Molecular And Cellular Endocrinology[JOURNAL]
Sun
200 papers
Pleiotropic signaling of single-chain thyrostimulin (GPB5-GPA2) on homologous glycoprotein hormone receptors (ScFSHR, ScLHR, ScTSHR) in the elasmobranch Scyliorhinus canicula reproduction.
Jeanne F, Pilet S, Combarnous Y … +4 more , Bernay B, Dufour S, Favrel P, Sourdaine P
Mol Cell Endocrinol · 2025 Jul · PMID 40254178 · Publisher ↗
The pituitary glycoprotein hormones (GPHs) control several physiological processes in vertebrates such as reproduction and metabolism. They include the luteinizing hormone (LH), the follicle-stimulating hormone (FSH), an...
The pituitary glycoprotein hormones (GPHs) control several physiological processes in vertebrates such as reproduction and metabolism. They include the luteinizing hormone (LH), the follicle-stimulating hormone (FSH), and the thyroid-stimulating hormone (TSH), which activate their cognate leucine-rich repeat G protein-coupled receptors (LGRs), LHR, FSHR, and TSHR. Each GPH consists of a common α subunit and a specific βFSH, βLH or βTSH subunit. More recently, two supplementary GPH proteins, GPA and GPB, were identified in nearly all bilaterians and are the ancestors of the pituitary GPH α- and β-subunits, respectively. Chondrichthyans (holocephalans and elasmobranchs), the sister group of bony vertebrates, are the most ancient clade to possess diversified GPH subunits. In the present study, GPA2, GPB5, TSHβ2, but not TSHβ1, and TSHR sequences have been identified in several elasmobranch genomes, and their 3D models were analyzed. Functional hormone-receptor interactions were studied in the small-spotted catshark (Scyliorhinus canicula) and showed that conditioned media from cells expressing the recombinant single-chain ScGPB5-ScGPA2 were more effective than independent subunits in activating ScTSHR, ScFSHR, and ScLHR. Expression profiles were analyzed by real-time PCR, in situ hybridization, and immunohistochemistry along the male genital tract, other male and female tissues, and female tissues. A broader tissue distribution expression was observed for tshr and gpa2 than for gpb5, which was mainly observed in the testes. In testis, expression of tshr and gpb5 by Sertoli cells and of gpa2 by germ cells suggested paracrine/autocrine functions of GPA2/GPB5/GPHR signaling during spermatogenesis. This study complements the data on GPA2 and GPB5 by studying a chondrichthyan of phylogenetic interest for understanding the evolution of endocrine regulation in vertebrates.
5,7,3',4',5'-pentamethoxyflavone (PMF) exhibits anti-obesity and neuroprotective effects in an obese zebrafish model.
Vohra MS, Ahmad B, Taylor ER … +6 more , Benchoula K, Fong IL, Parhar IS, Ogawa S, Serpell CJ, Wong EH
Mol Cell Endocrinol · 2025 Jul · PMID 40252912 · Publisher ↗
Obesity is a multi-chronic illness characterized by superfluous fat accumulation, contributing to significant metabolic and neurological complications. Current therapeutic approaches have limited efficacy and notable sid...
Obesity is a multi-chronic illness characterized by superfluous fat accumulation, contributing to significant metabolic and neurological complications. Current therapeutic approaches have limited efficacy and notable side effects, underscoring an urgent demand for novel, safer alternatives. This study is the first to investigate the anti-obesity potential of 5,7,3',4',5'-pentamethoxyflavone (PMF) in vivo using a zebrafish model. Our findings demonstrate that PMF administration exerts pronounced anti-obesogenic effects, evidenced by reductions in blood glucose, plasma triglycerides, total cholesterol, hepatic low-density lipoproteins (LDL), and high-density lipoproteins (HDL). Mechanistically, PMF suppressed hepatic adipogenic and lipogenic gene expression while promoting lipid catabolism through activation of peroxisome proliferator-activated receptor-alpha (PPAR-α) and its downstream enzymes, including acyl-CoA oxidase 1 (ACOX1), medium-chain acyl-CoA dehydrogenase (ACADM), and carnitine palmitoyl transferase 1B (CPT-1β). Additionally, PMF markedly mitigated oxidative stress by lowering malondialdehyde (MDA) and nitric oxide (NO) levels, accompanied by increased antioxidant enzyme activities, including superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GSH-Px), and glutathione S-transferase (GST). Notably, PMF effectively prevented obesity by suppressing food intake, downregulating orexigenic genes, and enhancing anorexigenic signals. Furthermore, PMF exhibited neuroprotective properties by elevating brain-derived neurotrophic factor (BDNF) and its receptor tropomyosin receptor kinase B2 (TrkB2), revealing a novel link between metabolic and neurological regulation. This study provides pioneering, comprehensive in vivo evidence supporting PMF as a promising therapeutic candidate with dual beneficial roles in metabolic health and neuroprotection.
Impact of BPA and its analogs on sperm hyperactivity, acrosome reaction, epigenetic profiles and in vitro embryo development.
Davis OS, Scandlan OLM, Potestio EA … +4 more , Robinson C, Hickey KD, Ross M, Favetta LA
Mol Cell Endocrinol · 2025 Jul · PMID 40252911 · Publisher ↗
Bisphenols, particularly BPA, are ubiquitous environmental contaminants known to affect male reproductive health. However, their specific impacts on sperm function and subsequent embryo development remain understudied es...
Bisphenols, particularly BPA, are ubiquitous environmental contaminants known to affect male reproductive health. However, their specific impacts on sperm function and subsequent embryo development remain understudied especially for BPA's commonly used replacements, BPS and BPF. This study investigated the effects of direct sperm exposure to BPA, BPS, and BPF on fertilization capacity and embryo development using a bovine model, as translational for humans. Sperm samples were exposed to 0.05 mg/mL of each bisphenol in vitro. Parameters, including hyperactivity and acrosome reaction, as well as fertilization outcomes, such as developmental rates and blastocyst quality, were further evaluated following IVF. miRNA profiles were also analyzed in sperm and embryos to detect potential biomarkers of bisphenol exposure. We found that BPF significantly increased sperm hyperactivity, and BPA decreased acrosome reaction levels (p < 0.05). Cleavage and blastocyst rates were also notably decreased in embryos derived from BPA-exposed sperm (p < 0.05). Furthermore, blastocysts produced from BPA, BPS and BPF treated sperm all had significantly lower cell counts and increased DNA fragmentation (p < 0.05). Although no statistically significant changes in miRNA levels were observed, this study highlights some of the detrimental effects of bisphenols on bovine sperm and subsequent embryo development, with potential implications for human reproductive health.
Exploratory analysis of differences at the transcriptional interface between the maternal and fetal compartments of the sheep placenta and potential influence of fetal sex.
Halloran KM, Saadat N, Pallas B … +2 more , Vyas AK, Padmanabhan V
Mol Cell Endocrinol · 2025 Jun · PMID 40222550 · Full text
An understanding of the inner workings of the placenta is imperative to elucidate how the maternal and fetal compartments coordinate to mediate fetal development. The two compartments can be separated and studied before...
An understanding of the inner workings of the placenta is imperative to elucidate how the maternal and fetal compartments coordinate to mediate fetal development. The two compartments can be separated and studied before term in sheep, a feat not possible in humans, thus providing a valuable translational model. This study investigated differential expression of gene signaling networks in the maternal and fetal compartments of the placenta and explored the potential influence of fetal sex. On approximately gestational day 120 (term: 147 days), ewes were euthanized and fetuses removed and sexed. Placentomes [n = 5 male, n = 3 female] were collected, and caruncles (maternal) and cotyledons (fetal) were separated and sequenced to assess RNA expression. Analysis revealed 2627 differentially expressed genes (FDR<0.01, abslog2FC ≥ 2) contributing to key transcriptional differences between maternal and fetal compartments, which suggested that the maternal compartment drives extracellular signaling at the interface whereas the fetal compartment controls internal mechanisms crucial for fetal-placental development. X-chromosome inactivation equalized expression of a vast majority of X-linked genes in the fetal compartment. Additionally, the female placenta had more fine-tuned regulation of key pathways for fetal-placental development, such as DNA replication, mRNA surveillance, and RNA transport, compared to males, which had enrichment of metabolic pathways including TCA cycle and galactose metabolism. These findings, in addition to supporting differences in expression in the maternal and fetal placental compartments and the possible influence of fetal sex, offer a transcriptional platform to compare placental perturbations that occur at the maternal-fetal interface that contribute to adverse pregnancy outcomes.
N-acetylcysteine influence on PI3K/Akt/mTOR and sphingolipid pathways in rats with MASLD induced by HFD: a promising new therapeutic purpose.
Sztolsztener K, Michalak D, Chabowski A
Mol Cell Endocrinol · 2025 Jun · PMID 40220949 · Publisher ↗
Sphingolipid and glucose metabolism play important roles in the induction and progression of severe liver disorders like metabolic dysfunction-associated steatotic liver disease (MASLD). The perturbation in sphingolipid...
Sphingolipid and glucose metabolism play important roles in the induction and progression of severe liver disorders like metabolic dysfunction-associated steatotic liver disease (MASLD). The perturbation in sphingolipid formation may improve the liver structure and functioning and may constitute the potential therapeutic options for the development of simple steatosis and its progression to steatohepatitis. This study aims to assess the influence of N-acetylcysteine (NAC) on the sphingolipid and insulin signaling pathways in rats subjected to standard or high-fat diets. Sphingolipid level was measured using high-performance liquid chromatography (HPLC). A multiplex assay kit determined the level of phosphorylated form of proteins included in the PI3K/Akt/mTOR pathway. The immunoblotting estimated the expression of proteins from sphingolipid and insulin transduction pathways. A histological Oil red O staining was used to assess the hepatic accumulation of lipid droplets. Molecular docking was applied to showcase NAC interaction with PI3K/Akt/mTOR pathway proteins. NAC decreased dihydroceramide and ceramide levels and increased phosphorylation of sphingosine and sphinganine. This antioxidant also enhanced phosphorylated Akt, GSK3α/β, and P70 S6 kinase and decreased phosphorylated S6RP. In silico docking analysis of insulin signaling molecules evidenced the higher binding affinity of NAC with all tested proteins, i.e., IRS1, PTEN, Akt, GSK3α/β, P70 S6 kinase, and S6RP, suggesting a potential protective influence on insulin resistance development, which is one of the criteria for MASLD diagnosing. Based on these data, NAC improved the hepatic insulin sensitivity and sphingolipid synthesis and storage, improving and restoring glucose homeostasis.
Maternal dopamine agonist treatment before pregnancy reverses infertility and hyperprolactinemia in hCG-overexpressing mice through lactation: Evidence of generational effects.
Ratner LD, Marcial Lopez A, Di Giorgio NP … +3 more , Poutanen M, Huhtaniemi I, Rulli SB
Mol Cell Endocrinol · 2025 May · PMID 40187547 · Publisher ↗
Dopamine agonists, such as cabergoline (Cab), have demonstrated efficacy in restoring reproductive function in cases of hyperprolactinemia and hormonal dysregulation. This study investigates the long-term consequences of...
Dopamine agonists, such as cabergoline (Cab), have demonstrated efficacy in restoring reproductive function in cases of hyperprolactinemia and hormonal dysregulation. This study investigates the long-term consequences of maternal Cab treatment on the reproductive phenotype of the progeny in a female transgenic (TG) mouse model with hyperprolactinemia and infertility due to human chorionic gonadotropin (hCG) β-subunit overexpression. The TG females that received Cab between weeks 3-4 of life exhibited a reversion of hyperprolactinemia and infertility, whereas WT females retained their fertility. When TG-cab- or WT-Cab-treated females were crossed with WT or TG males, respectively, their female TG offspring showed a reversal of precocious puberty, regularization of estrous cycles, fertility, and prevention of hyperprolactinemia and prolactinomas. Despite the persistent high LH/hCG bioactivity, the normalization of prolactin levels led to a reduction in ovarian luteinization markers and progesterone levels. The TG female pups born to either WT-cab- or TG-cab-treated females exhibited a normalized phenotype, thus suggesting that the effects were indeed due to maternal Cab administration, and not to the transgene. Cross-fostering experiments showed that the long-lasting programming effect of maternal Cab on offspring occurred during lactation because the TG female pups from non-treated WT female/TG male pregnancies, but nursed by Cab-treated females, were free from the altered TG phenotype. These results suggest that Cab treatment before pregnancy may have a multigenerational effect on the hypothalamic-pituitary-gonadal axis of the offspring, mediated during lactation. This highlights potential implications for generational health and clinical practices regarding the use of dopamine agonists during lactation.
The multi-level effect of chlorpyrifos during clownfish metamorphosis.
Reynaud M, Vianello S, Lee SH … +7 more , Salis P, Wu K, Frederich B, Lecchini D, Besseau L, Roux N, Laudet V
Mol Cell Endocrinol · 2025 Jun · PMID 40187546 · Publisher ↗
Chemical pollution in coastal waters, particularly from agricultural runoff organophosphates, poses a significant threat to marine ecosystems, including coral reefs. Pollutants such as chlorpyrifos (CPF) are widely used...
Chemical pollution in coastal waters, particularly from agricultural runoff organophosphates, poses a significant threat to marine ecosystems, including coral reefs. Pollutants such as chlorpyrifos (CPF) are widely used in agriculture and have adverse effects on marine life and humans. In this paper, we investigate the impact of CPF on the metamorphosis of a coral reef fish model, the clownfish Amphiprion ocellaris, focusing on the disruption of thyroid hormone (TH) signalling pathways. Our findings reveal that by reducing TH levels, CPF exposure impairs the formation of characteristic white bands in clownfish larvae, indicative of metamorphosis progression. Interestingly, TH treatment can rescue these effects, establishing a direct causal link between CPF effect and TH disruption. The body shape changes occurring during metamorphosis are also impacted by CPF exposure, shape changes are less advanced in CPF-treated larvae than in control conditions. Moreover, transcriptomic analysis elucidates CPF's effects on all components of the TH signalling pathway. Additionally, CPF induces systemic effects on cholesterol and vitamin D metabolism, DNA repair, and immunity, highlighting its broader TH-independent impacts. Pollutants are often overlooked in marine ecosystems, particularly in coral reefs. Developing and enhancing coral reef fish models, such as Amphiprion ocellaris (Cuvier, 1830), offers a more comprehensive understanding of how chemical pollution affects these ecosystems. This approach provides new insights into the complex mechanisms underlying CPF toxicity during fish metamorphosis, shedding light on the broader impact of environmental pollutants on marine organisms.
Follicular fluid profiling unveils anti-Müllerian hormone alongside glycolytic and mitochondrial dysfunction as markers of polycystic ovary syndrome.
Vale-Fernandes E, Carrageta DF, Moreira MV … +10 more , Guerra-Carvalho B, Rodrigues B, Sousa D, Brandão R, Leal C, Barreiro M, Tomé A, Alves MG, Oliveira PF, Monteiro MP
Mol Cell Endocrinol · 2025 May · PMID 40185328 · Publisher ↗
Polycystic ovary syndrome (PCOS) is a prevalent endocrine disorder affecting women of reproductive age, yet the molecular mechanisms influencing its pathophysiology remain poorly defined. A comprehensive prospective case...
Polycystic ovary syndrome (PCOS) is a prevalent endocrine disorder affecting women of reproductive age, yet the molecular mechanisms influencing its pathophysiology remain poorly defined. A comprehensive prospective case-control study was conducted to elucidate the follicular fluid (FF) hormone and metabolite profile in women with PCOS and its implications for oocyte maturation and fertilization. The study involved 40 age- and body mass index (BMI)-matched women undergoing in vitro fertilization (IVF), including 20 diagnosed with PCOS and 20 controls with infertility due to tubal or male factors. A distinctive hormone profile in the FF of women with PCOS was identified, characterized by significantly higher anti-Müllerian hormone (AMH) levels (24.90 ± 17.61 vs. 16.68 ± 17.67 pmol/L, p = 0.0039) and lower progesterone (8253 ± 4748 vs. 25362 ± 10862 ng/mL, p < 0.0001) and estradiol levels (388.23 ± 210.58 vs. 651.48 ± 390.79 ng/mL, p = 0.0208) compared to normoovulatory controls. Moreover, a metabolite fingerprint associated with glycolytic and mitochondrial dysfunction was observed, as evidenced by lower lactate (4575.44 ± 1507.76 vs. 5595.34 ± 1073.32 μmol/L, p = 0.0182) and formate (64.51 ± 16.06 vs. 75.81 ± 16.63 μmol/L, p = 0.0351) levels and higher citrate levels (136.93 ± 52.53 vs. 109.15 ± 24.17 μmol/L, p = 0.0409) in the FF of women with PCOS. These findings suggest that the molecular profile of the FF in women with PCOS might be related to granulosa cell glycolytic and mitochondrial dysfunction, which can have a negative impact on oocyte fertilization potential. The study provides an integrative analysis of the FF hormone and metabolite profile in women with PCOS, offering insights into the molecular mechanisms underlying the reproductive dysfunctions associated with this condition.
Establishment of a tri co-culture model for human feto-placental steroidogenesis and investigation of the antidepressant vortioxetine.
Öztürk S, Sarac BE, Odabaş S … +2 more , Karaaslan C, Süloğlu AK
Mol Cell Endocrinol · 2025 May · PMID 40185327 · Publisher ↗
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Mass spectrometric profiling of primary estrogens and estrogen metabolites in human stool and plasma partially elucidates the role of the gut microbiome in estrogen recycling.
Li VW, Dong TS, Funes D … +8 more , Hernandez L, Kushnir NR, Nair D, Jacobs JP, Reddy ST, Mayer EA, Chang L, Meriwether D
Mol Cell Endocrinol · 2025 Jun · PMID 40180172 · Full text
Primary estrogens and estrogen metabolites are commonly measured in human plasma and serum, but there exist almost no recent reports for human stool. This knowledge gap limits our understanding of the relationships betwe...
Primary estrogens and estrogen metabolites are commonly measured in human plasma and serum, but there exist almost no recent reports for human stool. This knowledge gap limits our understanding of the relationships between systemic and gut estrogens. We developed a highly sensitive liquid chromatography-mass spectrometry/mass spectrometry (LC-MS/MS) method to determine, in human plasma and stool, the free and conjugated levels of estrone, estradiol, and estriol together with their additional hydroxyestrogen and methoxyestrogen metabolites. We investigated human stool and plasma estrogens in healthy control men; in follicular and luteal phase premenopausal women; and in postmenopausal women. Most estrogens were present in plasma and stool of all groups, while the plasma and stool levels of hydroxyestrogen and methoxyestrogen metabolites but not estrone were correlated. In stool, estrogens were higher in premenopausal women, with estrogens increasing across the menstrual cycle. We combined these LC-MS/MS measures with shotgun metagenomic sequencing of the stool microbiomes. Estrogen deconjugation enzyme gene copy numbers (β-glucuronidase and arylsulfatase) were higher in premenopausal women; while the gene copy number of β-glucuronidase + arylsulfatase, but not β-glucuronidase alone, correlated with deconjugated stool estrogens in all groups. Moreover, β-glucuronidase + arylsulfatase gene copy numbers correlated with combined plasma estrogens in men and with individual plasma estrogen metabolites in men and premenopausal women. These results support the hypothesis that gut microbial β-glucuronidase and arylsulfatase control the deconjugation of gut estrogens while modulating systemic levels through the uptake and recirculation of these deconjugated estrogens. The intestine may thus constitute an important additional compartment in estrogen physiology.
Obesity prevention by different exercise protocols (HIIT or MICT) involves beige adipocyte recruitment and improved mitochondrial dynamics in high-fat-fed mice.
Santana-Oliveira DA, Souza-Tavares H, Fernandes-da-Silva A … +4 more , Marinho TS, Silva-Veiga FM, Daleprane JB, Souza-Mello V
Mol Cell Endocrinol · 2025 May · PMID 40157711 · Publisher ↗
AIM: This study evaluated the effects of high-intensity interval training (HIIT) and moderate-intensity continuous training (MICT) on UCP1-dependent and UCP1-independent thermogenic and mitochondrial dynamics markers in...
AIM: This study evaluated the effects of high-intensity interval training (HIIT) and moderate-intensity continuous training (MICT) on UCP1-dependent and UCP1-independent thermogenic and mitochondrial dynamics markers in the inguinal sWAT of high-fat-fed mice. METHODS: Sixty male C57BL/6 mice (3 months old) were divided into six experimental groups: control diet (C), C + HIIT (C-HIIT), C + MICT (C-MICT), high-fat diet (HF), HF + HIIT (HF-HIIT) and HF + MICT (HF-MICT). The diet and exercise protocols started simultaneously and lasted ten weeks. RESULTS: HIIT and MICT prevented body mass gain and fat pad expansion, improved insulin sensitivity, and induced browning in C-fed and HF-fed animals. Chronic intake of a HF diet caused adipocyte hypertrophy with a proinflammatory adipokine profile and impaired the expression of thermogenic and mitochondrial dynamics markers. However, both exercise intensities increased anti-inflammatory adipokine concentrations and improved gene markers of mitochondrial dynamics, resulting in sustained UCP1-dependent and UCP1-independent thermogenic markers and maintenance of the beige phenotype in inguinal sWAT. The principal component analysis placed all trained groups opposite the HF group and near the C group, ensuring the effectiveness of HIIT and MICT to prevent metabolic alterations. CONCLUSIONS: This study provides reliable evidence that, regardless of intensity, exercise is a strategy to prevent obesity by reducing body fat accumulation and inducing browning. The anti-inflammatory adipokine profile and the increased expression of UCP1-dependent and UCP1-independent thermogenic markers sustained active beige adipocytes and mitochondrial enhancement to halt metabolic disturbances due to HF-feeding in exercised mice.
An endocrinological perspective on polycystic ovarian syndrome.
Basak S, Dixit AK, Dey RK … +4 more , Puia L, Bora M, Kumar Y R S, Babu G
Mol Cell Endocrinol · 2025 May · PMID 40147712 · Publisher ↗
Polycystic ovarian syndrome (PCOS) is a complex endocrinological disorder that involves dysfunctions across multiple endocrine axes, including the hypothalamic-pituitary-gonadal (HPG), hypothalamic-pituitary-adrenal (HPA...
Polycystic ovarian syndrome (PCOS) is a complex endocrinological disorder that involves dysfunctions across multiple endocrine axes, including the hypothalamic-pituitary-gonadal (HPG), hypothalamic-pituitary-adrenal (HPA) and hypothalamic-pituitary-thyroid (HPT) axes. Our review focuses on understanding the pathophysiology of PCOS through an endocrinological perspective, emphasizing the complex interactions between multiple endocrine axes. We have discussed the roles of the HPG, HPA, and HPT axes in PCOS. Dysregulation of the HPG axis, particularly the altered gonadotropin-releasing hormone pulse frequency resulting in elevated ratio of luteinizing hormone to follicle stimulating hormone, is central to the hyperandrogenism and anovulation, observed in PCOS. We have further highlighted the contributions of the HPA and HPT axes, where elevated adrenal androgen levels and hypothyroidism intensifies the phenotypes of PCOS. Additionally, insulin resistance and hyperinsulinemia, commonly associated with PCOS, aggravates hormonal disturbances and heighten the risk of metabolic complications such as type 2 diabetes and cardiovascular diseases. Elevated levels of anti-Müllerian hormone have also been emphasized as a key factor in inhibiting follicular growth, leading to impaired ovarian function and hyperandrogenism. This review further supports that PCOS is a multifactorial condition involving complex feedback mechanisms between the endocrine, metabolic, and reproductive systems. Furthermore, there remains a huge scope for deciphering the precise molecular interactions between the HPG, HPA, and HPT axes in PCOS, which could pave the way for targeted therapies for better management of both the endocrine and metabolic aspects of this disorder. This review will benefit researchers to get an endocrine perspective on PCOS.
Exploring the functional, protective, and transcriptomic effects of GIP on cytokine-exposed human pancreatic islets and EndoC-βH5 cells.
Henriksen K, Jørgensen A, Kaur S … +4 more , Gerwig R, Brøgger Svane CA, Knop FK, Størling J
Mol Cell Endocrinol · 2025 May · PMID 40122442 · Publisher ↗
Immune-mediated beta-cell destruction and lack of alpha-cell responsiveness to hypoglycaemia are hallmarks of type 1 diabetes pathology. The incretin hormone glucose-dependent insulinotropic polypeptide (GIP) may hold th...
Immune-mediated beta-cell destruction and lack of alpha-cell responsiveness to hypoglycaemia are hallmarks of type 1 diabetes pathology. The incretin hormone glucose-dependent insulinotropic polypeptide (GIP) may hold therapeutic potential for type 1 diabetes due to its insulinotropic and glucagonotropic effects, as well as its cytoprotective effects shown in rodent beta cells. To further increase our understanding of GIP's effects on human beta cells, we here examined the functional, protective, and transcriptomic effects of GIP in human EndoC-βH5 beta cells and isolated human islets in the presence or absence of proinflammatory cytokines (interferon (IFN)-γ ± interleukin (IL)-1β) as a mimic of type 1 diabetes. GIP dose-dependently augmented glucose-stimulated insulin secretion from EndoC-βH5 cells and increased insulin and glucagon secretion from human islets at high and low glucose concentrations, respectively. The insulinotropic effect of GIP in EndoC-βH5 cells was abrogated by KN-93, an inhibitor of calcium/calmodulin-dependent protein kinase 2 (CaMK2). GIP did not prevent cytokine-induced apoptosis in EndoC-βH5 cells or human islets, and GIP did not protect against cytokine-induced functional impairment in EndoC-βH5 cells. GIP treatment of human islets for 24 h had no effects on the transcriptome and did not modulate cytokine-induced transcriptional changes. However, GIP augmented IL-1β + IFNγ-induced secretion of interleukin (IL)-10 and c-c motif chemokine ligand (CCL)-2 from human islets while decreasing the secretion of c-x-c motif chemokine ligand (CXCL)-8. In EndoC-βH5 cells, GIP reduced IFN-γ-induced secretion of tumor necrosis factor (TNF)-α, IL-2, IL-6, and IL-10 but increased the secretion of CXCL8, CCL2, CCL4, and CCL11. In conclusion, our results suggest that the insulinotropic effect of GIP is CaMK2-dependent. Furthermore, our findings indicate that GIP neither exerts cytoprotective effects against cytokines nor modulate the transcriptome of human islets. GIP may, however, exert selective modulatory effects on secreted inflammatory factors from cytokine-exposed beta cells and islets.
Donepezil alleviates hepatic steatosis by mitigating ER stress via the AMPK/autophagy pathway.
Cho W, Choi SW, Lim DS … +6 more , Gwon HJ, Abd El-Aty AM, Ahmet Aydemir H, Hong SA, Jeong JH, Jung TW
Mol Cell Endocrinol · 2025 May · PMID 40118333 · Publisher ↗
Donepezil (Do), a drug known for its ability to reduce neuronal inflammation and for its use in the treatment of Alzheimer's disease, has shown promise in combating hepatic lipid accumulation in hyperlipidemic conditions...
Donepezil (Do), a drug known for its ability to reduce neuronal inflammation and for its use in the treatment of Alzheimer's disease, has shown promise in combating hepatic lipid accumulation in hyperlipidemic conditions and endoplasmic reticulum (ER) stress, a factor associated with alterations in hepatic lipid metabolism. However, the mechanisms by which these problems are alleviated have not been fully elucidated. In this study, we investigated the effects of Do on hepatic lipid metabolism through both in vitro and in vivo studies. We examined the expression of proteins associated with lipogenesis and ER stress via immunoblot analysis, and hepatic lipid accumulation was assessed via oil red O staining. In addition, autophagosome formation was analyzed by counting MDC-positive cells. Our results demonstrated that Do treatment improved hepatic lipid metabolism and reduced the expression of ER stress markers, resulting in decreased lipogenic lipid deposition and apoptosis in the hepatocytes and livers of hyperlipidemic mice. Mechanistically, knocking down AMPK or inhibiting autophagy with 3-methyladenine (3 MA) attenuated the effects of Do on palmitate-exposed hepatocytes. These results suggest that Do alleviates hepatic ER stress via the AMPK/autophagy pathway and AMPK-mediated fatty acid oxidation, resulting in improved hepatic lipid metabolism and reduced hepatic steatosis and apoptosis. Our study provides evidence that Do may be a promising therapeutic approach for Alzheimer's disease patients with metabolic dysfunction-associated steatotic liver disease (MASLD).
Sexual dimorphisms in endocrinopathies: Their impact on the evolution of metabolic diseases.
Kataki C
Mol Cell Endocrinol · 2025 May · PMID 40096881 · Publisher ↗
Sexual dimorphisms, the biological differences between males and females, are well-documented across various endocrine disorders. These dimorphisms not only influence the presentation and progression of endocrinopathies...
Sexual dimorphisms, the biological differences between males and females, are well-documented across various endocrine disorders. These dimorphisms not only influence the presentation and progression of endocrinopathies but also play a critical role in the development and evolution of metabolic diseases. This review explores the intricate relationship between sexual dimorphisms and endocrinopathies such as Diabetes Mellitus, Thyroid disorder, Cushing's syndrome, Addison's disease, polycystic ovary syndrome (PCOS), Hypogonadism in males and acromegaly, and their subsequent effects on metabolic dysfunctions like insulin resistance, obesity, and cardiovascular diseases. By examining the hormonal, genetic, and environmental factors underlying these gender-specific differences, we aim to elucidate how sexual dimorphisms contribute to the disparate prevalence, clinical outcomes, and treatment responses observed in metabolic disorders. This review highlights the significance of considering sexual dimorphisms in advancing the understanding of metabolic diseases.
cFos-mediated β-Arrestin1 in the RVLM alleviates sympathetic hyperactivity induced by ovariectomy.
Yan J, Meng Q, Hao F … +1 more , Xu M
Mol Cell Endocrinol · 2025 May · PMID 40096880 · Publisher ↗
Sympathetic hyperactivity is a key feature of cardiovascular dysfunction in postmenopausal women and is closely linked to the onset, progression, and outcomes of cardiovascular events. However, the mechanisms underlying...
Sympathetic hyperactivity is a key feature of cardiovascular dysfunction in postmenopausal women and is closely linked to the onset, progression, and outcomes of cardiovascular events. However, the mechanisms underlying sympathetic nerve hyperactivity due to menopause remain unclear. β-arrestin is a versatile class of intracellular proteins that were initially discovered for their ability to disrupt the G protein-coupled receptors (GPCRs) signaling by binding to activated receptors. A notable reduction in the expression of β-arrestin1 in the rostral ventrolateral medulla (RVLM) associated with increased sympathetic activity and elevated blood pressure (BP) in spontaneously hypertensive rats. It has been reported that the cellular oncogene fos (cFos), as a transcription factor, plays a crucial role in BP regulation. This study aimed to investigate whether β-arrestin1, regulated by cFos in the RVLM, contributes to sympathetic hyperactivity induced by menopause. Bilateral ovariectomy (OVX) was performed to establish a postmenopausal rat model. We found that the expression of β-arrestin1 in the RVLM of OVX rats was reduced, whereas estrogen supplementation increased the expression of β-arrestin1. Furthermore, overexpression of β-arrestin1 in the RVLM of OVX rats attenuated the sympathetic hyperactivity. Conversely, reducing β-arrestin1 expression in the RVLM compromised the cardioprotective effects of estrogen in OVX rats. Additionally, inhibiting the expression of the transcription factor cFos in the RVLM of OVX rats diminished the estrogen-induced increase in the expression of β-arrestin1. These findings suggest that estrogen enhances the expression of β-arrestin1 mediated by cFos in the RVLM of OVX rats, thereby alleviating sympathetic nerve hyperactivity and hypertension.
New perspectives about the article "Dual inhibition of AKT and ERK1/2 pathways restores the expression of progesterone Receptor-B in endometriotic lesions through epigenetic mechanisms".
Dutta S, Lee J, Banu SK … +1 more , Arosh JA
Mol Cell Endocrinol · 2025 May · PMID 40081755 · Publisher ↗
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Antioxidants improve the viability of diabetic bone marrow MSCs without rescuing their pro-regenerative secretome function.
Maartens M, Vlok M, van de Vyver M
Mol Cell Endocrinol · 2025 May · PMID 40057223 · Publisher ↗
Bone marrow mesenchymal stem cell (BM-MSC) dysfunction and poor viability are prominent in diabetes and limit their therapeutic efficacy. A proteomic investigation was performed to assess disease associated alterations a...
Bone marrow mesenchymal stem cell (BM-MSC) dysfunction and poor viability are prominent in diabetes and limit their therapeutic efficacy. A proteomic investigation was performed to assess disease associated alterations and the efficacy of antioxidants to rescue cellular function. BM-MSCs were isolated from obese diabetic mice (B6.Cg-Lep/J) cultured in the presence or absence of N-acetylcysteine (NAC) and ascorbic acid-2phosphate (AAP). Label free Liquid Chromatography and Mass Spectrometry (LC-MS) analysis detected 5079 proteins with 251 being differentially expressed between treatment groups. NAC/AAP improved cellular growth/viability post isolation by up-regulating proteins involved in redox status, ATP synthesis, Rho-GTPase signaling and modulated the immunophenotype of BM-MSCs. Despite a single application of the secretome not providing any advantage for wound bed regeneration in full thickness excisional diabetic wounds, the intracellular proteome illustrated the potential mechanisms of action by which NAC/AAP targeted the respiratory chain and modulated the immune phenotype of BM-MSCs. Given these observations, antioxidant supplementation might be more effective as prophylactic strategy to protect MSCs against functional decline instead of using it as a restorative agent and warrants further investigation.
Exploring different mechanisms of reactive oxygen species formation in hypoxic conditions at the hippocampal CA3 area.
Alves JL, Quinta-Ferreira RM, Quinta-Ferreira ME … +1 more , Matias CM
Mol Cell Endocrinol · 2025 May · PMID 40054836 · Publisher ↗
Hypoxia can lead to severe consequences for brain function, particularly in regions with high metabolic demands such as the hippocampus. Excessive production of reactive oxygen species (ROS) during hypoxia can initiate a...
Hypoxia can lead to severe consequences for brain function, particularly in regions with high metabolic demands such as the hippocampus. Excessive production of reactive oxygen species (ROS) during hypoxia can initiate a cascade of oxidative stress, evoking cellular damage and neuronal dysfunction. Most of the studies characterizing the formation of ROS are performed in the context of ischemia induced by oxygen-glucose deprivation, thus, the role of hypoxia in less severe conditions requires further clarification. The aim of this work was to identify the major mechanisms of ROS generation and assess flavoprotein autofluorescence changes. For ROS detection, the slices were incubated with the indicator HDCFDA, while intrinsic FAD-linked autofluorescence was recorded from indicator free slices. All signals were measured under hypoxia, at the hippocampal mossy fiber synapses of CA3 area, which were chemically stimulated using 20 mM KCl. The results suggest that ROS is formed in the mitochondria, during moderate hypoxia. The blockage of mitochondrial complexes I, III and IV with rotenone, myxothiazol and sodium azide, respectively, and of the mitochondrial calcium uniporter with Ru265, led to the abolishment of ROS changes and to an increase of FAD-linked autofluorescence (with the exception of the complexes III and IV). The blockage of the enzyme oxidases NADPH and xanthine oxidase also impaired ROS formation and rose FAD-linked autofluorescence. Thus, the blockage of any of the steps of the process of ROS formation, namely the activation of critical MRC complexes, calcium entry into the mitochondria, or enzyme oxidases activity, ceases the production of ROS.
The spleen-liver axis supports obesity-induced systemic and fatty liver inflammation via MDSC and NKT cell enrichment.
Brummer C, Singer K, Renner K … +9 more , Bruss C, Hellerbrand C, Dorn C, Reichelt-Wurm S, Gronwald W, Pukrop T, Herr W, Banas M, Kreutz M
Mol Cell Endocrinol · 2025 May · PMID 40054835 · Publisher ↗
Obesity promotes adipose tissue inflammation and leads to impaired local but also systemic immune cell homeostasis. This chronic low-grade inflammation plays a significant role in the development of obesity-associated se...
Obesity promotes adipose tissue inflammation and leads to impaired local but also systemic immune cell homeostasis. This chronic low-grade inflammation plays a significant role in the development of obesity-associated secondary diseases such as metabolic associated fatty liver disease or cancer. The spleen as the central organ of immune cell regulation is anatomically directly connected to the visceral adipose tissue and the liver via the portal vein circulation. However, the inter-organ crosstalk and linkage between obesity-induced systemic, hepatic and splenic immune cell dysregulation is not clearly outlined. In this study blood, spleen, and liver immune cells of non-obese wildtype vs. leptin deficient obese BTBR mice were isolated and analyzed in terms of leukocyte composition by flow cytometry. Significant differences between circulating, spleen- and liver-resident immune cell distribution revealed, that obesity-induced hepatic and systemic immune cell dysregulation is distinct from splenic immune cell reprogramming. Fatty liver inflammation was associated with splenic myeloid derived suppressor cell (MDSC) and natural killer T cell (NKT) enrichment whereas loss of hepatic T and B cells was not reflected by the splenic lymphocyte landscape. Correlation analysis confirmed a selective strong positive correlation between spleen and liver MDSC and NKT cell distribution indicating that the spleen-liver axis modulates obesity-induced immune dysregulation in a cell-specific manner. Similar results were observed in a diet-induced obesity mouse model. These data provide novel insights into the role of the spleen-liver axis in obesity-induced inflammation and foster the understanding of obesity-associated complications such as fatty liver disease and cancer.
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