Molecular and Cellular Endocrinology最新文献

{"title":"Developmental programming: gestational exposure to excess testosterone disrupts maternal steroid homeostasis and perturbs the steroid-lipid relationship in sheep","authors":"Nadia Saadat ,&nbsp;Rehma Saeed ,&nbsp;Brooke Pallas ,&nbsp;Arpita K. Vyas ,&nbsp;Richard J. Auchus ,&nbsp;Vasantha Padmanabhan","doi":"10.1016/j.mce.2025.112706","DOIUrl":"10.1016/j.mce.2025.112706","url":null,"abstract":"<div><div>Gestational hyperandrogenism may disrupt the steroid and lipid metabolism homeostatic balance that is important for pregnancy progression. We hypothesized that excess gestational testosterone would disrupt the maternal steroid profile and the steroid-lipid relationship. Using sheep, we investigated maternal delta-4 (Δ4) and delta-5 (Δ5) steroids and the steroid-lipidome relationship in gestational testosterone excess (n = 12, 100 mg T-propionate days 30–90 of gestation twice-weekly intramuscularly) and control (n = 5, vehicle) Suffolk sheep. Steroids were measured using liquid chromatography-tandem mass spectrometry and lipids by shotgun lipidomics. Principal component analysis showed clear separation of control and the gestational testosterone excess groups. The main impact of testosterone excess was on the Δ5 pathway, with reductions in 17-OH pregnenolone, androstenediol, allopregnanolone, and androsterone. In the Δ4 pathway only a trend for reduced androstenedione and a large magnitude increase in corticosterone and decrease in 11-deoxycorticosterone was observed. Dimensionality reduction partial least squares regression models revealed disruptive impact of testosterone-excess on the steroid-lipid relationship prevailing in controls namely with lipid biosynthesis and metabolism and enrichment in cholesterol biosynthetic, circadian clock and transcriptional regulatory, and liver steatosis pathways. Disrupted steroid-lipid associations in the gestational testosterone excess group showed linkage to complex disease-profiles centering on lipid metabolism and transport, cholesterol, and of relevance to hyperlipidemia, gestational diabetes, and hypertension in the enrichment analysis. Fewer lipid species were associated with individual steroids in gestational testosterone excess group, indicative of loss of the majority of the homeostatic steroid-lipid associations. This study provides a novel screening insight into the steroid-lipid relationship that prevails during normal pregnancy and the disruptive impact of hyperandrogenism in perturbing this homeostasis.</div></div>","PeriodicalId":18707,"journal":{"name":"Molecular and Cellular Endocrinology","volume":"613 ","pages":"Article 112706"},"PeriodicalIF":3.6,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145636099","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Role of FKBP5 in adipose tissue function: Implications for obesity and insulin sensitivity","authors":"Rutger Laterveer ,&nbsp;Susanne Hetty ,&nbsp;Argyri Mathioudaki ,&nbsp;Martin H. Lundqvist ,&nbsp;Maria K. Svensson ,&nbsp;Magnus Sundbom ,&nbsp;Petros Katsogiannos ,&nbsp;Jan W. Eriksson ,&nbsp;Maria J. Pereira","doi":"10.1016/j.mce.2025.112718","DOIUrl":"10.1016/j.mce.2025.112718","url":null,"abstract":"<div><div>FK506-binding protein 51 (FKBP51, encoded by the <em>FKBP5</em> gene) is a key regulator of glucocorticoid signaling and has been implicated in metabolism and insulin sensitivity, but its specific role in human adipose tissue remains unclear. This study investigated the role of FKBP51 in human adipose tissue and its impact on glucose metabolism and insulin signaling. <em>FKBP5</em> was measured in paired subcutaneous (SAT) and omental (OAT) adipose tissue samples from 56 subjects with and without obesity, and in SAT from individuals with obesity during weight loss up to 104 weeks post-bariatric surgery. Furthermore, FKBP51 knockdown adipocytes were used to study its effects on insulin signaling and glucose uptake. <em>FKBP5</em> gene expression, but not protein expression, was significantly lower in obese individuals in both SAT and OAT compared to lean and overweight subjects, and it inversely correlated with insulin resistance measured by homeostatic model assessment of insulin resistance (HOMA-IR). After bariatric surgery, <em>FKBP5</em> expression in SAT increased to levels similar to those in non-obese controls. Knockdown of <em>FKBP5</em> in human adipocytes reduced <em>GLUT1</em> gene expression and insulin-stimulated AKT Ser473 phosphorylation, however, maximal insulin-stimulated glucose uptake rate remained unchanged. Our findings suggest that <em>FKBP5</em> levels in adipose tissue are reduced in obesity, and this decrease impairs insulin signaling in adipocytes without altering maximal glucose capacity, indicating a limited effect on glucose uptake under the tested conditions.</div></div>","PeriodicalId":18707,"journal":{"name":"Molecular and Cellular Endocrinology","volume":"613 ","pages":"Article 112718"},"PeriodicalIF":3.6,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145763113","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The in vivo metabolism of 11-oxyandrogens and 11-oxyprogesterones: novel pathways in the steroid metabolome","authors":"Amanda Cecilia Swart ,&nbsp;Bianca Heyns ,&nbsp;Martin Kidd ,&nbsp;Rialet Pieters ,&nbsp;Stephen Lawrence Atkin","doi":"10.1016/j.mce.2025.112719","DOIUrl":"10.1016/j.mce.2025.112719","url":null,"abstract":"<div><div>The steroid metabolome remains incomplete as the metabolic pathways of the 11-oxyprogestogens and 11-oxyandrogens, biosynthesized in the adrenal and converted in the periphery, have never been characterized <em>in vivo</em>.</div><div>This study aims to identify these 11-oxy steroids in the human hair follicle. Hair segments provide a matrix representing one month of steroid production, unaffected by the circadian rhythm. Steroids were extracted from 37 segments using a novel automated method, and 52 steroids were analyzed using ultra-performance convergence chromatography-tandem mass spectrometry.</div><div>Quantification of intermediates and end-products of 11-hydroxyprogesterone, 21-deoxycortisol, 11-hydroxyandrostenedione and 11-hydroxytestosterone identified nine novel 11-oxy steroids and showed: 11-hydroxyprogesterone metabolites &gt;21-deoxycortisol metabolites: 170–1400 v. 190–540 pg/mg; 11-oxyandrogens &gt; classical androgens: 600–1500 v. 110–350 pg/mg; active 11-oxyandrogens &gt; active classical androgens: in females, 36.5 v. 1.3 pg/mg, and in males, 60.75 v. 11.7 pg/mg. The most abundant active androgen in both genders was 11-hydroxydihydrotestosterone; 11-ketodihydrotestosterone was detected in males only; 11-hydroxytestosterone levels were comparable, and 11-ketotestosterone levels were higher in males. The most abundant 11-oxyprogestogens in both genders were 11-ketoprogesterone (55.7–2173.8 pg/mg) and two metabolites, 11-oxo-17-hydroxyallopregnanolone (11KPdione) and 11,17-dihydroxyallopregnanolone (11OHPdiol). Metabolites included the neurosteroid, alfaxalone (11-ketoallopregnanolone), and another potential neurosteroid 11-hydroxyallopregnanolone.</div><div>This is the first targeted study profiling the 11-oxyandrogens and the 11-oxyprogestogens and their respective metabolites in humans. Novel <em>in vivo</em> steroidogenic pathways have been confirmed, not necessarily linked to clinical conditions, having utility in clinical diagnostics reliant on the steroid metabolome.</div></div>","PeriodicalId":18707,"journal":{"name":"Molecular and Cellular Endocrinology","volume":"613 ","pages":"Article 112719"},"PeriodicalIF":3.6,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145756948","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Role of visfatin on early embryogenesis in normal weight and obese mice. Studies on siRNA induced knockdown model","authors":"Patrycja Kurowska ,&nbsp;Shinnosuke Honda ,&nbsp;Genta Tanaka ,&nbsp;Gao Yuwei ,&nbsp;Naojiro Minami ,&nbsp;Agnieszka Rak ,&nbsp;Shuntaro Ikeda","doi":"10.1016/j.mce.2025.112702","DOIUrl":"10.1016/j.mce.2025.112702","url":null,"abstract":"<div><div>Visfatin/Nampt, an adipokine upregulated in obesity, has been implicated in oocyte maturation, but its role in early embryogenesis remains poorly understood. This study investigated visfatin/Nampt function during preimplantation development in normal-weight and high-fat diet–induced obese mice.</div><div><em>Nampt</em> mRNA expression was examined in embryos from the 1-cell to the blastocyst stage, and siRNA-mediated <em>Nampt</em> silencing was performed at the 1-cell stage. Embryo development was assessed by cleavage and blastocyst formation rates, while molecular effects were evaluated via qPCR analysis of maternal-effect and proliferation/apoptosis, differentiation genes, immunofluorescence detection of pluripotency/differentiation markers, and transcriptome profiling (RNA-seq). The functional reproductive outcomes, including implantation rates, offspring number, and ovarian gene expression (qPCR) in the progeny, were also analyzed.</div><div><em>Nampt</em> expression decreases during early embryogenesis. <em>Nampt</em> silencing impaired blastocyst formation in obese mice and altered lineage marker expression, increasing NANOG in normal-weight embryos and reducing GATA6-positive cells in obese embryos. Transcriptomic analysis of normal-weight blastocysts revealed 73 upregulated and 24 downregulated genes enriched in pathways regulating apoptosis, energy metabolism, and development. Although the implantation rates and offspring numbers were unchanged, offspring from <em>Nampt</em>-silenced embryos presented altered ovarian gene expression linked to steroidogenesis and oogenesis.</div><div>This work provides the first transcriptomic analysis of blastocysts following siRNA-mediated <em>Nampt</em> silencing and demonstrates that visfatin/Nampt modulates early lineage allocation in a manner dependent on maternal metabolic status. These findings extend visfatin research beyond oocyte maturation and highlight its potential contribution to embryonic programming.</div></div>","PeriodicalId":18707,"journal":{"name":"Molecular and Cellular Endocrinology","volume":"612 ","pages":"Article 112702"},"PeriodicalIF":3.6,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145530784","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Brain derived neurotrophic factor promotes oocyte maturation through the TrkB-MAPK-PI3K pathway in zebrafish","authors":"Chinelo Uju,&nbsp;Suraj Unniappan","doi":"10.1016/j.mce.2025.112703","DOIUrl":"10.1016/j.mce.2025.112703","url":null,"abstract":"<div><div>Brain-derived neurotrophic factor (BDNF) was previously reported as a positive modulator of zebrafish reproduction, yet the mechanism of action of BDNF that elicits this function is unknown. We hypothesized that the pro-reproductive effects of BDNF in female zebrafish are mediated by TrkB signaling. In zebrafish liver (ZFL) cells, a TrkB antagonist (ANA-12) blocked the stimulatory effect of BDNF on transcript abundance of vitellogenin <em>(vtg1</em>, <em>2</em>, <em>4</em>, and <em>7)</em> and <em>steroidogenic factor 1</em> (<em>sf-1</em>). No changes were observed in hepatocyte nuclear factor 4 alpha, specificity protein 1, cAMP response element-binding protein 1a, or forkhead box L2. Blocking the mitogen-activated protein kinase (MAPK), phosphatidylinositol 3-kinase (PI3K), and phospholipase C gamma (PLC-γ) pathways significantly attenuated BDNF-induced upregulation of <em>vtg</em> and <em>sf-1</em> transcripts. Total vtg protein was increased by BDNF, an effect that was blunted when TrkB, MAPK, PI3K, or PLC-γ were blocked. The estrogen receptor alpha (Esrα) fluorescence immunoreactivity in the ZFL cells treated with BDNF was significantly reduced in the presence of ANA-12. In the zebrafish follicles, BDNF-induced oocyte maturation was attenuated by TrkB, MAPK-, and PI3K inhibitors, but not a PLC-γ blocker. Similarly, the positive effects of BDNF on maturation-related genes 3β-hydroxysteroid dehydrogenase 2 enzyme (<em>3bhsd2</em>), cytochrome P450 family 17, hyaluronan synthase 2, luteinizing hormone receptor, and prostaglandin synthase 2 were significantly attenuated when TrkB, MAPK, or PI3K was blocked. PLC-γ inhibition prevented the BDNF-induced upregulation of <em>3bhsd1</em> in the oocytes. This study demonstrates that BDNF promotes vitellogenesis via the TrkB-MAPK/PI3K/PLC-γ signaling pathways. Meanwhile, BNDF enhances oocyte maturation through the TrkB-MAPK/PI3K pathways in zebrafish.</div></div>","PeriodicalId":18707,"journal":{"name":"Molecular and Cellular Endocrinology","volume":"612 ","pages":"Article 112703"},"PeriodicalIF":3.6,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145541334","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"In vitro activation of brown adipocyte thermogenesis by fermented hypholomine B-enriched Sanghuangporus sanghuang mycelia through FNDC5/Irisin pathway","authors":"I-Chen Li ,&nbsp;Yu-En Chan ,&nbsp;Yu-Li Lin ,&nbsp;Tzong-Yuan Wu ,&nbsp;Liang-Yi Wu ,&nbsp;Ching-Yi Tsai ,&nbsp;Hsin-Tang Lin ,&nbsp;Chin-Chu Chen","doi":"10.1016/j.mce.2025.112705","DOIUrl":"10.1016/j.mce.2025.112705","url":null,"abstract":"<div><div>In the face of the global obesity epidemic (globesity), we present the first comprehensive investigation of fermented <em>Sanghuangporus sanghuang</em> mycelia extract (SS-IM1) and its novel bioactive compound hypholomine B in brown adipose tissue activation. Using HEK293 cells with FNDC5 promoter-EGFP constructs and differentiated 3T3-L1 adipocytes, we demonstrate that both compounds significantly enhance FNDC5 expression and irisin secretion. We reveal distinct mechanistic profiles: SS-IM1 showed superior efficacy in irisin induction and thermogenesis activation, while isolated hypholomine B demonstrated unprecedented potency in reducing lipid accumulation. Seahorse analysis revealed enhanced mitochondrial respiration and UCP1-mediated proton leak, confirming their thermogenic effects. Furthermore, we discovered that SS-IM1 uniquely enhanced glucose uptake through GLUT4 upregulation. These findings not only elucidate novel molecular mechanisms underlying the anti-obesity effects of <em>S. sanghuang</em> but also establish hypholomine B as a promising first-in-class therapeutic candidate for addressing the worldwide challenges of obesity and metabolic disorders.</div></div>","PeriodicalId":18707,"journal":{"name":"Molecular and Cellular Endocrinology","volume":"612 ","pages":"Article 112705"},"PeriodicalIF":3.6,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145596771","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Androgen deprivation induces distinct muscle-specific transcriptional changes to genes regulating glucose, lipid, and amino acid metabolism","authors":"Wayne A. Ayers-Creech ,&nbsp;Jennifer L. Steiner ,&nbsp;Grant R. Laskin ,&nbsp;Bradley S. Gordon","doi":"10.1016/j.mce.2025.112704","DOIUrl":"10.1016/j.mce.2025.112704","url":null,"abstract":"<div><h3>Background</h3><div>Androgens such as testosterone regulate whole-body metabolic homeostasis. Low androgen levels lead to undesirable shifts in metabolism including lower glucose oxidation, greater lipid reliance, and altered amino acid metabolism. Skeletal muscle is a primary site regulating fuel substrate metabolism, but whether all muscles contribute to the undesirable metabolic shifts in response to low androgen levels is unclear.</div></div><div><h3>Methods and results</h3><div>Male mice underwent sham or castration surgery and muscles were harvested 7, 14-, 21-, 28-, or 49-days post-surgery. The content of genes related to glucose, lipid, and amino acid metabolism were assessed in the tibialis anterior (TA) and gastrocnemius muscles. The content of genes related to glucose metabolism were altered in a manner consistent with lower rates of oxidation in both the TA and gastrocnemius following castration although the magnitudes of change were generally more pronounced in the TA. Genes related to lipid oxidation were altered in a manner consistent with higher oxidation rates only in the TA following castration. Genes related to amino acid catabolism were paradoxically unaltered or even lower in both muscles in response to castration.</div></div><div><h3>Conclusion</h3><div>These findings indicate that the TA undergoes more pronounced transcriptional changes related to glucose and lipid metabolism compared to the gastrocnemius, likely contributing more to whole-body metabolic shifts during androgen deprivation.</div></div>","PeriodicalId":18707,"journal":{"name":"Molecular and Cellular Endocrinology","volume":"612 ","pages":"Article 112704"},"PeriodicalIF":3.6,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145577833","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Serotonin promotes aggressive features in breast cancer cells by modulating proliferation and migration, hormone receptors and HER2 expression","authors":"Larissa Pereira Paixão ,&nbsp;José Xavier do Nascimento Junior ,&nbsp;Maria Eduarda Sant'Ana Faria Do Espírito Santo ,&nbsp;Ricardo Imbroisi Filho ,&nbsp;João Gabriel Bernardo Leandro ,&nbsp;Davi Mundim ,&nbsp;Jessica Ristow Branco ,&nbsp;Luis Eduardo Santos ,&nbsp;Sérgio T. Ferreira ,&nbsp;Luciana Pizzatti ,&nbsp;Mauro Sola-Penna ,&nbsp;Patricia Zancan","doi":"10.1016/j.mce.2025.112692","DOIUrl":"10.1016/j.mce.2025.112692","url":null,"abstract":"<div><div>Serotonin (5-HT), a key regulator of epithelial homeostasis, plays a paradoxical role in breast cancer progression. This study investigates the impact of 5-HT signaling on hormone receptor expression, cell proliferation, therapeutic response, and tumor aggressiveness in breast cancer cells. We demonstrate that 5-HT activates transcriptional factors in MCF-7 cells, collectively enhancing cancer hallmarks such as sustained proliferation and invasiveness. Notably, 5-HT downregulates mRNA expression of estrogen receptor (ER), progesterone receptor (PR), and HER2, inducing a phenotype reminiscent of triple-negative breast cancer. Despite these phenotypic changes, acute 5-HT treatment does not impair the effectiveness of tamoxifen <em>in vitro</em>. <em>In vivo</em>, administration of fluoxetine, a selective serotonin reuptake inhibitor, accelerates tumor growth and increases malignancy in a murine model. These findings underscore the ability of 5-HT to reprogram hormone receptors expression profiles and to promote a more aggressive cancer phenotype.</div></div>","PeriodicalId":18707,"journal":{"name":"Molecular and Cellular Endocrinology","volume":"612 ","pages":"Article 112692"},"PeriodicalIF":3.6,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145431855","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Interrelationship between alcohol consumption, overnutrition, and pharmacotherapy for liver steatosis: Considerations and proposals","authors":"Rodrigo Valenzuela ,&nbsp;Camila Farías ,&nbsp;Yasna Muñoz ,&nbsp;Jessica Zúñiga-Hernández ,&nbsp;Luis A. Videla","doi":"10.1016/j.mce.2025.112676","DOIUrl":"10.1016/j.mce.2025.112676","url":null,"abstract":"<div><div>Alcoholism and overnutrition both contribute to the development of hepatic steatosis in humans. In alcoholic liver disease, steatosis is driven by (i) alcohol oxidation via alcohol dehydrogenase (ADH), which increases the NADH/NAD⁺ ratio, and (ii) induction of cytochrome P450 2E1 (CYP2E1), which elevates oxidative stress. Both pathways generate toxic acetaldehyde. Overnutrition is characterized by excessive energy intake, high consumption of refined carbohydrates and saturated fatty acids (FAs), and low intake of dietary fiber, fruits, vegetables, and n-3 polyunsaturated fatty acids (n-3 PUFAs). The increased NADH/NAD⁺ ratio inhibits the Krebs cycle and FA β-oxidation, redirecting acetyl-CoA toward <em>de novo</em> lipogenesis. This process is mainly regulated by insulin-mediated activation of sterol regulatory element-binding protein-1c (SREBP-1c) and suppression of peroxisome proliferator-activated receptor-α (PPAR-α) related to n-3 PUFA depletion, which further impairs FA β-oxidation and upregulates citrate carrier expression, promoting lipogenesis. Chronic exposure to either alcohol or overnutrition independently promotes steatosis; however, co-exposure significantly exacerbates the condition, as shown in emerging preclinical studies. In humans, the relationship remains complex and inconsistent. Several anti-steatotic agents have been explored, including n-3 PUFAs, vitamins (E, C, D), polyphenols (curcumin, resveratrol, anthocyanins), anti-craving medications (disulfiram, naltrexone, nalmefene, acamprosate), and appetite suppressants (e.g., topiramate), as well as combination therapies such as naltrexone with bupropion. Despite the range of available interventions, inconsistent outcomes in past clinical trials hinder the establishment of standardized protocols. This underscores the urgent need to investigate synergistic effects of combined risk factors to better guide therapeutic strategies for hepatic steatosis prevention and reversal, and inform the health professionals on these aspects.</div></div>","PeriodicalId":18707,"journal":{"name":"Molecular and Cellular Endocrinology","volume":"611 ","pages":"Article 112676"},"PeriodicalIF":3.6,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145274950","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Aerobic exercise attenuates intramyocellular lipid accumulation by upregulating vitamin D receptor","authors":"Ke Wang ,&nbsp;Jing-Hua Zhang ,&nbsp;Xiao-Ning Cui ,&nbsp;Yan-Jun Niu ,&nbsp;Jing-Jing Liu ,&nbsp;Shi-Qi Lu ,&nbsp;Xiao-Mei Liu ,&nbsp;Zheng Zhu ,&nbsp;Zhen-Bo Cao","doi":"10.1016/j.mce.2025.112677","DOIUrl":"10.1016/j.mce.2025.112677","url":null,"abstract":"<div><div>Vitamin D deficiency is a global public health problem associated with intramyocellular lipid (IMCL) accumulation, leading to insulin resistance. Aerobic exercise improves lipid metabolism, insulin sensitivity, and vitamin D levels. However, the mechanism by which aerobic exercise regulates IMCL remains unclear. C57BL/6J male mice were randomly divided into four groups: control (CON), vitamin D-deficient (VDD), control exercise, and vitamin D-deficient exercise (VDDE). Moreover, we generated skeletal muscle-specific vitamin D receptor (VDR)-knockout (mVDR^−/−) mice and classified them into four groups: VDR^flox/flox control (FC); mVDR^−/−; exercise and VDR^flox/flox control; and exercise and mVDR^−/− (emVDR^−/−). All exercise mice underwent a 12-week aerobic exercise program on a treadmill at speeds progressively increasing from 10 to 17 m/min. The VDD group mice exhibited decreased VDR expression, lipolysis factors (ATGL and Hormone-sensitive lipase (HSL)), and fatty acid oxidation (SIRT1 and PGC1α), and increased expression of lipid synthesis factors (DGAT1 and FATP1) compared with the CON group. Conversely, the VDDE group mice showed a significant increase in VDR, ATGL, HSL, SIRT1 and PGC1α expression, alongside a decrease in DGAT1, DGAT2, FATP1 and CD36 expression compared with the VDD group. Moreover, mVDR^−/− mice exhibited impaired lipid metabolism (FATP1, CD36, SREBP1C, DGAT1, DGAT2 and ATGL) and fatty acid oxidation (SIRT1 and PGC1α) compared with the FC group mice. However, emVDR^−/− mice did not show improved lipid metabolism or fatty acid oxidation related factors compared with mVDR^−/− mice. Therefore, aerobic exercise attenuates IMCL accumulation may by upregulating VDR associated with restored SIRT1/PGC1α signaling mediated lipid metabolism in skeletal muscle.</div></div>","PeriodicalId":18707,"journal":{"name":"Molecular and Cellular Endocrinology","volume":"611 ","pages":"Article 112677"},"PeriodicalIF":3.6,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145274997","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}