intrinsically exaggerate lipid accumulation during adipocyte development in vitro in combination with an increased amount of highly lipolytic visceral fat. PCOS-related adipose characteristics are intimately linked with hyperandrogenism through genetic inheritance and epigenetic events programmed during prenatal and postnatal life. Accordingly, evolutionary theory submits that such events in PCOS may have ancestral origins, providing survival advantages in 3 contexts: (1) food scarcity with risk of starvation; (2) infectious disease risks, alleviated by visceral and omental fat; and (3) benefits from increased muscularity. But such adaptations also involve costs, given that PCOS-related traits also tend to reduce reproduction, due to oligo-anovulation. This review examines the evolutionary origins of PCOS risk as a syndrome potentiated by environmental mismatches (especially contemporary obesity and low physical activity), combined with adaptive physiological systems governed by trade-offs between survival and reproduction. This hypothesis is supported by a plethora of recent studies on physiological and behavioral differences between subsistence-level and modern Westernized populations, and by analyses of survival-reproduction trade-offs in nonhuman mammals. Studies of PCOS models using prenatally testosterone-treated and naturally hyperandrogenic animal models provide crucial insights for understanding how today's illnesses likely emerged from ancient developmental-metabolic strategies, and how knowledge about the evolutionary past can help guide current research and the development of more effective therapies.

Glucagon-like peptide-1 (GLP-1) is produced within the central nervous system (CNS) by preproglucagon (PPG) neurons. This brain-derived GLP-1, rather than that released from the gut, is the physiological agonist for brain GLP-1 receptors (GLP-1Rs). With brain GLP-1Rs being a major target for eating suppression, understanding the physiology and the translational potential of PPG neurons is of pivotal importance, particularly since PPG neuron activation is also strongly associated with stress. This review critically summarizes the current knowledge of PPG neuron anatomy, physiology, and molecular makeup together with insight into the relevant research tools, and consideration of the different PPG neuron populations within the CNS, to provide an appraisal of the potential of these neurons as drug targets and the associated risks and benefits.