Endocrinology
· 2025 Dec · PMID 41287584
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Fibroblast growth factor 21 (FGF21) is a liver-derived hormone that regulates metabolism across multiple tissues. It can cross the blood-brain barrier and activate its receptor FGFR1c, in conjunction with co-receptor β-K...Fibroblast growth factor 21 (FGF21) is a liver-derived hormone that regulates metabolism across multiple tissues. It can cross the blood-brain barrier and activate its receptor FGFR1c, in conjunction with co-receptor β-Klotho, modulating neuronal activity. Previous studies have mapped the brain-wide distribution of FGFR1c and β-Klotho, suggesting potential FGF21 target regions. Notably, FGF21 has been shown to act on the hypothalamus to regulate feeding behavior and macronutrient preference, positioning it as a promising candidate for antiobesity therapies. In this study, we found that under a diet of normal chow, FGF21 primarily activated hypothalamic regions involved in metabolic control and suppressed activity in cortical areas related to cognition. Prolonged high-fat diet (HFD) treatment increased neuronal activity in regions involved in sensory processing, memory, and reward. In HFD-fed mice, FGF21 broadly activated additional regions linked to reproduction, thermoregulation, sensory function, and arousal. However, its ability to stimulate key metabolic nuclei, such as the periventricular hypothalamic nucleus, was impaired, suggesting the existence of selective central FGF21 resistance. These findings reveal that FGF21 modulates brain activity in a diet-dependent manner and that obesity alters its central effects.
Lazzaretti C, Sperduti S, Pelagatti G
… +14 more, Perri C, Baschieri L, Fusco C, De Carlini S, Canu G, Varani M, Nicoli A, Morini D, Villani MT, Fanelli F, Reiter E, Simoni M, Hanyaloglu AC, Casarini L
Endocrinology
· 2025 Dec · PMID 41271604
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LH/choriogonadotropin (hCG) receptor (LHCGR) and the G protein-coupled estrogen receptor (GPER) are coexpressed in the ovary and support reproduction. The latter is involved in pathophysiological conditions and has been...LH/choriogonadotropin (hCG) receptor (LHCGR) and the G protein-coupled estrogen receptor (GPER) are coexpressed in the ovary and support reproduction. The latter is involved in pathophysiological conditions and has been suggested as a potential therapeutic target. However, its role is still controversial, and several studies reported GPER to form heterocomplexes with other class A G protein-coupled receptors, modulating their signaling cascades. We evaluated if GPER interacts with LHCGR and impacts ligand-mediated pathways. In HEK293, LHCGR-GPER heteromers allosterically modulate LH/hCG-mediated signaling by preventing receptor coupling with Gq protein, leading to inhibition of phospholipase C pathway, and related transcriptional and mitogenic functions. This effect is prevented by mutant GPER unable to form heteromers with LHCGR. Interestingly, GPER expression has no effect on LH/hCG-induced Gs/cAMP/protein kinase A pathway activation, demonstrating selective inhibition of Gq pathway. These results were not recapitulated in cells displaying insufficient endogenous Gq protein expression levels, whereas they are recovered under exogenous Gq overexpression. Our data strengthen the concept that GPER may act as a modulator of other membrane G protein-coupled receptors, and a potential new target for treatment of tumors displaying Gq signalling.
Yuan Y, Steenbergen J, de Oliveira Santos Goulart A
… +2 more, Sabaté-Pérez A, Visser JA
Endocrinology
· 2025 Nov · PMID 41260614
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CONTEXT: Women with polycystic ovary syndrome (PCOS) and PCOS animal models have diminished brown adipose tissue (BAT) activity, potentially contributing to metabolic dysfunction. Besides classical androgens, adrenal 11-...CONTEXT: Women with polycystic ovary syndrome (PCOS) and PCOS animal models have diminished brown adipose tissue (BAT) activity, potentially contributing to metabolic dysfunction. Besides classical androgens, adrenal 11-oxygenated androgens are elevated in women with PCOS. However, it remains unknown whether these 11-oxygenated androgens affect BAT metabolism. OBJECTIVE: To study the effects of 11-ketotestosterone (KT) and 11-ketodihydrotestosterone (KDHT) on BAT metabolism. METHODS: The female mouse brown adipocyte cell line T37i was treated with increasing concentrations (0.1-10 µM) of testosterone (T), dihydrotestosterone (DHT), KT, or KDHT during or after differentiation. In addition, female mice received a daily injection of vehicle, DHT, KT, or KDHT (100 µg) for 1 day or 1 week. Adipose depots were collected for RNA sequencing (RNAseq) analysis and Gene Set Enrichment Analysis (GSEA). RESULTS: During differentiation, T, KT, DHT, and KDHT treatment of T37i cells dose-dependently reduced lipid droplet accumulation, and downregulated mRNA expression of adipogenic markers by up to 50%, with KDHT having the weakest effect. In mature T37i cells, only the high concentrations of these androgens exhibited inhibitory effects. RNAseq analysis revealed that DHT exposure induced the most differentially regulated genes in BAT, followed by KT and KDHT treatment. GSEA indicated that 1-day treatment with DHT and KT, but not KDHT, resulted in the downregulation of metabolic pathways in BAT. CONCLUSION: 11-Oxygenated androgens at high concentrations directly inhibit brown adipocyte differentiation in vitro and KT acutely downregulates BAT metabolic transcriptome in vivo, a result not observed with KDHT. These findings suggest that elevated 11-oxygenated androgens may impair BAT function, contributing to metabolic complications associated with hyperandrogenic conditions, including PCOS.
Endocrinology
· 2025 Dec · PMID 41258682
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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 cogni...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.
Lach GS, Brown FN, Lee AE
… +8 more, Kington ZA, Sanderson A, Cronin RN, Young JA, Bæk A, List EO, Kopchick JJ, Berryman DE
Endocrinology
· 2025 Dec · PMID 41250864
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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...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.
Deep concern has been raised about the reduced survival rate in patients with renal impairment, and efforts to identify comorbidities that could delay its progression are of paramount importance. Among them, thyroid dysf...Deep concern has been raised about the reduced survival rate in patients with renal impairment, and efforts to identify comorbidities that could delay its progression are of paramount importance. Among them, thyroid dysfunction has been postulated as one of the determinants of chronic kidney disease (CKD). It is worth noting that the relationship between the thyroid gland and the kidney is mutual. Although patients with CKD can exhibit changes in thyroid function tests that characterize non-thyroidal illness syndrome, thyroid hormones per se are critical regulators of kidney structure and function. A growing number of studies indicate that subclinical hypothyroidism is more common in people with CKD than in the general population and could be considered a risk factor for the development of CKD. However, it remains unclear whether hypothyroidism has a causal role in the development of CKD or whether levothyroxine treatment could minimize the progressive loss of kidney function in these patients. Overall, this narrative Review intends to explore the potential involvement of thyroid dysfunction, with a focus on hypothyroidism, as a reversible risk condition in the deterioration of renal function.
Zhou X, Smith DL, Lin J
… +2 more, HogenEsch E, Cedars MI
Endocrinology
· 2025 Nov · PMID 41233938
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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. W...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.
Endocrinology
· 2025 Nov · PMID 41222078
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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 brai...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.
Junnila A, Petruk N, Heikelä H
… +11 more, Postila P, Hakkarainen J, Martinez-Nieto G, Uceda-Rodriguez E, Ruiz-Pino F, Tena-Sempere M, Ohlsson C, Sipilä P, Heino TJ, Määttä J, Poutanen M
Endocrinology
· 2025 Dec · PMID 41219171
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17β-hydroxysteroid dehydrogenase 1 (HSD17B1) is the primary enzyme responsible for the activation of estrone (E1) to estradiol (E2) in ovaries and extra-gonadal tissues of both humans and rodents. In the present study, m...17β-hydroxysteroid dehydrogenase 1 (HSD17B1) is the primary enzyme responsible for the activation of estrone (E1) to estradiol (E2) in ovaries and extra-gonadal tissues of both humans and rodents. In the present study, molecular modeling identified the substitution of His222 in the human HSD17B1 enzyme with glycine in the mouse as the key determinant for the different steroid specificity between the species. Furthermore, Ser143Ala mutation at the active site of mouse HSD17B1 resulted in a total loss of E1 to E2 conversion by HSD17B1. This resulted in elevated intraovarian and circulating E1 concentrations in adult HSD17B1 Ser143Ala knock-in (HSD17B1-KI) females, but no changes in E2 concentrations were observed compared to the wild-type mice. Androstenedione and dihydrotestosterone were also elevated in the HSD17B1-KI ovaries, associated with elevated circulating LH. However, the effect of HSD17B1 inactivation on female reproductive development and function was mild, primarily resulting in a slight decrease in ovarian weight in older HSD17B1-KI mice, without notable effects on fertility. Expression of genes related to steroid biosynthesis, mitochondrial metabolism, and known markers of polycystic ovary syndrome was found to be upregulated in adult HSD17B1-KI ovaries. However, no alterations in the structure or function of extra-gonadal tissues were observed, and the uterus and bone phenotypes in the HSD17B1-KI females were unaffected. Our results demonstrate that the blockade of HSD17B1-dependent E2 synthesis is successfully compensated for in mouse in vivo, resulting in only a mild ovarian estrogen and androgen imbalance but no significant adverse effects on reproductive or bone health.
Sessions DT, Boulton DP, Spoelstra NS
… +4 more, Caino MC, Yu M, Goodspeed A, Richer JK
Endocrinology
· 2025 Dec · PMID 41216931
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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+ B...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.
Capozzi A, Ambroggio S, Cagnacci A
… +4 more, Gambacciani M, Lello S, DI Carlo C, Executive Committee of the Italian Society of Gynecology of the Third Age (SIGiTE) and the Italian Society of Menopause (SIM)
Premature ovarian insufficiency (POI) is a critical condition affecting young women before the median age of menopause and consisting of spontaneous oligo-amenorrhea for at least four months associated with follicle stim...Premature ovarian insufficiency (POI) is a critical condition affecting young women before the median age of menopause and consisting of spontaneous oligo-amenorrhea for at least four months associated with follicle stimulating hormone (FSH) levels ≥25 UI/L detected before 40 years of age. Several causes like genetic abnormalities, autoimmune diseases, drugs and/or pelvic surgery may favor this condition that is associated with a deeper clinical impact on women's health compared to physiological menopause. Specifically, cardiovascular and musculoskeletal systems as well as brain could be especially affected by the early loss of ovarian hormones. Therefore, appropriate treatment is necessary to adequately narrow the biological gap with the average age of menopause. Hormone replacement therapy (HRT) is the treatment of choice, regardless of the presence of neurovegetative symptoms. Transdermal high dosage of natural estradiol is generally preferred to guarantee the preservation of cardio-metabolic and bone health. When contraception is required, oral estroprogestins (EPs) maybe considered. A referral to reproductive experts for fertility preservation techniques should be considered case by case.
Mastropierro RL, Tabares FN, Riaño Gomez JM
… +8 more, Bizzozzero-Hiriart M, Velazquez C, Pascual F, Cutini P, Massheimer V, Bettler B, Lux-Lantos VA, Di Giorgio NP
Endocrinology
· 2025 Nov · PMID 41206596
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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 tiss...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.
De Robles G, Wiggins KD, Del Mundo Z
… +5 more, Ujagar N, Nguyen CM, Seldin MM, Pacheco-Sanchez G, Nicholas DA
Endocrinology
· 2025 Nov · PMID 41206437
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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....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.
Anaya ES, Dion W, Saha PK
… +7 more, Cox AR, de Groot E, Ahmed AA, Felix JB, Zhu B, Pangas SA, Hartig SM
Endocrinology
· 2025 Dec · PMID 41206127
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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 lipoatrop...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.