Search Results (160)

Homeodomain-interacting protein kinase 2 (HIPK2) is an important regulator of various transcription factors and cofactors, which are involved in cell growth, cell death, and embryonic development. Previously, it has been reported that HIPK2 is upregulated during white fat development. However, the expression and functional role of HIPK2 during adipogenesis remain unclear. Here, we investigated the expression and biological function of HIPK2 during the adipogenesis of 3T3-L1 cells. Importantly, protein and mRNA expression of HIPK2 were significantly upregulated in a time-dependent manner during 3T3-L1 preadipocyte differentiation. Notably, distinct pharmacological inhibitors revealed the pivotal roles of p38 MAPK and PKC in the induction of HIPK2 expression during differentiation of 3T3-L1 cells. Moreover, knockdown of HIPK2 significantly reduced lipid storage and triglyceride (TG) levels without cytotoxicity during 3T3-L1 preadipocyte differentiation. At the mechanistic level, HIPK2 knockdown reduced the expression of CCAAT/enhancer-binding protein-α (C/EBP-α), peroxisome proliferator-activated receptor-γ (PPAR-γ), fatty acid synthase (FAS), perilipin A, leptin, and resistin, as well as the phosphorylation of signal transducer and activator of transcription-3 (STAT-3) during 3T3-L1 preadipocyte differentiation. Taken together, these results revealed that HIPK2 expression is significantly upregulated in p38 MAPK- and PKC-dependent manners, and this upregulation of HIPK2 plays a critical role in lipid accumulation during differentiation of 3T3-L1 cells, which is mediated by control of the expression and phosphorylation levels of C/EBP-α, PPAR-γ, STAT-3, FAS, and perilipin A. Full article

Metabolic dysfunction-associated steatotic liver disease (MASLD) and its progressive form, metabolic dysfunction-associated steatohepatitis (MASH), represent a growing global health burden driven by complex interactions among hepatic lipid accumulation, insulin resistance, chronic inflammation, and mitochondrial dysfunction. Exercise remains the cornerstone of lifestyle therapy for MASLD/MASH; however, its therapeutic benefits extend well beyond weight reduction and involve coordinated molecular adaptations across multiple organ systems. In this review, we introduce hepatic mitochondrial reprogramming as a conceptual framework describing the coordinated remodeling of mitochondrial energetics, quality-control pathways, and redox homeostasis that collectively restore metabolic flexibility and hepatocellular resilience. Exercise activates key metabolic regulators, including AMP-activated protein kinase (AMPK), peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α), and sirtuin signaling, promoting mitochondrial biogenesis, fatty acid oxidation, oxidative phosphorylation, and mitophagy while suppressing hepatic lipogenesis and oxidative injury. Skeletal muscle-derived myokines, alterations in gut microbial metabolism, and thyroid hormone signaling converge upon hepatic mitochondrial function through complementary endocrine and metabolic pathways. Together, these adaptations reduce hepatic steatosis, lipotoxicity, inflammation, and fibrogenesis while improving insulin sensitivity and metabolic flexibility. Emerging evidence further suggests that exercise-induced mitochondrial remodeling may complement pharmacologic therapies targeting hepatic metabolism, including thyroid hormone receptor-β agonists. Although multi-omics technologies continue to expand our understanding of these adaptive responses, the present review emphasizes the underlying molecular and physiological mechanisms through which exercise remodels hepatic mitochondrial function. We propose that exercise acts as a systems-level mitochondrial remodeling stimulus integrating skeletal muscle-, gut-, and thyroid-derived signals to improve hepatic metabolism and attenuate MASLD/MASH progression. This conceptual framework provides a mechanistic basis for precision exercise prescriptions and future combination therapeutic strategies targeting mitochondrial health. Full article

Carbon monoxide (CO) is a gasotransmitter generated by heme oxygenase (HO) isoforms during heme catabolism. The inducible HO-1 produces CO under conditions of redox imbalance, such as oxidative stress and inflammation. On the other hand, HO-2 constitutively generates CO, primarily during the physiological turnover of heme. Extensive evidence indicates that CO exerts autocrine effects by targeting hemoproteins, including soluble guanylyl cyclase, cyclooxygenase, and cytochromes. Furthermore, CO regulates many biological processes within the brain, including mitochondrial biogenesis, potassium channel activity, mitogen-activated protein kinase and phosphatidylinositol-3-kinase/Akt signaling. It also controls the activity of transcription factors, such as hypoxia-inducible factor-1 and peroxisome proliferator-activated receptor-γ. Through these mechanisms, CO modulates inflammatory gene expression, promotes anti-apoptotic signaling, and contributes to local stress responses. Conversely, CO produced in the hypothalamus inhibits the stress-induced release of corticotropin-releasing hormone and arginine vasopressin under pro-inflammatory conditions, resulting in reduced adrenocorticotropin hormone release and cortisol secretion from the anterior pituitary and adrenal cortex, respectively. Moreover, hypothalamic CO acts in a paracrine manner to modulate glucocorticoid release during psychological stress, including restraint or water deprivation. Together, these findings support the view that endogenous CO is a key modulator of the stress axis, exerting pleiotropic effects that integrate neuroendocrine, immune, and metabolic responses. Full article

Background/Objectives: Periodontitis grade reflects differences in disease progression and risk, yet the underlying host-response signatures that distinguish grade B from grade C are not fully elucidated. Nuclear receptors involved in inflammation and tissue homeostasis may contribute to these biological differences. The present study aimed to evaluate the expression of peroxisome proliferator-activated receptor-γ (PPAR-γ), retinoid X receptor-α (RXR-α), and vitamin D receptor (VDR) in gingival tissues from periodontally healthy individuals and from patients with grade B and grade C periodontitis, with the primary comparison focusing on grade-related differences within the same disease stage (stage 3). Methods: Forty-five participants were allocated to three groups: Group 1, healthy controls; Group 2, stage 3 grade B periodontitis; and Group 3, stage 3 grade C periodontitis. Clinical parameters, including plaque index (PI), gingival index (GI), and clinical attachment loss (CAL), were recorded. Fibroblast and inflammatory cell density, and immunohistochemical expression levels of PPAR-γ, RXR-α, and VDR were assessed on histological sections. Results: Compared with healthy controls, both periodontitis groups showed lower fibroblast cell counts and higher inflammatory cell counts. PPAR-γ expression was significantly higher in Group 3 than in the other groups, whereas RXR-α and VDR expression were higher in Group 1 than in Groups 2 and 3. Conclusions: These findings suggest that increasing disease grade within stage 3 periodontitis is associated with increased PPAR-γ expression, whereas RXR-α and VDR expression primarily distinguish healthy from diseased gingival tissues. This nuclear receptor profile may help explain biological differences between healthy, grade B and grade C periodontitis and support future risk-stratified host-modulatory approaches. Full article

Lindera sericea var. sericea (Japanese common name: “Kekuromoji”) is a deciduous shrub belonging to the Lauraceae family. Mainly distributed in Japan and Korea, L. sericea has been traditionally used as a source of essential oils and has not been characterized as a medicinal plant. In this study, we aimed to isolate and identify compounds that activate Takeda G protein-coupled receptor 5 (TGR5) and peroxisome proliferator-activated receptor-γ (PPARγ). Bioactivities were evaluated using a dual-color real-time bioluminescence monitoring system. The methanolic extract of L. sericea showed significant dose-dependent TGR5 activation and modest PPARγ activation. Spectroscopic analysis identified rac-pinocembrin (rac-1) and rac-pinostrobin (rac-2) as the major bioactive compounds in the methanolic extract. Reporter assays revealed that rac-2 is a TGR5 activator, whereas both rac-1 and rac-2 are modest PPARγ activators. We then separated the enantiomers of pinocembrin (1) and pinostrobin (2) using chiral column chromatography. Both enantiomers of 2 contributed comparably to TGR5 activation, whereas each pair of enantiomers (1 and 2) exhibited similar activity within the same compound toward PPARγ. These findings suggest that L. sericea is a promising source of bioactive compounds with potential metabolic regulatory activity. Full article

Background and Objectives: Heterotopic ossification (HO) involves abnormal bone growth in soft tissues. Current treatments are ineffective and prone to adverse effects, suggesting the need for new HO therapies. Intramembranous bone growth is led by osteoblasts. Since osteoblastogenesis and adipogenesis are opposed and mutually controlled processes, this study aims to identify a new repurposed therapeutic tool to inhibit osteoblastogenesis through adipogenesis promotion. Methods: We performed docking experiments between peroxisome proliferator-activated receptor-γ and bone metabolism-affecting drugs, namely, thiazolidinediones (rosiglitazone, pioglitazone), indomethacin, and dexamethasone, to test tritherapy antiosteoblastogenic effect. Mouse mesenchymal stem cells (C3H10T1/2), human osteoblast-like cells (SaOS2 and primary preosteoblasts), and mouse chondrocytes (ATDC5) were differentiated in the presence of these compounds. The effects on osteoblastogenesis, adipogenesis, and endochondral ossification were analysed through marker gene expression via RT–qPCR. Additionally, primary human HO cells and a congenital HO patient were treated with the selected drug combination (P-tritherapy). Results: Tritherapy significantly and synergistically promoted the expression of an adipogenic marker (fatty acid-binding protein 4) and decreased the expression of an osteoblastogenic marker (osteopontin). In an endochondral ossification model, it reduced ossification markers (collagen-2α1) expression, and in HO cells, it increased adipogenesis markers’ expression. Clinically, P-tritherapy administration prompted bone resorption in a patient with progressive osseous heteroplasia. Conclusions: Tritherapy induced adipogenesis while inhibiting osteoblastogenesis and endochondral ossification, demonstrating its potential as a new therapeutic tool to prevent abnormal bone growth. These results were consistent with bone turnover modification observed in a congenital HO patient. This concordance underscores tritherapy potential for rapid and safe translation to prevent HO. Full article

This study aimed to elucidate the role of peroxisome proliferator-activated receptor-γ (PPAR-γ) in regulating macrophage efferocytosis during the pathogenesis of chronic apical periodontitis (CAP). Clinical specimens, rat periapical lesion models, and an in vitro model simulating the CAP inflammatory milieu were employed to examine the contribution of PPAR-γ to efferocytosis throughout disease progression. The expression of PPAR-γ in vivo was assessed by single-cell RNA sequencing and immunohistochemical (IHC) staining. Pearson’s correlation and linear trend tests were conducted to investigate the association between PPAR-γ and macrophage efferocytosis during CAP progression. Pharmacological modulation of PPAR-γ was further conducted using rosiglitazone (RSG) as an agonist and GW9662 as an antagonist, followed by an assessment of efferocytosis-related parameters and inflammatory responses. Both clinical specimens and animal models demonstrated a progressive reduction in PPAR-γ expression and macrophage efferocytosis during CAP. Notably, PPAR-γ attenuated efferocytosis impairment and significantly reduced pathogen-induced inflammatory responses in macrophages. These findings indicate that defective macrophage efferocytosis contributes to the exacerbation of CAP severity, whereas targeting PPAR-γ may represent a promising therapeutic strategy to alleviate inflammation in periapical lesions by restoring efferocytic capacity. Collectively, this study highlights PPAR-γ as a potential therapeutic target warranting further investigation in CAP treatment. Full article

Mitochondrial dysfunction is a key factor in the pathophysiology of major depressive disorder (MDD) and treatment-resistant depression (TRD), connecting oxidative stress, neuroinflammation, and reduced neuroplasticity. Physical exercise induces specific mitochondrial changes linked to improvements in mental health. The aim of this paper was to examine emerging evidence regarding the effects of physical exercise on mitochondrial function and treatment-resistant depression, highlighting the clinical importance of the use of mitochondrial biomarkers to personalize exercise prescriptions for patients with depression, particularly those who cannot tolerate standard treatments. Physical exercise improves mitochondrial function, enhances biogenesis and neuroplasticity, and decreases oxidative stress and neuroinflammation. Essential signaling pathways, including brain-derived neurotrophic factor, AMP-activated protein kinase, active peroxisome proliferator-activated receptor-γ coactivator-1α, and Ca²⁺/calmodulin-dependent protein kinase, support these effects. Most studies have concentrated on the impact of low- and moderate-intensity aerobic exercise on general health. However, new evidence suggests that resistance exercise and high-intensity interval training also promote healthy mitochondrial adaptations, although the specific exercise intensity required to achieve this goal remains to be determined. There is strong evidence that exercise is an effective treatment for MDD, particularly for TRD, by promoting specific mitochondrial adaptations. However, key gaps remain in our understanding of the optimal exercise dose and which patient subgroups are most likely to benefit from it (Graphical Abstract). Full article

Background/Objectives: Obesity is a significant global health concern, and the natural bioactive compounds with anti-obesity effects remain challenging. This study aims to examine the anti-obesity effect and the potential mechanism of Vaccinium oldhamii fruit water extract (VOW). Methods: Lipid accumulation, AMP-activated protein kinase (AMPK) activity, and Wnt/β-catenin signaling were evaluated in 3T3-L1 cells. In high-fat and high-sucrose diet (HFHSD)-induced obese mice, body weight, food intake, fat weight, serum lipid profiles, and adipogenic transcription factors were assessed. The most effective VOW fraction was selected by Oil Red O (ORO) staining and its mechanism was studied in 3T3-L1 cells. Results: VOW treatment significantly inhibited cellular lipid accumulation and suppressed phosphorylation of AMPK and its downstream protein, acetyl-CoA carboxylase (ACC). VOW also decreased adipogenic-associated protein expressions such as the peroxisome proliferator-activated receptor-γ (PPAR-γ), CCAAT/enhancer-binding proteins α (C/EBP α), sterol regulatory element binding protein-1c (SREBP-1c), and fatty acid synthase (FAS). The enhanced effect of VOW was abolished by the knockdown of AMPK with siRNA. The inhibitory effect of VOW on differentiation depended on the treatment period, even though VOW treatment downregulated the C/EBP β expression at the early phase of differentiation. VOW dramatically reduced activation of AMPK, thereby downregulating adipogenic-associated proteins. Furthermore, the butanol fraction (BtOH) of VOW showed the most powerful effect of VOW dose-dependently reduced lipid accumulation by suppressing the phosphorylation of AMPK. Consistent with inhibited lipid accumulation in vitro, VOW reduced body weight and white adipose tissue weight in the HFHSD-induced obese animal model. Conclusions: Overall, our study suggested that the anti-adipogenesis effect of VOW and its BtOH fraction involved the activation of AMPK. Full article

The metabolic poise, or balance, between glycolysis and fatty acid oxidation (FAO) has recently been found to play a critical role in osteogenic differentiation and homeostasis. While simulated microgravity (SMG) is known to impede osteoblast differentiation (OBD) by inhibiting the Wnt/β-catenin pathway, how it affects osteoblast metabolism in this context remains unclear. We previously analyzed the effect of SMG on the differentiation of pre-osteoblast MC3T3-E1 cells and found that it reduced focal adhesion kinase (FAK) activity. This, in turn, downregulated Wnt/β-catenin and two of its downstream targets critical for OBD bone morphogenic protein-2 (BMP2) and type-1 collagen (COL1) formation, leading to a reduction in alkaline phosphatase (ALP) activity and cell matrix mineralization. In this study, we further analyzed how SMG-induced alterations in energy metabolism contribute to the inhibition of OBD in MC3T3-E1 cells. Consistent with our earlier findings, we demonstrated that SMG inhibits OBD by downregulating the collective activity of FAK and the Wnt/β-catenin-BMP2-COL1 transcriptional pathway. Interestingly, we observed that SMG also reduces the abundance of sirtuin-1 (SIRT1), peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α) and carnitine palmitoyl transferase-1α (CPT1A), which are all key metabolic factors regulating mitochondrial number and FAO capacity. Accordingly, we found that the mitochondrial content and FAO potential of MC3T3-E1 cells were lower upon exposure to SMG but were both rescued upon administration of the FAK activator cytotoxic necrotizing factor-1 (CNF1), thereby allowing cells to overcome SMG-induced inhibition of OBD. Taken together, our study indicates that the metabolic regulator SIRT1 may be a new target for reversing SMG-induced bone loss. Full article

Obesity is characterized by the enlargement of adipose tissue due to an increased calorie intake exceeding the body’s energy expenditure. Changes in the size of adipose tissue can lead to harmful consequences, with excessive fat accumulation resulting in adipocyte hypertrophy and promoting metabolic dysfunction. These adiposity-associated pathologies can be influenced by dietary components and their potential health benefits. Lupeol, a pharmacologically active pentacyclic triterpenoid found in medicinal plants, vegetables, and fruits, has been shown to exhibit antioxidant and anti-inflammatory properties. This study investigated the role of lupeol on adipocyte hypertrophy by evaluating key adipogenic regulators in vitro. First, 3T3-L1 MBX mouse embryonic cells were differentiated into adipocytes and hypertrophy was induced using 500 µM palmitic acid. The treated adipocytes showed a significantly increased lipid droplet size, confirming adipocyte hypertrophy. Both adipocytes and hypertrophied adipocytes were then treated with or without 60 µM lupeol, following a dose-dependent study. Lipid droplet size was assessed and validated by Oil Red O staining. Western blot analysis was performed to measure the expression of adipogenic and inflammatory markers. Differentiated adipocytes showed increased fatty acid-binding protein 4 (FABP4) expression and Oil Red O staining, indicating an increased lipid content. Western blot analysis revealed that lupeol treatment reduced the expression of FABP4, peroxisome proliferator-activated receptor-γ (PPARγ), and adipokines. In conclusion, the results suggest that lupeol reverts the inflammatory and adipogenic markers that are enhanced in adipocyte hypertrophy. Through its anti-inflammatory effects, lupeol offers protective effects against adipocyte hypertrophy and contributes to reducing hypertrophic adiposity. Full article

Stroke is the leading cause of death and disability worldwide, with ischemic stroke accounting for the majority of these. HBA is the active ingredient in Gastrodia elata and has potential therapeutic effects on central nervous system diseases. In this study, the cell model of cerebral ischemia was replicated by the culture method of oxygen-glucose deprivation/reoxygenation, and the rat model of vascular dementia was established by the two-vessel occlusion method. Metabolomics technology was employed to analyze the metabolic changes in ischemic neurons induced by HBA, and potential therapeutic targets were verified. The protective effects of HBA on ischemic neurons and their mitochondria were examined through multiple indicators, and the related mechanisms were verified. HBA can improve post-ischemic cognitive impairment in rats, and its mechanism is related to the regulation of the choline-activated phospholipase D2/Sirtuin 1/peroxisome proliferator-activated receptor-γ coactivator 1α pathway to improve mitochondrial function and reduce autophagic activity to maintain mitochondrial homeostasis. It is concluded that HBA has a protective effect on neuronal damage and cognitive impairment caused by cerebral ischemia by regulating key metabolites and signaling pathways, and that it provides a new molecular target for the treatment of cerebral ischemia. Full article

Arsenic exposure can induce liver insulin resistance (IR) and diabetes (DM), but the underlying mechanisms are not yet clear. Circular RNAs (circRNAs) are involved in the regulation of the onset of diabetes, especially in the progression of IR. This study aimed to investigate the role of circRNAs in arsenic-induced hepatic IR and its underlying mechanism. Male C57BL/6J mice were given drinking water containing sodium arsenite (0, 0.5, 5, or 50 ppm) for 12 months. The results show that sodium arsenite increased circ_0000284 expression, decreased insulin-like growth factor 2 mRNA binding protein 2 (IGF2BP2) and peroxisome proliferator-activated receptor-γ (PPAR-γ), and inhibited cell membrane protein levels of insulin-responsive glucose transporter protein 4 (GLUT4) in the mouse livers, indicating that arsenic exposure causes liver damage and disruptions to glucose metabolism. Furthermore, sodium arsenite reduced glucose consumption and glycogen levels, increased the expression of circ_0000284, reduced the protein levels of IGF2BP2 and PPAR-γ, and inhibited GLUT4 protein levels in the cell membranes of insulin-treated HepG2 cells. However, a circ_0000284 inhibitor reversed arsenic exposure-induced reductions in IGF2BP2, PPAR-γ, and GLUT4 levels in the plasma membrane. These results indicate that circ_0000284 is involved in arsenite-induced hepatic insulin resistance through blocking the plasma membrane translocation of GLUT4 in hepatocytes via IGF2BP2/PPAR-γ. This study provides a scientific basis for finding early biomarkers for the control of arsenic exposure and type 2 diabetes mellitus (T2DM), and discovering new prevention and control measures. Full article

Transfer RNA-derived small RNAs (tsRNAs) are novel regulatory small non-coding RNAs that have been found to modulate many life activities in recent years. However, the exact functions of tsRNAs in follicle development remain unclear. Follicle development is a remarkably complex process that follows a strict hierarchy and is strongly associated with reproductive performance in ducks. The process of converting small yellow follicles into hierarchal follicles is known as follicle selection, which directly determines the number of mature follicles. We performed small RNA sequencing during follicle selection in ducks and identified tsRNA-00764 as the target of interest based on tsRNA expression profiles in this study. Bioinformatics analyses and luciferase reporter assays further revealed that peroxisome proliferator-activated receptor-γ (PPAR-γ) was the target gene of tsRNA-00764. Moreover, tsRNA-00764 knockdown promoted estrogen and progesterone synthesis and lipid deposition in duck granulosa cells, while a PPAR-γ inhibitor reversed the above phenomenon. Taken together, these results demonstrate that tsRNA-00764, differentially expressed in pre-hierarchal and hierarchy follicles, modulates estrogen and progesterone synthesis and lipid deposition by targeting PPAR-γ in duck granulosa cells, serving as a potential novel mechanism of follicle selection. Overall, our findings provide a theoretical foundation for further exploration of the molecular mechanisms underlying follicle development and production performance in ducks. Full article

This study evaluated changes over time in skeletal muscle atrophy, expressions of skeletal muscle anabolic and catabolic genes, and mitochondrial activity by skeletal muscle type in an adenine-induced chronic kidney disease (CKD) model. A CKD model was successfully established by feeding male Wistar rats a 0.75% adenine diet for 4 weeks starting at 8 weeks of age. Control and CKD groups were sacrificed at 12 and 20 weeks of age. The back muscles were analyzed histologically, and succinate dehydrogenase (SDH) staining was performed to evaluate mitochondrial activity. Gene expressions of myogenic determination gene number 1 and myogenin as indicators of muscle anabolism, atrogin-1 and muscle RING-finger protein-1 (MuRF1) as indicators of muscle catabolism, and peroxisome proliferator-activated receptor-γ coactivator-1-α as a marker of mitochondrial biogenesis were assessed. Type I and type II muscle cross-sectional areas (CSAs) were decreased at 12 weeks, but type I muscle CSA was recovered at 20 weeks. SDH staining was lower in CKD than in control rats at 12 weeks, but no significant difference was observed at 20 weeks. Increased expressions of myogenin, atrogin-1, and MuRF-1 were observed only at 12 weeks, but no differences were observed at 20 weeks. The adenine-induced CKD rat model appears to show changes in muscle atrophy over time. Full article