Lineage plasticity is a major mechanism by which prostate cancer adapts to therapeutic pressure, particularly following sustained inhibition of androgen receptor signaling. A central mediator of this process is BRN2, a POU3F2 neural lineage transcription factor that is normally suppressed in AR-dependent luminal prostate epithelium but becomes aberrantly activated during progression to castration-resistant and neuroendocrine prostate cancer. This review examines how BRN2 connects developmental neurogenesis to therapy-induced tumor reprogramming. We integrate insights from neurodevelopment and direct lineage reprogramming to describe how BRN2 maintains stem-like and neuroendocrine transcriptional states. Mechanistically, we discuss how AR suppression, cooperating oncogenic drivers, epigenetic remodeling, and post-translational modification activate BRN2 and reshape transcriptional networks involving SOX2, Wnt signaling, N-Myc, and EZH2. We also evaluate strategies to target BRN2 and its associated dependencies, including direct inhibition of BRN2 DNA binding and pharmacologic disruption of cooperating epigenetic complexes such as BRD4, EZH2, and LSD1, though EZH2 inhibition may paradoxically promote further neuroendocrine differentiation. We additionally assess BRN2 as a potential circulating biomarker, detectable in extracellular vesicles, though no clinical-grade assay has been validated. This review highlights BRN2 as a key transcriptional regulator of lineage plasticity in prostate cancer, with important implications for overcoming therapy resistance in advanced prostate cancer.
Intestinal epithelial differentiation is tightly regulated to maintain tissue homeostasis and systemic metabolic function. Although the intrinsic transcriptional programs governing enteroendocrine cell (EEC) development have been characterized extensively, the role of extrinsic immune signals in directing lineage specification is not completely understood. In particular, how cytokine signaling influences differentiation of EEC subtypes remains unclear. Here, we investigated the role of interleukin-22 (IL-22) in EEC differentiation using human induced pluripotent stem cell-derived intestinal organoids and in vivo models. IL-22 selectively increased proglucagon (GCG) expression and the number of glucagon-like peptide-1 (GLP-1)-positive EECs without affecting other EEC markers. This effect was associated with enhanced expression of the lineage-related transcription factors neurogenin 3 and forkhead box A2. Pharmacological inhibition of signal transducer and activator of transcription 3 (STAT3) signaling attenuated the IL-22-induced increases in GCG expression and GLP-1-positive cell abundance, indicating a role of STAT3 in mediating these effects. Mechanistically, relatively high expression of IL-22 receptor subunit alpha 1 in undifferentiated epithelial cells was associated with STAT3 activation induced by IL-22. Consistent with these findings, in vivo IL-22 administration increased intestinal GCG expression and GLP-1 levels in the circulation and intestinal tissue. Importantly, our findings indicate that IL-22 does not globally promote EEC differentiation but rather selectively directs epithelial lineage commitment toward the GCG-positive EEC fate. These results suggest that IL-22/STAT3 signaling induces human intestinal epithelial differentiation into GCG-positive EECs and may represent a strategy for modulating epithelial cell fate to influence systemic metabolic homeostasis.
BACKGROUND:Insulin deficiency (ID) causes severe metabolic defects and death if untreated, while insulin therapy does not fully restore metabolic homeostasis. Leptin therapy corrects metabolic abnormalities and promotes survival in rodents unable to produce insulin, suggesting the existence of insulin-independent glucoregulatory mechanisms. METHODS:We use mice with diphtheria toxin-induced pancreatic β-cell ablation, resulting in severe insulin deficiency. We assess hepatic translation by polysome profiling, ribosome profiling (Ribo-seq), and RNA sequencing. To identify leptin-responsive hepatic factors, we compare the hepatic translatome during intracerebroventricular leptin treatment and following leptin withdrawal. Regenerating islet-derived protein 3 alpha (Reg3α) is subsequently overexpressed in the liver of ID mice to assess its metabolic effects. RESULTS:ID suppresses hepatic mechanistic target of rapamycin complex 1 (mTORC1) signaling and global protein synthesis while extensively remodeling the hepatic translatome. Translation of anabolic and glucose-metabolism pathways is reduced, whereas transcripts involved in lipid metabolism are selectively enhanced. Leptin treatment markedly increases hepatic Reg3α translation. Hepatic Reg3α overexpression significantly improves hyperglycemia in ID mice without altering insulin-stimulated AKT phosphorylation in key metabolic tissues. These findings identify hepatic translational rewiring as an important feature of ID and Reg3α as an insulin-independent glucoregulatory factor.
BACKGROUND:Hashimoto thyroiditis (HT) is a prevalent autoimmune thyroid disease characterized by lymphocytic infiltration and autoantibody production. Our previous findings showed that enhancer of zeste homolog 2 (EZH2) and BACH transcriptional regulator 2 (BACH2) are upregulated in HT thyroid tissues. However, the role of EZH2 in B-cell-mediated autoimmunity remains unclear. OBJECTIVE:To investigate how EZH2 regulates B-cell responses in a spontaneous autoimmune thyroiditis (SAT) mouse model and to explore potential downstream epigenetic mechanisms, including BACH2. METHODS:A NOD.H-2h4 mouse model of SAT was used to assess the effect of the EZH2 catalytic activity inhibitor GSK126 on thyroid inflammation and B-cell responses. The human B-lymphocyte cell line GM12878 underwent EZH2 knockdown or was treated with GSK126 to evaluate BACH2 expression, H3K27me3 levels, and IgG secretion. Chromatin immunoprecipitation followed by quantitative polymerase chain reaction (ChIP-qPCR) and luciferase assays were employed to examine EZH2-dependent regulation of BACH2, and rescue experiments were conducted using BACH2 overexpression. RESULTS:In SAT mice, GSK126 reduced thyroid lymphocytic infiltration, decreased CD19+ and IgG+ B-cell infiltration, and lowered thyroidal IgG and serum IgG levels. In vitro, pharmacological inhibition of EZH2 catalytic activity or knockdown suppressed BACH2, reduced H3K27me3, and diminished IgG secretion. Luciferase and ChIP-qPCR assays supported EZH2-dependent regulation of BACH2, and BACH2 overexpression partially restored BACH2 expression but did not fully rescue IgG production after EZH2 methyltransferase activity inhibition. CONCLUSION:EZH2 contributes to B-cell-mediated immune responses and IgG production through epigenetic mechanisms in SAT. BACH2 may represent one downstream target of EZH2, but additional pathways are likely involved.
BHLHE40/DEC1 is a basic helix-loop-helix transcription factor (TF) that regulates circadian rhythm and T-cell responses. In hepatocytes, its function and interplay with other TFs are poorly understood. Employing a genome-wide approach, we show that its genomic binding strongly overlapped with that of carbohydrate response-element binding protein, a sugar-sensing TF and known inducer of BHLHE40 expression. Transcriptomic analysis of primary mouse hepatocytes revealed reduced expression of genes involved in genomic stability on Bhlhe40 knockdown by siRNA. Bhlhe40 depletion potentiated fructose responsiveness of genes involved in cell-cycle regulation. Strikingly, genomic binding of BHLHE40 extensively overlapped with enhancers occupied by PPARα, RXRα, and HNF4 nuclear receptors and BHLHE40 fine-tuned the expression of PPARα target genes. Using HEK293 cells, we further observed that BHLHE40 physically interacted with RXRα and PPARα cofactors. Collectively, our data suggest that through cooperation with carbohydrate response-element binding protein and nuclear receptors, BHLHE40 is a central regulator of hepatic gene expression with potential to integrate inputs from nutrient signals contributing to the metabolic flexibility of the liver.
PURPOSE:Adrenocortical carcinoma (ACC) is an aggressive malignancy with no approved targeted therapy and poor outcomes. METHODS:Using multiple patient-derived xenograft (PDX) and cell line xenograft (CLX) models, and a newly developed PDX model (CUACC9), we investigated the potential action of the multikinase inhibitor OTSSP167 for treatment of ACC. RESULTS:OTSSP167 effectively reduced tumor growth in wild-type TP53 (CUACC1) and mutant TP53 (H295R, CUACC9) in vivo tumor models. Immunohistochemical analysis of treated tumors verified apoptosis via caspase activation as a mechanism of OTSSP167 action. Further evaluation of downstream effectors via RNAseq and a reverse phase protein array (RPPA), using ACC cell lines matching the in vivo genetic diversity, demonstrated that OTSSP167 impeded cell cycle via G2/M arrest independent of TP53 status. In TP53 mutant lines, OTSSP167 enhanced DNA damage and inhibited protein synthesis. RSK1 was identified as a direct target of OTSSP167 activity in vitro. OTSSP167 also induced the G2/M checkpoint protein, WEE1, activation in all models, indicating an early adaptive response. Combining the WEE1 inhibitor AZD1775 with OTSSP167 significantly enhanced cytotoxicity in TP53 mutant lines, and reduced tumor growth in a TP53 mutant ACC model. CONCLUSION:Together these findings establish the feasibility of using OTSSP167 in ACC, especially in TP53 mutant ACC tumors. In addition, this study demonstrates the possibility of targeting the early adaptive response subsequent to exposure to OTSSP167 treatment. Our findings provide strong rationale for a future phase I clinical trial in ACC.
Bone marrow adipose tissue (BMAT) is now recognized as a functional fat depot distinct from extramedullary white and brown adipose tissues (WAT and BAT, respectively). BMAT expands in metabolic disorders such as obesity. However, the mechanism by which BMAT expands is less clear. Here, we present a comparative analysis of the transcriptomes of BMAT, WAT, and BAT from 20-week-old Sprague-Dawley rats fed a chow diet (12% kJ fat) using bulk RNA sequencing (RNA-seq). Gene-set enrichment analysis revealed overrepresentation of transcripts related to cellular proliferation and the population of adipoprogenitor cells in BMAT. To further study BMAT expansion, we introduced a 12-week dietary intervention of a Western diet (42% kJ fat). We first characterized obesity-related phenotypes such as adipocyte hypertrophy. Then, we compared the transcriptomes of femoral and tibial BMAT or gonadal WAT to the chow group. Western diet significantly increased body weight (P = .02), whole-body fat percentage (P = .009), adipocyte size in humeral BMAT (P = .02), and gonadal WAT (P = .005) compared with the chow group. BMAT had a more robust transcriptomic response to the Western diet than WAT. The transcriptome of BMAT was enriched in pathways related to lipid transport. In WAT, this enrichment was more related to lipid biosynthesis and modification. In summary, our data may suggest differences in the developmental maturity of BMAT relative to WAT and BAT in the chow group. A Western diet induces differential responses in the transcriptomes of BMAT and WAT related to lipid homeostasis. In BMAT, enrichment in the lipid transport pathways on the Western diet may suggest a role for BMAT in nutrient sensing and lipid uptake.
Superconserved receptors expressed in brain (SREB) are a family of orphan G protein-coupled receptors with 3 members in most vertebrates (GPR27 or SREB1, GPR85 or SREB2, and GPR173 or SREB3). They are associated with diverse physiological processes, ranging from glucose homeostasis to ovarian development. Despite a lack of confirmed ligands, our understanding of these receptors has increased based on interactions with putative SREB3 ligands such as phoenixin (PNX) and the development of synthetic SREB1 agonists (A8535 and PT-91). However, to date no studies have used these agonists in any complex vertebrate system. The objective of this study was to compare the in vitro transcriptomic responses to PNX-20, A8535, and PT-91 in the ovaries of 3 fishes with different SREB systems: (1) zebrafish (Danio rerio) that exhibit similar receptors to mammals, (2) mummichog (Fundulus heteroclitus) that lost a receptor but gained a fish-specific member, and (3) pufferfish (Dichotomyctere nigroviridis) that exhibit all 4 receptors. Agonist interactions with fish SREB1s were confirmed using in silico characterizations. Zebrafish exhibited the strongest transcriptome response, including agonist-induced changes in oxidative phosphorylation and cell adhesion pathways. Mummichog exhibited a less robust response, possibly related to receptor evolutionary divergence, while pufferfish exhibited an intermediate transcriptome response. Short-term agonist exposure did not alter ovarian steroid levels ([17]estradiol, 17-hydroxyprogesterone, cortisol, testosterone, or 11-ketotestosterone). Collectively, the data reveal previously unrecognized developmental, metabolic, neural, and vascular gene networks associated with SREB activation and suggest both receptor-specific signaling and functional overlap within this family.
Acromegaly is a rare disease caused by growth hormone (GH) hypersecretion from a pituitary adenoma. Pegvisomant is the only approved GH receptor antagonist (GHRA) and is administered via daily subcutaneous injections, which limits real-world effectiveness. Here, we report the discovery and characterization of MAR002, a novel, half-life extended monoclonal antibody GHRA. MAR002 was identified by immunizing transgenic mice with the extracellular domain of human and cynomolgus monkey GH receptor (GHR) and engineered with Fc modifications to limit effector function and extend serum half-life. MAR002 was benchmarked against pegvisomant in biophysical assays, cellular signaling inhibition studies, and a head-to-head pharmacokinetic/pharmacodynamic study in cynomolgus monkeys. MAR002 exhibited higher binding affinity to GHR and >100-fold more potent inhibition of GH-induced GHR signaling than pegvisomant (human half-maximal inhibitory concentration [IC50] 1.05 nM vs 122 nM). Epitope binning demonstrated simultaneous binding of MAR002 and GH to GHR, consistent with an allosteric, noncompetitive mechanism; notably, MAR002 inhibitory activity was maintained at supraphysiological GH concentrations, whereas pegvisomant activity was competitively reduced. In cynomolgus monkeys, a single 10 mg/kg intravenous dose of MAR002 sustained ≥50% IGF-1 suppression for 36 days compared with 15 days for an equimolar pegvisomant dose, with comparable maximal lowering (∼80%). These findings support clinical evaluation of MAR002 as a next-generation long-acting GHRA for acromegaly, with potential for reduced dosing frequency and more consistent suppression of the GH-IGF-1 axis.
Islet amyloid deposition derived from human islet amyloid polypeptide (hIAPP, amylin) is a hallmark of type 2 diabetes (T2D) and is tightly linked to progressive β-cell dysfunction and loss. It is now well established that the "toxic oligomer" hypothesis, in which soluble or intracellular hIAPP assemblies contribute to β-cell proteotoxicity and to the amplification of inflammatory stress, coexists with fibril associated and inflammation-driven mechanisms of toxicity. Regular physical activity (PA) is a cornerstone of T2D management and improves insulin sensitivity, glycemic control, ectopic lipid handling, and systemic inflammation, all of which could reduce β-cell secretory burden and the cellular milieu that favors hIAPP misfolding. However, direct demonstrations that PA delays or reduces islet amyloid formation remain scarce. This gap largely reflects methodological constrains in quantifying amyloid dynamics in humans and the absence of exercise studies with amyloid-specific endpoints. Herein, we synthesize mechanistic links by which exercise could influence hIAPP aggregation propensity (β-cell workload, glucolipotoxicity, endoplasmic reticulum stress, mitochondrial function, and inflammatory signaling) and highlight proteostasis pathways, particularly autophagy/lysosomal clearance, which are experimentally shown to defend β-cells against hIAPP oligomer toxicity. Overall, while direct evidence remains sparse, substantial mechanistic plausibility supports a link between PA and hIAPP amyloid biology. Future studies incorporating amyloid-specific outcomes are needed to determine whether exercise directly modifies amyloid formation, reduces oligomer burden, or primarily enhances β-cell resilience to proteotoxic stress.
Obesity prevalence has risen dramatically in recent decades, coincident with increasing human exposures to endocrine-disrupting chemicals (EDCs). Many EDCs act as "obesogens" by promoting adipogenesis and disrupting metabolism; however, little is known about their effects on neural circuits that regulate food reward and motivation. EDCs cause neurobiological and behavioral changes, implicating them in central energy balance regulation. In this experiment, we tested whether developmental exposure to the environmentally relevant EDC mixture NeuroMix (NMX) may have obesogenic-like effects in rats through central mechanisms. Using a dose-response approach, male and female rats were exposed perinatally to NMX (0, 0.1 ×, 1 ×, 10 × doses) and assessed for adult high-fat food and sucrose preference, thyroid hormones, and transcriptomics in reward and hypothalamic nuclei. Females exposed to the 1 × dose exhibited an increase in fatty food preference and consumption accompanied by appreciable weight gain. Males showed reduced thyroid hormone levels at the highest 10 × dose. NMX antagonized thyroid hormone receptor β in vitro, suggesting a potential molecular mechanism underlying the observed neuroendocrine effects. Transcriptomic analyses in 1 × rats identified the nucleus accumbens (NAc) as a key neural substrate in both sexes, with spliceosomal complex eigengenes in the NAc acting as correlates of high-fat food behaviors, and individual splicing factors emerging as possible neuromolecular mechanisms linking endocrine disruption to obesogenic eating. Together, this research demonstrates that environmentally relevant EDC mixtures exert sex- and dose-specific effects on food choice, thyroid hormones, and gene expression, highlighting neuromolecular reward mechanisms as potential contributors to environmentally mediated obesity risk.
Polycystic ovary syndrome (PCOS) is a common endocrine disorder with developmental origins. While the etiology is unclear, current postulates include epigenetic programming. Cell-type-specific epigenetic changes by which prenatal androgen excess programs the neuroendocrine axis have not been defined. Using single-nucleus (sn) multiome sequencing (single-nucleus ribonucleic acid sequencing [snRNAseq] + single-nucleus assay for transposase-accessible chromatin using sequencing [snATACseq]) of the mouse preoptic area, we profiled transcriptional and chromatin accessibility landscapes across 31 cell populations on postnatal day 18 to 22 in a prenatal androgenization (PNA) mouse model that produces neuroendocrine phenotypes that resemble hyperandrogenemic PCOS. Marker gene analysis identified 17 neuronal and 14 non-neuronal populations. We refined the gonadotropin-releasing hormone (GnRH) neuron cluster to 41 neurons by manual curation. Cross-dataset comparisons were used to characterize the molecular transcriptional identity of these clusters. Gene set enrichment analysis of mRNA expression data revealed enrichment of protein synthesis and oxidative phosphorylation pathways and suppression of TNF/NF-κB signaling and steroid responsiveness across several clusters in PNA animals. Pseudobulk differential chromatin accessibility testing across ∼30 600 peaks identified 15 false discovery rate-significant differentially accessible regions, including 2 loci in GnRH neurons at genomic regions of unknown function, suggesting prenatal androgen exposure changes chromatin accessibility in this and other cell types. Chromosome accessibility at most sex steroid receptor genes was surprisingly present in GnRH neurons. Reduced Pgk1 promoter accessibility in multiple glial populations suggests PNA alters epigenetic regulation of glial energy metabolism. These findings support a model of developmental programming in which prenatal androgen exposure produces cell-type-specific changes that include, but are not limited to, epigenetic remodeling to generate the PNA phenotype.
The endocrinology of equine pregnancy is unique, but many of its unusual phenomena closely resemble pregnancy in women. Placental estrone synthesis uses fetal adrenal androgen precursors in women, but from the fetal gonads in mares, peaking midway through the 11-month gestation. Unique to equine pregnancies, other estrogens like equilin, typified by an unsaturated B-ring sterol structure, are synthesized from 7-dehydrocholesterol (7-DHC), the immediate precursor to cholesterol, without cholesterol formation, peaking later in gestation. Currently, the spatial and temporal regulation underlying the redirection of 7-DHC from cholesterol to B-ring unsaturated steroid synthesis in equine fetal gonads remains unknown. Here, we investigate the developmental dynamics of the equine fetal gonads from the fourth to eleventh gestational month using RNA sequencing, immunofluorescence imaging, RNAScope, and gas chromatography-mass spectrometry. Our results suggest that placental estrone synthesis correlates with the expression of the last enzyme in the cholesterol synthesis pathway, 7-dehydrocholesterol reductase (DHCR7) in the fetal gonad, and its downregulation may drive the accumulation of 7-DHC and the synthesis of B-ring unsaturated steroids. B-ring unsaturated steroid secretion is the hallmark of Smith-Lemli-Opitz Syndrome in humans, resulting from mutations in the gene encoding DHCR7 in affected patients. This naturally occurring phenomenon in equine pregnancies may offer a unique comparative model for understanding the metabolic consequences of 7-DHC accumulation in these patients and a platform for drug development.
Glucocorticoid-induced adrenal insufficiency (GIAI) can persist for months after discontinuation of chronic corticosteroid therapy, placing patients at risk for life-threatening adrenal crises. This prolonged suppression has been attributed primarily to delayed restoration of hypothalamic-pituitary signaling based on indirect measures of central axis activity. To identify the rate-limiting site of hypothalamic-pituitary-adrenal (HPA) axis recovery, we evaluated the timing of functional and histologic recovery at each node of the axis following 8 weeks of dexamethasone (DEX) treatment in adult, male mice. Dexamethasone administration fully suppressed HPA axis activity. Unexpectedly, within 1 week of DEX withdrawal, hypothalamic Crh mRNA and plasma adrenocorticotropic hormone (ACTH) rebounded above control levels, whereas corticosterone (CORT) remained suppressed for an additional 7 weeks. Dexamethasone-treated adrenals were markedly atrophic and contained large clusters of lipid-filled macrophages. Even after adjusting for macrophage content, CORT secretion was disproportionately low relative to the remaining adrenocortical cell mass despite supraphysiologic ACTH stimulation. The adrenal is thus the principal site of postwithdrawal GIAI, involving adrenocortical cell loss and a superimposed defect in steroidogenesis. We next tested whether preserving adrenal trophic signaling during glucocorticoid exposure could prevent GIAI. Adrenal function recovered more slowly in mice treated with DEX and daily cosyntropin (a synthetic ACTH analog) compared to those treated with DEX alone. In contrast, mice with nonsuppressible endogenous ACTH due to targeted hypothalamic deletion of the glucocorticoid receptor maintained normal adrenal architecture and steroidogenic capacity despite prolonged DEX treatment. Pharmacologic treatments that mimic sustained trophic signaling to the adrenal during chronic glucocorticoid treatment may thus prevent GIAI.
Adrenal morphogenesis and aldosterone production depend on tightly regulated signaling pathways. While β-catenin (βCat)-dependent Wnt signaling in the zona glomerulosa (zG) has been extensively studied, the role of βCat-independent Wnt signaling remains poorly defined. Emerging evidence indicates that βCat-independent Wnt signaling also regulates zG cells and that genetic variants in associated loci are linked to aldosterone dysregulation, including hypoaldosteronism and primary aldosteronism. βCat-independent Wnt signaling acts through distinct transmembrane co-receptors, including the ROR family proteins (receptor tyrosine kinase-like orphan receptors 1 and 2, ROR1/2). To determine whether signaling via these co-receptors regulates adrenal morphogenesis and/or aldosterone production, we employed zG-specific ROR1/2 knockout mice. Our results showed that ROR1/2 were dispensable for zG formation and size but were required for normal zG adherens junction integrity. In addition, ROR1/2 were important for transdifferentiation of zG cells into zona fasciculata cells and zG cell survival. Finally, ROR1/2 were important for overall levels of Cyp11b2 expression and aldosterone production. Taken together, these results identified an important role for ROR1/2-dependent signaling, in the regulation of zG function and maintenance of aldosterone production and suggest its dysregulation may contribute to hypoaldosteronism and primary aldosteronism.
Maternal pancreatic β cells undergo functional and structural changes to adapt to increased metabolic demands during pregnancy. Lactogen signaling via the prolactin receptor (PRLR) contributes to these adaptations by increasing β-cell mass, insulin transcription, and glucose-stimulated insulin secretion. In other lactogen-responsive tissues such as the mammary glands and specific hypothalamic nuclei, gestation induces epigenetic changes, some of which persist long after birth. We have previously found that PRL treatment in islets regulates the expression of epigenetic modifiers. However, whether lactogen signaling in β cells mediates epigenetic changes to regulate chromatin accessibility has not been examined. Therefore, our objective was to determine whether PRLR signaling alters chromatin accessibility of β cells to facilitate transcriptional regulation. Using single-cell assay for transposase-accessible chromatin using sequencing (scATAC), we identified differentially accessible regions (DARs) in β cells that had 718 overrepresented motifs following PRL treatment of murine islets. Validating this approach, these included motifs bound by established PRLR signaling effectors such as the STAT family of transcription factors (TFs). Using RNA-sequencing we identified transcriptional changes in 41 TFs whose motifs were overrepresented in DARs, including several previously linked to PRLR signaling within β cells, including Myc, Mafb, and Esr1. Importantly, we also identified TFs not previously associated with PRLR signaling, including OVOL2, an established regulator of epigenetic landscape within cells. OVOL2 is a TF involved in epithelial to mesenchymal transition inhibition and energy homeostasis with unknown roles in pancreatic β cells. Here, we establish that OVOL2 acts as a negative regulator of lactogen-dependent effects on β-cell proliferation, establishing a novel regulator of PRLR signaling.
The transcriptional landscape of the gastric mucosa in response to opposing nutritional states remains poorly defined. Here, we profiled gastric mucosal gene expression changes induced by diet-induced obesity (DIO) and calorie restriction (CR) in mice and investigated the physiological role of Decidual Protein Induced by Progesterone 1 (Depp1) using newly generated Depp1-knockout (KO) mice. RNA sequencing revealed that DIO elicits a predominantly proinflammatory transcriptional program in the gastric mucosa, whereas CR upregulates genes involved in peptide transport and extracellular matrix organization while downregulating immunity-related pathways. Among CR-induced genes, Depp1 exhibited the strongest positive correlation with expression of gene encoding the gastric hormone ghrelin. qRT-PCR confirmed enrichment of Depp1 in gastric ghrelin cells and demonstrated CR-induced upregulation of Depp1 in additional tissues, including liver, kidney, and pancreas; notably, hepatic induction by CR was absent in ghrelin-KO mice. Despite this association, Depp1-KO mice displayed normal metabolic responses to CR, including preserved glucose homeostasis. In contrast, following 16 weeks of ad libitum high-fat diet feeding, male Depp1-KO mice exhibited greater weight gain, hyperphagia, increased fat and lean mass, and impaired glucose tolerance compared with wild-type littermates. These phenotypes were accompanied by selective hepatic gene expression changes affecting Pgc1a, Pck1, and Igf1. Collectively, these findings identify Depp1 as a CR-induced, ghrelin-associated gene that influences hepatic transcriptional responses yet is dispensable for short-term adaptation to CR, while also implicating Depp1 as a protective factor against metabolic dysfunction during DIO through mechanisms that remain to be defined.
Prostate cancer (PCa) represents a hormone-dependent malignancy where androgen receptor (AR) signaling plays a central role in disease initiation, progression, and therapeutic resistance. Recent advances have revealed that long noncoding RNAs (lncRNAs) constitute a critical regulatory layer in PCa, with implications for endocrine signaling pathways. lncRNAs orchestrate complex gene regulatory networks through diverse molecular mechanisms including chromatin remodeling, AR splice variant regulation, competitive endogenous RNA networks, translational control, and metabolic reprogramming. In castration-resistant PCa, dysregulated lncRNAs contribute to resistance against androgen deprivation therapy and next-generation AR antagonists such as enzalutamide. This review synthesizes current knowledge on lncRNA biology in PCa, emphasizing lncRNA relationships with AR signaling and endocrine resistance mechanisms. We discuss key lncRNAs that modulate AR activity, metabolic adaptation, and lineage plasticity. Additionally, we examine structure-function relationships that enable rational therapeutic design, lncRNA roles in bone metastasis and neuroendocrine differentiation, and lncRNA clinical utility as biomarkers for disease progression and treatment stratification. Therapeutic strategies include antisense oligonucleotides, small-molecule inhibitors of lncRNA-protein interaction disruptors, and combination approaches with DNA-damaging agents and AR inhibitors. Understanding lncRNA-mediated endocrine regulation provides insights into PCa biology and offers avenues for overcoming therapeutic resistance in advanced disease.
In diabetic patients, hypoglycemia-associated autonomic failure (HAAF) is a potentially lethal condition that results in attenuation of critical protective responses to low blood glucose, following repeated prior hypoglycemic episodes. The underlying mechanism(s) of HAAF is not fully understood. We previously demonstrated that activation of catecholamine (CA) neurons in the ventrolateral medulla (VLM) is both required and sufficient to elicit key protective responses to glucose deficit. Here we test the hypothesis that repeated selective activation of VLM CA neurons is sufficient to induce HAAF, even in the absence of glucose deficit. Using stereotaxic injections of an adeno-associated virus in female TH-Cre transgenic rats, we transfected rostral C1 CA neurons to express hM3D(Gq). In these rats, we found that a single clozapine-N-oxide (CNO) injection evoked robust hyperglycemia, with a magnitude and time course similar to those evoked by the glucoprivic agent, 2-deoxy-D-glucose (2DG). However, following repeated CNO injections in these same rats, the hyperglycemic response evoked by either CNO or 2DG were significantly attenuated. Moreover, plasma epinephrine levels, and Fos expression in VLM CA neurons and in the adrenal medulla, also were attenuated following repeated CNO injections. This constellation of effects is similar to those that define HAAF. Taken together our results suggest that repeated stimulation of VLM CA neurons mimics and could be a cause of the impairment of counterregulatory responses associated with pathogenesis of HAAF.
