Diabetic gastroenteropathy represents a frequent complication of diabetes mellitus, characterized by complex disturbances of gastrointestinal motility and neurochemical signaling. The neuropeptide B/W signaling system, c...Diabetic gastroenteropathy represents a frequent complication of diabetes mellitus, characterized by complex disturbances of gastrointestinal motility and neurochemical signaling. The neuropeptide B/W signaling system, consisting of neuropeptide B (NPB), neuropeptide W (NPW), and their receptors NPBWR1 and NPBWR2, has recently emerged as a potential modulator of metabolic and autonomic functions; however, its role within the gastrointestinal tract and its modulation by diabetes remains poorly understood. In this study, we systematically investigated the expression and functional relevance of the NPB/W signaling system along the gastrointestinal tract, using experimental models of type 1 and type 2 diabetes mellitus. Adult lean Zucker rats, streptozotocin-treated rats, and Zucker Diabetic Fatty rats were examined at early and advanced stages of diabetes. Gene expression was assessed in multiple gastrointestinal regions using RT-qPCR, while protein expression and localization in the colon were also analyzed by Western blot and immunofluorescence. In addition, ex vivo colonic contractility was evaluated to determine functional responses to NPB and NPW. All components of the NPB/W signaling system were detected throughout the gastrointestinal tract. Diabetes induced region-specific and stage-dependent alterations in gene expression, with more pronounced changes observed in the insulin-deficient model. Both NPB and NPW exerted concentration-dependent inhibitory effects on colonic contractility. Taken together, our findings demonstrate that the NPB/W signaling system is an integral component of gastrointestinal regulation and is differentially affected by diabetes. These alterations may contribute to impaired colonic motility observed in diabetic gastroenteropathy and highlight the NPB/W pathway as a potential target for future therapeutic interventions.
Thyroid hormones (TH) are essential regulators of energy metabolism and reproductive function. Hypothyroidism is a highly prevalent endocrine disorder and a risk factor for male infertility; however, its effects on the m...Thyroid hormones (TH) are essential regulators of energy metabolism and reproductive function. Hypothyroidism is a highly prevalent endocrine disorder and a risk factor for male infertility; however, its effects on the molecular pathways regulating testicular energy metabolism remains poorly understood. This study investigated the impact of hypothyroidism on insulin expression, insulin signaling, and glycogen regulation in the testis. Male Wistar rats were divided into control (CT) and hypothyroid (Hypo) groups, with hypothyroidism induced by methimazole (0.03%) in the drinking water for 21 days. Testicular mRNA expression of insulin and glucose transporters were evaluated by qPCR, while proteins related to insulin signaling, glucose metabolism, and glycophagy were analyzed by Western blot. Testicular insulin content was assessed by immunohistochemistry. Hypothyroidism reduced testosterone levels, decreased testicular mass, and impaired sperm parameters. It increased insulin receptor total protein levels and phosphorylation, without changes in the phospho/total ratio, while IRS-1, p-IRS1, AKT, p-AKT, and PTP-1B remained unchanged. Slc2a1 expression was upregulated and Slc2a3 downregulated, indicating adaptative changes in glucose uptake. Protein levels of AMPK, p-AMPK, GSK-3β, and p-GSK-3β remained unchanged. Increased total and phosphorylated GYS levels were observed without changes in the phospho/total ratio, suggesting potential modulation of glycogen metabolism. Although expression of the glycogen-binding protein STBD1 was increased, reduced GABARAPL1 levels suggest impaired glycophagy, consistent with unchanged testicular glycogen content observed in the hypothyroid group. Furthermore, testicular insulin expression remained unaffected. These findings suggest that hypothyroidism-induced testicular dysfunction is not primarily driven by local insulin resistance but may involve impaired glycogen mobilization via glycophagy.
Historically, the assessment of endocrine disruption has relied on fixed exposure metrics, neglecting the crucial influence of chemical kinetics on hormonal effects. This review introduces the concept of kinetic manageme...Historically, the assessment of endocrine disruption has relied on fixed exposure metrics, neglecting the crucial influence of chemical kinetics on hormonal effects. This review introduces the concept of kinetic management of endocrine disruption, focusing on how factors such as absorption, tissue partitioning, metabolism, and persistence influence the degree, timing, and extent of hormonal interference. We present emerging evidence that highlights how lipophilic accumulation in endocrine organs, the bioactivity of metabolites, and delayed internal release can create a disconnect between the external dose and its biological outcomes. By fusing pharmacokinetics with the dynamics of hormone receptors, feedback regulation, and vulnerabilities specific to different life stages, we propose a holistic framework that combines toxicology, endocrinology, and predictive modeling. This kinetic‒endocrine paradigm opens up significant opportunities for advanced risk assessment, precision in endocrine health safeguarding, and the deliberate creation of safer chemicals and therapeutic solutions.
Excessive lipid accumulation in skeletal muscle contributes to insulin resistance. Salt-inducible kinase 1 (SIK1) is known to be involved in myogenic differentiation, yet its role in lipid-induced skeletal muscle insulin...Excessive lipid accumulation in skeletal muscle contributes to insulin resistance. Salt-inducible kinase 1 (SIK1) is known to be involved in myogenic differentiation, yet its role in lipid-induced skeletal muscle insulin resistance remains unclear. Here, we identified the functional role of SIK1 in skeletal muscle insulin resistance under lipid overload and delineated the underlying signaling mechanisms. In C2C12 myotubes, palmitate markedly increased SIK1 expression and phosphorylation at Thr182, and further impaired insulin-stimulated Akt phosphorylation and glucose uptake. These effects were blocked by SIK1 knockdown or pharmacological inhibition of SIK. The palmitate-induced upregulation of SIK1 and the associated insulin signaling defects were abolished by inhibition of TGFβ receptor 1 or knockdown of Smad2/3. Moreover, genetic or pharmacological inhibition of SIK1 restored the palmitate-reduced cAMP levels in myotubes, and inhibition of PDE4 similarly rescued cAMP levels and insulin signaling, mimicking the effects of SIK1 suppression. Consistent with these in vitro findings, SIK1 and TGFβ1-Smad2/3 signaling were upregulated while cAMP levels were decreased in skeletal muscle of diet-induced obese (DIO) mice. Either SIK inhibition or blockade of TGFβ1-Smad2/3 signaling restored the impaired insulin-stimulated Akt phosphorylation in isolated skeletal muscle. Together, we demonstrate that SIK1 is upregulated under lipid overload via TGFβ1-Smad2/3 signaling, thereby triggering PDE4-dependent cAMP degradation and consequent insulin resistance in skeletal muscle. These findings establish SIK1 as a critical mediator of lipid overload-induced insulin signaling defects in skeletal muscle.
This study aimed to analyze the protective effects of Honokiol-loaded oral solid lipid nanoparticles (Honokiol-SLNs) on pancreatic beta-cells (β-cells) in an experimental model of type 1 diabetes. Streptozotocin (STZ) in...This study aimed to analyze the protective effects of Honokiol-loaded oral solid lipid nanoparticles (Honokiol-SLNs) on pancreatic beta-cells (β-cells) in an experimental model of type 1 diabetes. Streptozotocin (STZ) injection (150 mg/kg) was used to induce diabetes in male Swiss mice. Honokiol-SLNs were administered daily during the 28-day experimental phase, commencing after the onset of hyperglycemia. After the experiment, β-cell activity, apoptosis, oxidative stress, and inflammation were assessed in pancreatic tissue and blood. In vitro experiments have preliminarily validated the ability of Honokiol-SLNs to inhibit α-amylase and α-glucosidase, suggesting potential anti-diabetic effects. Furthermore, administering Honokiol-SLNs (5 mg/kg) to animals significantly reduced blood glucose levels, as well as food and water consumption, and increased body weight, serum insulin levels, and pancreatic insulin levels. Additionally, it was demonstrated that Honokiol-SLNs inhibited apoptosis by reducing the expression of cleaved caspase-3, exhibited beneficial antioxidant properties by enhancing nuclear factor erythroid 2-related factor 2 (Nrf2), and mitigated inflammation by suppressing nuclear factor kappa B (NF-κB). Honokiol-SLNs substantially reversed pancreatic histological and spectroscopic aberrations. Moreover, reduced oxido-nitrosative stress and pro-inflammatory cytokines correlated with raised antioxidant capacity. These results imply that by suppressing oxidative stress and triggering antioxidant, anti-inflammatory, and anti-apoptotic actions, Honokiol-SLNs may shield pancreatic β-cells and enhance their function.
The rising prevalence of e-cigarette use has raised concerns regarding potential adverse effects on male reproductive and endocrine health, yet its impact on testosterone regulation remains poorly defined. This narrative...The rising prevalence of e-cigarette use has raised concerns regarding potential adverse effects on male reproductive and endocrine health, yet its impact on testosterone regulation remains poorly defined. This narrative review critically synthesizes evidence from preclinical in vivo and in vitro models and from human observational studies to evaluate how e-cigarette exposure may influence testosterone homeostasis and hypothalamic pituitary gonadal axis function. Across experimental models, e-cigarette aerosols and their constituents consistently impair Leydig cell function and testosterone biosynthesis through convergent mechanisms involving oxidative stress, inflammatory signaling, mitochondrial dysfunction, epigenetic modification, and suppression of key steroidogenic enzymes. Several of these mechanisms overlap with those described for combustible cigarette exposure, whereas others, particularly those related to aerosolized solvents, flavoring agents, and device-derived metals, appear more specific to e-cigarettes. In contrast, the available human evidence is limited to cross-sectional studies and yields inconsistent findings, with the largest population-based study reporting no significant differences in circulating testosterone concentrations between e-cigarette users and non-users. Collectively, the evidence supports biological plausibility for e-cigarette-associated disruption of testosterone steroidogenesis but remains insufficient to establish causality in humans. This review therefore identifies critical methodological gaps and highlights priorities for longitudinal, biomarker-anchored human studies required to determine the clinical relevance and reversibility of e-cigarette-associated endocrine disruption.
BACKGROUND: Premature ovarian insufficiency (POI) is characterized by early loss of ovarian function, hypoestrogenism, and infertility. α-Klotho, an aging-suppressor protein, has been implicated in reproductive aging, bu...BACKGROUND: Premature ovarian insufficiency (POI) is characterized by early loss of ovarian function, hypoestrogenism, and infertility. α-Klotho, an aging-suppressor protein, has been implicated in reproductive aging, but its role in POI and ovarian steroidogenesis remains unclear. METHODS: Systemic α-Klotho KO female mice and age-matched WT were evaluated by ovarian histology, estrous cycle monitoring, serum hormone ELISA, RNA sequencing, qPCR, immunofluorescence, and western blotting to assess ovarian morphology, gonadotropin signaling, and estrogen steroidogenic pathway. α-Klotho was knocked down in KGN cells and primary human granulosa cells (hGCs). Transcriptomic and untargeted metabolomic profiling, together with qPCR, WB, and E2 ELISA tests, were used to assess steroidogenic enzyme expression and metabolic alterations. RESULTS: α-Kl-deficient female mice exhibited a POI-like phenotype, including reduced ovarian size and weight, broad follicle depletion with increased atresia, persistently diestrus estrous status (10-12 weeks), and markedly decreased serum E2. Serum LH and FSH, ovarian LHR, FSHR and early steroidogenic enzymes was also downregulated in α-Kl KO female mice. While α-Kl knockdown in KGN cells and primary hGCs caused only limited changes in key granulosa-cell steroidogenic markers and did not significantly impair FSH-stimulated E2 accumulation in androgen-supplemented hGCs cultures. KGN transcriptomic and metabolomic analyses mainly indicated inflammatory and broad metabolic reprogramming rather than robust estrogen-biosynthesis pathway disruption. CONCLUSION: α-Klotho deficiency is associated with severe in vivo ovarian steroidogenic dysfunction and a POI-like phenotype, whereas in vitro granulosa-cell α-KL knockdown shows limited direct effects on E2 steroidogenic machinery, supporting an association with HPO-axis and gonadotropin downregulation.
Cartilage endplate (CEP) degeneration is a primary cause of intervertebral disc degeneration (IVDD) and subsequent low back pain (LBP). While n-3 polyunsaturated fatty acids (PUFAs) have been confirmed to suppress inflam...Cartilage endplate (CEP) degeneration is a primary cause of intervertebral disc degeneration (IVDD) and subsequent low back pain (LBP). While n-3 polyunsaturated fatty acids (PUFAs) have been confirmed to suppress inflammation and delay IVDD, their effects and molecular mechanisms on LBP remain unclear. This study utilized C57BL/6 wild-type (WT) and fatty acid transgenic-1 (fat-1) transgenic (TG) mice to establish aged mouse model and lumbar spine instability (LSI) models. Behavioral tests revealed pronounced LBP symptoms and accelerated CEP degeneration in WT-aged and WT LSI mice. Conversely, TG mice exhibited significantly improved hypersensitivity and attenuated CEP degeneration. The elevation of endogenous n-3 PUFA substantially suppressed the elevated expression of substance P (SP) in degenerative CEPs. In vitro, IL-1β and SP established a positive feedback loop of expression in chondrocytes. n-3 PUFAs inhibited IL-1β/SP expression and release by downregulating key receptors (IL-1R1, NMDAR, and NK1R), thereby disrupting the positive feedback loop associated with IL-1 and SP and improving the CEP inflammatory microenvironment. These findings shed light on the mechanism through which n-3 PUFAs alleviate LBP by modulating neuropeptide expression in chondrocytes.
Agouti-related peptide (AgRP) and neuropeptide Y (NPY) neurons in the arcuate nucleus integrate metabolic and inflammatory signals to control food intake. FAM237B (Gm8773/NPGM) is a putative orexigenic peptide enriched i...Agouti-related peptide (AgRP) and neuropeptide Y (NPY) neurons in the arcuate nucleus integrate metabolic and inflammatory signals to control food intake. FAM237B (Gm8773/NPGM) is a putative orexigenic peptide enriched in a subset of AgRP neurons, yet misannotated as a long non-coding RNA in mice that has since been recognized as a 139 aa microprotein. Here, we combine evolutionary, transcriptomic, and physiological approaches to define FAM237B as an ancient, metabolically regulated neuropeptide within NPY/AgRP neurons. Comparative genomics and synteny analysis show that the Fam237b gene is conserved from jawless vertebrates to mammals and likely predates AgRP, with a highly conserved C-terminal region and sequence consistent with prohormone processing. Single-cell and bulk RNA sequencing reveal that Fam237b is enriched in mouse arcuate AgRP neurons and present at lower levels in the human hypothalamus. In NPY/AgRP hypothalamic cell models and in mice, Fam237b expression rises with fasting or serum withdrawal and is suppressed by insulin in parallel with Agrp. Insulin-mediated repression of Fam237b requires PI3K, but not MEK, signaling. Finally, pro-inflammatory stimuli (LPS, IL-6, and TNF-α) robustly increase Fam237b mRNA in primary hypothalamic cultures and NPY/AgRP cell models. These findings position FAM237B as an evolutionarily conserved micropeptide with a role in hypothalamic regulation of food intake and energy homeostasis, whose expression is jointly tuned by energy status, insulin signaling, and neuroinflammation.
BACKGROUND: Metabolic diseases, particularly those related to obesity and diabetes, are strongly associated with chronic oxidative stress. The hypothalamus, responsible for energy regulation, becomes susceptible to oxida...BACKGROUND: Metabolic diseases, particularly those related to obesity and diabetes, are strongly associated with chronic oxidative stress. The hypothalamus, responsible for energy regulation, becomes susceptible to oxidative damage under high-fat and high-sugar diets. Nrf2, a crucial transcription factor for antioxidant defense, plays a significant role in combating oxidative stress, but its impact on hypothalamic pathways, including tyrosine metabolism, remains unexplored. METHODS: Obese rats (DIO) were induced using a high-fat diet plus 10% (w/v) fructose-glucose syrup (F-55) in drinking water (HFHFD) and treated with ginsenoside Rg1. We performed RNA sequencing on hypothalamic tissues and conducted GO/KEGG pathway enrichment analysis to identify key differentially expressed pathways. Western blotting and BV2 cell experiments were used for gene validation. RESULTS: Rg1 intervention improved body weight gain, glucose tolerance, and significantly reduced hypothalamic oxidative stress levels in DIO rats. Transcriptome analysis showed that Rg1 significantly enriched tyrosine metabolic pathways in the hypothalamus. Further validation showed that Rg1 treatment downregulated the expression of the key enzymes Aldh3a1, Aox3, and Dct. Notably, pharmacological inhibition of Nrf2 in BV2 cells significantly attenuated the regulatory effects of Rg1 on these genes. CONCLUSION: Rg1 ameliorated HFHFD-induced metabolic impairment and was associated with reduced hypothalamic oxidative stress signaling, supporting a potential role of Nrf2-related tyrosine metabolic pathways and suggesting that peripheral Rg1 may modulate hypothalamic circuits via both direct and indirect peripheral-to-central mechanisms, with implications for managing obesity and type 2 diabetes.
BACKGROUND: White adipose tissue (WAT) is a key endocrine organ regulating lipid and glucose homeostasis. Early metabolic disturbances may disrupt its endocrine function through epigenetic mechanisms; however, how DNA me...BACKGROUND: White adipose tissue (WAT) is a key endocrine organ regulating lipid and glucose homeostasis. Early metabolic disturbances may disrupt its endocrine function through epigenetic mechanisms; however, how DNA methylation contributes to prediabetes and its reversal remains largely unexplored. OBJECTIVE: To characterize genome-wide DNA methylation changes in visceral WAT from prediabetic rats and after dietary normalization. METHODS: Male rats were fed a standard diet for 70 days and divided into 3 groups: Control (C) received tap water, Fructose (F) consumed a 10% fructose solution, and FC drank a 10% fructose solution for 21 days followed by tap water for 49 days. Plasma parameters were measured and Whole Genome Bisulfite Sequencing was performed on visceral WAT to identify differential CpG methylation, followed by pathway enrichment and network analyses. RT-qPCR was used to evaluate gene expression. RESULTS: Fructose intake induced a prediabetic phenotype, which was reversed by dietary normalization. In visceral WAT, 1151 differentially methylated CpG sites were identified and 330 genes enriched in oxidative phosphorylation and thermogenesis, key regulators of adipocyte endocrine and mitochondrial function. A stringent analysis showed a subset of CpG sites associated with Kdm4c, Ces1f, and Uxs1, whose expression was modified, suggesting functional implications for endocrine regulation of adipocyte metabolism. Notably, several methylation alterations persisted despite metabolic recovery, indicating incomplete epigenetic reversal. CONCLUSIONS: Fructose-induced prediabetes produces DNA methylation changes in visceral white adipose tissue. Despite normalization of plasma parameters in the FC group, several epigenetic alterations persisted, highlighting their potential role in early metabolic disturbances leading to T2D.
Bone homeostasis is strongly influenced by adipose tissue, since both cell types coexist in the bone marrow and communicate through soluble mediators. This interaction may create an osteo-adipogenic imbalance that favors...Bone homeostasis is strongly influenced by adipose tissue, since both cell types coexist in the bone marrow and communicate through soluble mediators. This interaction may create an osteo-adipogenic imbalance that favors adipogenesis over osteogenesis, contributing to conditions such as osteoporosis, often associated with increased marrow adiposity. In this study, we examined the effects of adipocyte-conditioned medium (CM) on osteoblasts. Although CM did not induce cytotoxicity and even increased cell viability, it markedly impaired osteoblastic function. CM-treated cells showed an absence of calcium deposition and significantly reduced alkaline phosphatase (ALP) activity, indicating a blockade in differentiation. Proteomic analysis revealed downregulation of key extracellular matrix proteins, including fibronectin, asporin, and periostin, which are essential for matrix organization and mineralization. Conversely, proteins related to inflammation and oxidative stress, such as GAPDH, vimentin, and the acidic 60S ribosomal protein, were upregulated. STRING network analysis identified clusters enriched in stress response, protein folding, and cytoskeletal remodeling, while matrix-associated proteins appeared fragmented and underrepresented. Long exposure to late CM showed further enrichment of ribosomal and translational proteins, suggesting a shift toward stress adaptation rather than matrix production. Hemoglobin overexpression and reduced histone isoforms indicated NF-κB activation, oxidative stress, and adverse epigenetic alterations. Overall, these findings indicate that the adipocyte secretome creates a microenvironment detrimental to osteoblast differentiation, marked by impaired mineralization, inflammatory signaling, oxidative stress, and cytoskeletal and epigenetic dysfunction. These insights highlight potential molecular pathways that may be targeted to restore osteogenesis under pathological conditions.
Brown and beige adipose tissues, which contain high levels of mitochondria and UCP1, are crucial for energy expenditure and metabolic homeostasis. Previous studies have established that G protein-coupled receptors (GPCRs...Brown and beige adipose tissues, which contain high levels of mitochondria and UCP1, are crucial for energy expenditure and metabolic homeostasis. Previous studies have established that G protein-coupled receptors (GPCRs) play a critical role in mediating adaptive thermogenesis and browning. While the β3-adrenoceptor (β3-AR) serves as the key β-adrenergic GPCR driving adipose thermogenesis in mice, its minimal presence in human adipocytes hinders its therapeutic application. This study identifies adhesion G protein-coupled receptor L4 (ADGRL4) as a potential GPCR target for inducing adipose browning. In vitro experiments demonstrated that ADGRL4 activation promotes beige adipocyte differentiation, significantly upregulates UCP1 expression, and reduces lipid droplet accumulation. In vivo, ADGRL4 activation induces the development of beige fat in mice fed a normal chow diet without causing systemic effects. In mice fed a high-fat diet, ADGRL4 activation reduces fat deposition, decreases body weight, alleviates glucose intolerance, and ameliorated obesity and associated metabolic dysfunction. Furthermore, mechanistic investigations revealed that ADGRL4 specifically enhances AKT phosphorylation without altering total AKT levels, thereby activating a downstream signaling cascade that elevates UCP1 expression. This coordinated regulation through the p-AKT/UCP1 axis substantiates the role of ADGRL4 in driving adipose browning and identifies it as a promising molecular target for the treatment of obesity and associated metabolic disorders.
To analyze the effects of hyperandrogenemia (HA) in polycystic ovary syndrome (PCOS) on negative and positive regulators of endometrial receptivity. Fifty-four women with PCOS undergoing total embryo freezing were classi...To analyze the effects of hyperandrogenemia (HA) in polycystic ovary syndrome (PCOS) on negative and positive regulators of endometrial receptivity. Fifty-four women with PCOS undergoing total embryo freezing were classified into four phenotypes: classical type A, classical type B, ovulatory type C, and normoandrogenic type D. Hyperandrogenemia was present in phenotypes A-C and absent in phenotype D. Twenty-five age-matched infertile women without clinical or biochemical features of PCOS served as controls. Endometrial sampling was performed on day five after oocyte retrieval. Relative PCX mRNA and protein levels, together with HOXA10 and HOXA11 mRNA expression, were evaluated. Immunohistochemical analysis was performed to assess the spatial distribution of PCX, and H-score values were compared between the PCOS and control groups. PCX mRNA expression and protein concentration were significantly higher in the PCOS group compared with controls (all p < 0.001), consistent with the significantly higher H-score values observed in the PCOS group (p < 0.001). In contrast, HOXA10 and HOXA11 mRNA expression levels were significantly reduced in PCOS patients (all p < 0.001). Among PCOS phenotypes, those associated with hyperandrogenemia exhibited significantly lower HOXA10 and HOXA11 expression than the normoandrogenic phenotype (all p < 0.005). PCX mRNA and protein levels were significantly higher in classical and ovulatory hyperandrogenic phenotypes compared with the normoandrogenic group (all p < 0.005). PCX was identified as a negative predictor of HOXA10 and HOXA11 expression, while testosterone negatively predicted HOXA10 and HOXA11. Insulin resistance and testosterone were positive predictors of PCX expression, whereas progesterone levels on the day of oocyte retrieval and on day five after retrieval were negative predictors of PCX expression. Hyperandrogenemia disrupts the physiological mid-luteal downregulation of PCX and the upregulation of HOXA10 and HOXA11, leading to impaired endometrial receptivity and displacement of the implantation window in PCOS.
Excessive intake of saturated fatty acids, particularly during adolescence, a critical growth period, disrupts metabolic processes in the body. GeneCards has linked palmitic acid (PA), a major saturated fatty acid, to li...Excessive intake of saturated fatty acids, particularly during adolescence, a critical growth period, disrupts metabolic processes in the body. GeneCards has linked palmitic acid (PA), a major saturated fatty acid, to lipotoxicity. We demonstrated that PA intake impairs the function of bone-forming cells by suppressing cellular defense against oxidative markers, leading to apoptosis and increased ER stress. Excess PA dysregulates glucose homeostasis by altering GLUT4 (insulin-regulated glucose transporter) and compromising skeletal health. In contrast, Withaferin A (WFA), an electrophilic steroidal lactone containing an α,β-unsaturated carbonyl moiety, counteracts palmitic acid-induced oxidative stress by limiting excessive reactive oxygen species generation, restoring redox potential, improving insulin signalling, and secondarily reactivating the Wnt/β-catenin mediated osteogenesis. Lipotoxic conditions were emulated in in vivo growing (adolescent) C57BL/6J mice after palmitic acid (PA) administration for 15 days. Subsequent GC-MS analysis of the serum revealed significant alterations in the metabolic profiles of fatty acids. PA results in compromised bone volume/tissue volume due to a deteriorated bone microarchitecture. This reduces bone mineral density (BMD) and impairs mechanical properties, indicating weakened bones. These data were corroborated by a significant decrease in the levels of serum biomarkers, such as P1NP, osteocalcin, and insulin. Our findings highlight the detrimental effects of PA overload during the window of rapid skeletal growth, leading to lipid accumulation and negatively impacting bone modeling.
Nakamura M, Nakai K, Tsujinaka-Sawai E
… +16 more, Kurose R, Tanaka H, Umehara M, Sawai S, Yamamoto S, Minamida A, Yamauchi-Sawada H, Sunahara Y, Matoba Y, Nakamura I, Yamashita N, Kamezaki M, Kirita Y, Tamagaki K, Matoba S, Kusaba T
INTRODUCTION: Streptozotocin (STZ) is transported into pancreatic β-cells and renal proximal tubular epithelial cells via GLUT2, where it induces DNA damage. Although repeated low-dose (RLD) STZ administration is widely...INTRODUCTION: Streptozotocin (STZ) is transported into pancreatic β-cells and renal proximal tubular epithelial cells via GLUT2, where it induces DNA damage. Although repeated low-dose (RLD) STZ administration is widely used to induce diabetes while minimizing toxicity, its renal effects remain underexplored. AIM: To determine whether RLD STZ causes proximal tubular injury and whether sodium-glucose cotransporter 2 (SGLT2) inhibition mitigates such damage. METHODOLOGY: Male mice received a single high dose (150 mg/kg) or RLD STZ (50 mg/kg/day for five days). Some mice were pretreated with an SGLT2 inhibitor. Renal and pancreatic tissues were analyzed for DNA damage, tubular injury, and membrane transporter expression. RESULTS: Both regimens induced DNA damage in renal proximal tubules and pancreatic islets, reducing the expression of tubular membrane transporters. SGLT2 inhibitor pretreatment attenuated tubular injury under the RLD regimen but did not affect islet DNA damage or diabetes incidence. Nevertheless, transporter expression in proximal tubules was preserved. CONCLUSION: Both single high dose and RLD STZ administration induces proximal tubular injury and subsequent reduction of membrane transporter expression. SGLT2 inhibitor pretreatment mitigates latent STZ-induced tubular injury but does not influence diabetes onset. The interpretation of results on type 1 diabetic nephropathy using RLD STZ administration should consider the potential presence of tubular epithelial cell injury.