This Review discusses the current state of knowledge on the contribution of the gut microbiome as a potential key actor in defining how we age. The gut microbiome is a complex ecosystem that establishes lifelong dynamic...This Review discusses the current state of knowledge on the contribution of the gut microbiome as a potential key actor in defining how we age. The gut microbiome is a complex ecosystem that establishes lifelong dynamic interactions with the host at multiple levels (several gut-organ axes), differently influencing ageing patterns and age-related disease onset and progression across populations. Accordingly, the definition of a 'normative' gut microbiome remains elusive, depending largely on the interaction with the external environment. In this complex scenario, the causal role of the gut microbiome in defining the ageing trajectory and its precise contribution to various organ-specific age-related diseases is still uncertain in clinical terms and could be context specific. Multiparametric and uniqueness indexes within a given population have shown a certain capacity for predicting disability and mortality. However, the gut microbiome is shaped over time by exposure to different intrinsic and environmental factors, resulting in a high degree of inter-individual variability, a key phenomenon that should be considered to develop novel personalized strategies to counteract age-related disease and frailty.
Nagata N, Sugiyama R, Kohno S
… +12 more, Yamazaki T, Arai S, Sasaki G, Xu P, Morishige JI, Iba T, Miyazaki R, Takahashi C, Chang YT, Fujiwara T, Fujiwara H, Ando H
Endocrinology
· 2026 Mar · PMID 41749434
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The circadian clock plays a critical role in coordinating energy metabolism across tissues, including brown adipose tissue (BAT), a major site of nonshivering thermogenesis. This study aimed to elucidate the cell-autonom...The circadian clock plays a critical role in coordinating energy metabolism across tissues, including brown adipose tissue (BAT), a major site of nonshivering thermogenesis. This study aimed to elucidate the cell-autonomous role of the peripheral circadian clock in brown adipocyte thermogenesis using an in vitro model independent of extrinsic cues. Primary brown adipocytes were differentiated from the stromal vascular fraction of interscapular BAT isolated from C57BL/6J mice. An in vitro model of BAT clock disruption was established by siRNA-mediated knockdown of the core clock gene Bmal1. Thermogenic function was assessed via measurement of oxygen consumption rate (OCR) using an extracellular flux analyzer. To further assess the thermogenic process, protein expression levels of lipolytic enzymes and mitochondrial oxidative phosphorylation (OXPHOS) complexes were analyzed by Western blotting. Bmal1 knockdown markedly reduced both basal and β-adrenergic-stimulated OCR, indicating impaired thermogenic function, despite comparable cellular differentiation, preserved β-adrenergic responsiveness, and elevated uncoupling protein 1 (UCP1) expression. Notably, Bmal1-deficient cells exhibited decreased protein expression of key lipolytic enzymes, adipose triglyceride lipase and hormone-sensitive lipase, as well as multiple mitochondrial OXPHOS subunits, suggesting decreased free fatty acid supply and reduced mitochondrial ability to generate the proton gradient required for UCP1-mediated thermogenesis. The peripheral circadian clock in brown adipocytes supports thermogenic function by regulating lipid mobilization and mitochondrial oxidative function; thus its disruption may lead to decreased energy expenditure and increased susceptibility to metabolic disorders.
Nahar K, Basu R, Ahmad A
… +4 more, Pettis JA, Gamage U, Holub JM, Kopchick JJ
Endocrinology
· 2026 Mar · PMID 41742787
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The binding of human growth hormone (hGH) to the human growth hormone receptor (hGHR) is a key endocrinological process that controls critical aspects of cell growth, proliferation, and differentiation. Mechanistically,...The binding of human growth hormone (hGH) to the human growth hormone receptor (hGHR) is a key endocrinological process that controls critical aspects of cell growth, proliferation, and differentiation. Mechanistically, this sequential, asymmetric binding event involves the interaction between a single hGH molecule and distinct sites (sites 1 and 2) on the extracellular domain of a preformed hGHR homodimer. Our group recently identified S1H, a rationally designed peptide sequence mimetic of the hGH site 1-binding helix (residues 36-51) that disrupts the hGH-hGHR interaction and inhibits hGH-mediated phosphorylation of signal transducer and activator of transcription 5 (STAT5) in hGHR-positive cell lines. Structure-activity relationship studies revealed a positive correlation between helical propensity and inhibitory potency of the S1H peptide, prompting the design of structurally "stabilized" S1H variants (SS1H) with improved biological activity. In this study, we employed a chemical strategy, termed hydrocarbon stapling, to generate a series of SS1H peptides that proved to be more helical, proteolytically stable, and biologically active compared to linear (unstructured) S1H. Notably, one SS1H derivative (SS1HB) inhibited hGH-induced STAT5 phosphorylation in hGHR-positive human bladder cancer cells more effectively than pegvisomant, the only hGHR antagonist currently approved by the FDA. Collectively, our results demonstrate that hydrocarbon stapling improves the antagonistic effects of S1H peptides and elevates their potential as chemical probes to study the molecular mechanisms of hGH signaling. It is also anticipated that SS1H peptides will serve as potent lead compounds for developing next-generation therapeutics designed to treat endocrine disorders that manifest along the hGH-hGHR signaling axis.
Endocrinology
· 2026 Mar · PMID 41735769
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Androgen biosynthesis is physiologically necessary for generating the principal stimulus for androgen receptor (AR) signaling and thus plays an essential role for development of the normal prostate, prostate cancer growt...Androgen biosynthesis is physiologically necessary for generating the principal stimulus for androgen receptor (AR) signaling and thus plays an essential role for development of the normal prostate, prostate cancer growth, and the development of resistance to hormonal therapies. Testosterone and dihydrotestosterone are both potent endogenous androgens that stimulate AR signaling. While the role of gonadal androgens in stimulating prostate cancer progression has been recognized for over 80 years, the appreciation for nongonadal precursor steroids in prostate cancer has been more limited in duration of time, attention, and focus in the field. Nevertheless, the very clearly established role of nongonadal androgens in enabling prostate cancer progression, especially in the absence of gonadal testosterone, frames the essentiality of androgen metabolic processes for dictating prostate cancer clinical behavior. Here, the role of androgen metabolism in prostate cancer is reviewed, particularly within the context of hormonal therapy and hormone therapy resistance, and with emphasis on recent advances.
Taya M, Gray E, Srivastava T
… +5 more, Chee WY, Fleming GF, DeVilbiss AW, Bennett LB, Conzen SD
Endocrinology
· 2026 Mar · PMID 41732082
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High ovarian cancer cell glucocorticoid receptor (GR) expression is associated with reduced progression-free survival (PFS) despite standard debulking surgery and adjuvant chemotherapy. Although not previously linked to...High ovarian cancer cell glucocorticoid receptor (GR) expression is associated with reduced progression-free survival (PFS) despite standard debulking surgery and adjuvant chemotherapy. Although not previously linked to tumor-cell GR expression, a "cold" (immune-suppressive) ovarian cancer tumor microenvironment (TME) is also associated with poor prognosis. In this study, analysis of The Cancer Genome Atlas (TCGA) ovarian cancer database revealed that NR3C1 (GR) mRNA was positively correlated with immunosuppressive cytokine gene expression. Higher tumor NR3C1 expression also associated with gene expression encoding cellular markers of immunosuppressive myeloid-derived suppressor cells (MDSCs) and regulatory T cells (Tregs). In vitro, GR activation in human and mouse ovarian cancer cell lines led to increased secretion of pro-tumorigenic cytokines, including G-CSF, M-CSF, TGFβ2, and CXCL2. Co-treatment with a GR agonist (mimicking endogenous cortisol) and a selective GR modulator (SGRM) significantly reduced cytokine secretion. In human xenograft mouse models, systemic administration of a SGRM decreased serum immunosuppressive cytokine concentrations and mouse MDSC tumor infiltration, suggesting that tumor-cell GR activity and cytokine secretion contribute to MDSC generation and recruitment. Additionally, in a syngeneic model of GR-positive ovarian cancer, both pharmacologic GR antagonism and tumor cell-specific GR knockdown reduced intratumoral and circulating MDSCs, as well as intratumoral Tregs. Collectively, these findings suggest that ovarian cancer-cell GR activity contributes to maintaining a highly immunosuppressive TME through secretion of tumor-derived cytokines. We conclude that ovarian cancer cell GR activity has a previously unrecognized role in inhibiting anti-tumor immunity and that systemic GR modulation could improve immunotherapy outcomes in ovarian cancer.
Jin Y, Schultz H, Ongaro L
… +12 more, Schang G, Zhou X, Alonso CAI, Zamojski M, Nudelman G, Mendelev N, Onuma S, Welt CK, Bilezikjian LM, Sealfon SC, Ruf-Zamojski F, Bernard DJ
Endocrinology
· 2026 Apr · PMID 41717998
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Activin-class ligands of the transforming growth factor β family induce follicle-stimulating hormone (FSH) production by pituitary gonadotrope cells in mice via the actions of the transcription factors SMAD3, SMAD4, and...Activin-class ligands of the transforming growth factor β family induce follicle-stimulating hormone (FSH) production by pituitary gonadotrope cells in mice via the actions of the transcription factors SMAD3, SMAD4, and FOXL2, which bind to cis-elements in the FSHβ subunit (Fshb) promoter. An enhancer region for murine Fshb transcription was identified in vitro. However, deletion of the region using CRISPR-Cas9 did not affect FSH synthesis or secretion in mice. Using single-nucleus ATAC-seq of whole murine pituitaries, we identified 3 additional open chromatin regions upstream of Fshb exclusively in gonadotropes. These regions, as well as the Fshb gene, were fully or partially closed in gonadotropes of FSH-deficient mice with genetically or pharmacologically inactivated activin type II receptors. The initially characterized enhancer region did not significantly alter basal or activin-stimulated murine Fshb promoter-reporter activity in homologous LβT2 cells. In contrast, the other 3 open chromatin regions enhanced basal and activin A-stimulated Fshb promoter-reporter activity in LβT2 cells, with the 2 most distal showing the greatest effects. These 2 regions were open, exhibited enrichment of the enhancer mark H3K27ac, and were bound by SMAD2/3 and FOXL2 in response to activin A in LβT2 cells. The most distal enhancer exhibited strong FOXL2 and weak SMAD4 binding in gel shift assays. SMAD4, but not FOXL2, directly bound the other distal enhancer. Mutation of defined FOXL2 and SMAD4 cis-elements diminished enhancer activity in reporter assays in LβT2 cells. Collectively, the data indicate that there may be as many as 4 activin-sensitive enhancers upstream of murine Fshb.
Read GH, Pacheco JV, Baumann B
… +7 more, Richards ZA, Deaton R, Macias V, Kajdacsy-Balla A, Kittles R, Abern MR, Nonn L
Endocrinology
· 2026 Feb · PMID 41703746
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African American men experience a higher incidence and severity of prostate cancer relative to European American men, and there is a range of risk factors that may contribute to this disparity. Prostate adenocarcinoma or...African American men experience a higher incidence and severity of prostate cancer relative to European American men, and there is a range of risk factors that may contribute to this disparity. Prostate adenocarcinoma originates from the epithelium, which is significantly influenced by signaling from the surrounding fibromuscular stroma. To identify ancestry-associated differences in the stroma, gene expression profiling was compared between laser-capture microdissected prostate cancer stroma from patients of African descent and those of European descent. Estrogen receptor signaling was the top differential pathway between the groups, with the steroid hormone dehydrogenase HSD17B7 identified as the most differentially expressed gene. In a separate cohort of patients, protein expression of HSD17B7 was higher in African American patients relative to European American patients in a radical prostatectomy tissue microarray, validating the transcriptional findings. African American patients also exhibited significantly increased levels of HSD17B7 protein in the stroma surrounding benign areas compared to the stroma near tumors. These studies provide important evidence of ancestry-associated differences in stromal estrogen signaling.
Maskey S, Stocker WA, Alesi LR
… +8 more, Pankhurst MW, Herron-Vellacott HWG, Harrison SG, Spiller CM, Hagg A, Winship AL, Harrison CA, Walton KL
Endocrinology
· 2026 Mar · PMID 41700980
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Anti-Müllerian hormone (AMH) is produced by granulosa cells within growing ovarian follicles and limits the number of follicles reaching ovulation. AMH is synthesized as a precursor protein comprising N-terminal prodomai...Anti-Müllerian hormone (AMH) is produced by granulosa cells within growing ovarian follicles and limits the number of follicles reaching ovulation. AMH is synthesized as a precursor protein comprising N-terminal prodomains and C-terminal mature domains, separated by a furin-like cleavage motif (RXXR). Proteolytic maturation of AMH (140 kDa) is required to release the bioactive mature dimer (25 kDa), which potentiates signaling via AMH receptors (AMHR2 and ALK2/3). However, the abundance of unprocessed AMH in human follicular fluid suggests that cleavage within the ovary is inefficient. This study hypothesized that enhancing AMH maturation would increase AMH activity in vitro and in vivo. Using targeted mutagenesis, we optimized the murine AMH cleavage site (from wild-type (WT) 443RTGR445 to 443RKKR445) and showed in vitro that this favored production of bioactive AMH. We then introduced this mutation into the Amh gene in C57Bl6/J mice using CRISPR/Cas9 and assessed the consequences for female reproduction. Analyses of 12-week-old AmhRKKR/RKKR mice revealed that the ovaries were significantly lower in mass (-25%, P < .05) relative to AmhWT/WT controls. Despite differences in ovarian masses, estrous cyclicity, and fertility were unaltered. Although maturing follicle numbers did not differ, ovaries from 12- and 24-week-old AmhRKKR/RKKR females contained a greater proportion of atretic secondary follicles (1.6- to 4-fold more, P < .05), underscoring AMH's role in preantral follicle survival. Analyses of adult male AmhRKKR/RKKR mice indicated that testis mass and morphology were unaltered. These findings support a physiological role for ovarian AMH in limiting preantral follicle survival and indicate that enhancing AMH maturation is otherwise nondisruptive to female reproduction.
Menopause brings a series of endocrine changes that significantly increase the risk of developing metabolic syndrome (MetS), a condition characterized by central obesity, dyslipidemia, hypertension, and insulin resistanc...Menopause brings a series of endocrine changes that significantly increase the risk of developing metabolic syndrome (MetS), a condition characterized by central obesity, dyslipidemia, hypertension, and insulin resistance. In this context, the gut microbiota has gained relevance as a key modulating factor in the pathophysiology of MetS in postmenopausal women. The decline in estrogen levels affects microbial diversity and composition, promoting a dysbiotic environment marked by the loss of beneficial bacteria, such as Akkermansia muciniphila and Bifidobacterium spp., and an increase in proinflammatory, lipopolysaccharide (LPS)-producing microorganisms, such as Proteobacteria and Escherichia coli. This imbalance leads to increased intestinal permeability and endotoxin translocation, triggering systemic low-grade inflammation associated with various MetS components. Clinical studies have identified correlations between specific microbial taxa, metabolites such as imidazole propionate and phenylacetylglutamine, and clinical markers of metabolic dysfunction. In this scenario, dietary intervention emerges as an effective therapeutic tool. Dietary patterns like the Mediterranean diet - rich in polyphenols, fiber, and monounsaturated fats - have shown beneficial effects on gut microbiota modulation, enhancing short-chain fatty acid production, reducing inflammation, and improving metabolic homeostasis. Likewise, the DASH diet and plant-based dietary patterns have demonstrated potential in the prevention and management of MetS in postmenopausal women. In conclusion, the interaction between gut microbiota, metabolism, and postmenopausal hormonal changes represents a critical axis in the development of MetS. Personalized dietary approaches aimed at restoring eubiosis may offer an effective strategy to improve metabolic health in this vulnerable population.
Endocrinology
· 2026 Feb · PMID 41685823
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Leptin receptor positive (LepR+) cells are multipotent stromal cells and a source of osteogenic and adipogenic cells. Inactivation of Notch signaling in LepR+ cells increases bone mass in mature mice, but the target gene...Leptin receptor positive (LepR+) cells are multipotent stromal cells and a source of osteogenic and adipogenic cells. Inactivation of Notch signaling in LepR+ cells increases bone mass in mature mice, but the target gene responsible was not identified. Because in LepR+ cells the expression of the Notch target gene Hes1 prevails over that of other genes, we explored the role of the Hes1 deletion in LepR+ cells. To this end, LepR-Cre;Hes1Δ/Δ mice were compared to Hes1loxP/loxP littermates. Male and female 5-month-old LepR-Cre;Hes1Δ/Δ mice exhibited an increase in femoral bone volume/total volume due to an increase in trabecular number; vertebral (L3) and cortical bone was not affected. Bone histomorphometry demonstrated decreased osteoclast number and eroded surface, decreased osteoblast number only in male mice, and no changes in bone formation. Neither osteogenesis nor adipogenesis was modified by the Hes1 deletion in bone marrow stromal cell cultures, although Tnfsf11 (encoding RANKL) was suppressed in osteogenic cultures of Hes1Δ/Δ cells. Single-cell RNA sequencing of femurs from 5-month-old LepR-Cre;Hes1Δ/Δ and control mice revealed the presence of 23 cell clusters including clusters composed of hematological cells (myeloid, B cells, and neutrophils), endothelial cells, and osteoblasts. There were no substantial differences in gene expression, cluster distribution, or trajectory finding between control and Hes1 inactivated cells. In conclusion, Hes1 inactivation in LepR+ cells results in an increase in bone mass secondary to a decrease in RANKL, osteoclast number, and bone resorption, but HES1 has little influence on osteogenesis or adipogenesis in bone.
Endocrinology
· 2026 Mar · PMID 41668460
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Water movement across cell membranes through aquaporin water channels creates osmotic equilibrium between extracellular and intracellular fluid compartments. Plasma osmolality is tightly regulated by the kidneys and brai...Water movement across cell membranes through aquaporin water channels creates osmotic equilibrium between extracellular and intracellular fluid compartments. Plasma osmolality is tightly regulated by the kidneys and brain through the process of osmoregulation. The antidiuretic hormone, arginine vasopressin (AVP), is normally released from the posterior pituitary in response to increased osmolality or decreased intravascular volume. Defects in the synthesis or release of AVP result in AVP deficiency (AVP-D) and the syndrome of central diabetes insipidus, characterized by inappropriate aquaresis leading to hyperosmolality and insatiable thirst. While most cases of AVP-D are due to local mechanical, infiltrative, compressive, infectious, or inflammatory processes, some recreational and pharmacological substances can cause AVP-D. In this review, we discuss the history and current knowledge about these substances, including cannabinoids, ethanol, κ opioid receptor agonists, phenytoin, and anesthetic agents.
Patients with diabetes are disproportionately affected by cardiovascular and kidney disease. Mineralocorticoid receptor (MR) antagonists show organ protection against cardiovascular and renal injury; however, major side...Patients with diabetes are disproportionately affected by cardiovascular and kidney disease. Mineralocorticoid receptor (MR) antagonists show organ protection against cardiovascular and renal injury; however, major side effects including hyperkalemia and reduced renal function limit their use in individuals with diabetic complications. The nonsteroidal MR modulator balcinrenone may offer end-organ protection with fewer side effects. We compared responses to balcinrenone and eplerenone delivered from 8 weeks postinduction of streptozotocin (STZ)-induced type 1 diabetes in male mice. RNA sequencing revealed diabetes induced modulation of immune function, and metabolic and vascular targets in the kidney, which were similarly attenuated by balcinrenone or eplerenone treatment. Urine K+ excretion was lower following eplerenone treatment, but not balcinrenone treatment, compared to diabetes without treatment. We identified a 5.90-fold increase in the expression of K+ transporter G protein-activated inward rectifier potassium channel 1 in eplerenone- but not balcinrenone-treated diabetic mice. Balcinrenone and eplerenone similarly attenuated the diabetes-induced reduction in peak E-wave/A-wave velocity compared to mice without treatment at 15 weeks post-STZ. Gene markers of cardiac injury, B-type natriuretic peptide, and β-myosin heavy chain protein were higher in diabetic vs nondiabetic left ventricles (LVs). Conversely, gene expression of Ca2+ ion channel subunits, voltage-dependent L type, calcium channel subunit α 1C, and ryanodine receptor 2 in LV was lower in diabetic but not eplerenone- or balcinrenone-treated diabetic mice. Although balcinrenone and eplerenone similarly modified cardiac changes, potassium excretion was greater with balcinrenone, consistent with a reduced risk of hyperklemia with the nonsteroidal MR modulator.
Behler-Janbeck F, Baranowsky A, Stenzel P
… +6 more, Neven M, Yorgan T, Amling M, Worthmann A, Heeren J, Schinke T
Endocrinology
· 2026 Feb · PMID 41645473
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Bone remodeling, mediated by bone-forming osteoblasts and bone-resorbing osteoclasts, is a physiologically relevant process controlled by several local and systemic regulatory mechanisms. Recent evidence in mice has sugg...Bone remodeling, mediated by bone-forming osteoblasts and bone-resorbing osteoclasts, is a physiologically relevant process controlled by several local and systemic regulatory mechanisms. Recent evidence in mice has suggested that it is also affected by housing temperature, which provides a basis to identify novel molecular regulators of bone remodeling. Here, we compared the skeletal phenotype of mice housed at thermoneutral (30 °C), room (22 °C), or cold (6 °C) temperature for 1 or 4 weeks. We observed that cold exposure for 1 week differentially affected osteoclastogenesis and osteoblast activity, which caused a significant reduction of trabecular number and cortical thickness after 4 weeks. Cold exposure is known to induce type II iodothyronine deiodinase (DIO2) expression in thermogenic adipose tissues. Because this enzyme catalyzes the deiodination of T4 to the active thyroid hormone T3, we addressed the question whether the cold-induced bone loss depends on DIO2. Importantly, however, we found that Dio2 deficiency in male and female mice did not affect the cold-induced reduction of trabecular and cortical bone mass, demonstrating that this process does not depend on thyroid hormone activation. To identify potential metabolic differences between the different groups of mice, we additionally performed lipidomic analyses. Here, we observed a remarkable reduction of specific lipid species after cold exposure, suggesting that either the systemic catabolic metabolism or the decrease of specific lipid species cause cold-induced bone loss. Taken together, although our data demonstrate that sustained cold exposure has a remarkable negative impact on bone mass, future studies are needed to identify causative molecules.
Joshi S, Patel A, Raja R
… +1 more, Rajagopalan KN
Endocrinology
· 2026 May · PMID 41631715
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Adipose tissue, long regarded as exclusively an energy reservoir, is now recognized as an active endocrine organ with significant immunomodulatory functions. As global obesity rates rise, understanding how adipokines inf...Adipose tissue, long regarded as exclusively an energy reservoir, is now recognized as an active endocrine organ with significant immunomodulatory functions. As global obesity rates rise, understanding how adipokines influence the immune response is increasingly critical. In this review we focus on three key adipokines-leptin, adiponectin, and resistin-and how they modulate immune function. With each adipokine, we begin by exploring its basic biology in the context of immune function. We then discuss mouse and human studies that explore each adipokine's role in the response to infection. We close by suggesting potential uses of each adipokine as a biomarker and/or therapy in infection.