PHYTOMEDICINE
·
2024
·
IF 6.7
Huijian Chen,Pengxin Liu,Ruitao Yu,Nabijan Mohammadtursun,Ainiwaer Aikemu,Xinzhou Yang
Background and purpose Swertiamarin (STM), a secoiridoid glycoside from Swertia chirayita (Roxb.) H. Karst , has been shown to decrease body weight, blood glucose, and blood lipids by inhibiting adipose tissue hypertrophy. However, the underlying mechanisms remain unclear. In particular, adipose thermogenesis is a novel avenue for exploring the pharmacological effects of STM. We aim to investigate the efficacy of STM on type 2 diabetes mellitus (T2DM), with a focus on underlying mechanisms, particularly the activation of ADRB3/UCP1 thermogenic signaling pathways. Methods T2DM model was established by a high-fat diet (HFD) and streptozotocin (STZ) in C57BL/6 J male mice. Mice were given to either 100 or 200 mg kg -1 /day of STM, or 200 mg kg -1 /day of metformin (Glucophage) via intragastric administration for 7 weeks. In vitro, 3T3-L1 cells were differentiated into adipocytes. Molecular markers related to ADRB3-UCP1 signals, lipolysis, and mitochondrial function were detected. Results STM-treated diabetic mice showed a reduction of body weight, fat mass, and blood glucose/lipids and an improvement in insulin sensitivity. Bioinformatics analysis indicated STM promoted lipid metabolism and mitochondrial function, features by closely associated with adipose thermogenesis. STM upregulated the lipolysis-related genes and p-HSL protein in inguinal subcutaneous white adipose tissue (igSWAT) and brown adipose tissue (BAT). STM-treated mice processed a more active energy metabolism. Additionally, the ADRB3-UCP1 signals, mitochondrial-related genes, and oxidative phosphorylation were improved in igSWAT and BAT. In vitro , we found STM interacted with ADRB3, increasing glucose uptake, glycerol release, ADRB3-UCP1 signals, p-HSL expression, mitochondrial content, oxidative phosphorylation complex expression with improved mitochondrial Δ ψ m, as well as reduced lipid accumulation in adipocytes. All these effects were reversed upon ADRB3 inhibition. Conclusion This study identifies a previously unknown role of STM activating ADRB3/UCP1 signals in adipose tissue, suggesting a potential strategy for treating T2DM.
研究领域:
药理学
·
内分泌学
·
分子生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Food Science and Human Wellness
·
2023
·
IF 7
Yuhan Meng,Weili Li,Chenxing Hu,Si Chen,Haiyang Li,Feifei Bai,Lujuan Zheng,Ye Yuan,Yuying Fan,Yifa Zhou
Obesity-induced type 2 diabetes is mainly due to excessive free fatty acids leading to insulin resistance. Increasing thermogenesis is regarded as an effective strategy for hypolipidemia and hypoglycemia. Ginsenoside is a natural active component in Panax ginseng C.A. Meyer, and some of them enhance thermogenesis. However, there are few studies on the mechanism and target of ginsenosides enhancing thermogenesis. Using thermogenic protein uncoupling protein 1 (UCP1)-luciferase reporter assay, we identified ginsenoside F1 as a novel UCP1 activator in the ginsenosides library. Using pull down assay and inhibitor interference, we found F1 binds to β3-adrenergic receptors (β3-AR) to enhance UCP1 expression via cAMP/PKA/CREB pathway. We also investigated the ability of F1 on energy metabolism in obesity-induced diabetic mice, including body weight, body composition and energy expenditure. The results of proteomics showed that F1 significantly up-regulated thermogenesis proteins and lipolytic proteins, but down-regulated fatty acid synthesis proteins. Ginsenoside F1 increased thermogenesis and ameliorated insulin resistance specifically by promoting the browning of white adipose tissue in obese mice. Additionally, ginsenoside F1 improves norepinephrine-induced insulin resistance in adipocytes and hepatocytes, and shows a stronger mitochondria respiration ability than norepinephrine. These findings suggest that ginsenoside F1 is a promising lead compound in the improvement of insulin resistance.
研究领域:
药理学
·
内分泌学
·
代谢学
·
分子生物学
✓ 已验证
DOI
高影响因子
RENAL FAILURE
·
2025
·
IF 3
Neng Bao,Ming-Jia Gu,Qiu-Ya Huang,Hai-Jian Sun,Xue-Xue Zhu,Xin Gu,Jin Wang,Xiang Yu,Qing-Bo Lu,Ya-Fen Yu
Purpose This study aims to investigate the protective effect of baicalin on sepsis-associated acute kidney injury (SA-AKI) and its molecular mechanism.Materials and methods An SA-AKI mouse model was established via lipopolysaccharide (LPS) injection. Baicalin’s effects on renal function, oxidative stress, and apoptosis were evaluated using histopathology, dihydroethidium, and terminal deoxynucleotidyl transferase dUTP nick end labeling staining. Bioinformatics, molecular docking, ribonucleic acid (RNA) sequencing, and Western blotting were employed to investigate the role of baicalin in regulating the peroxisome proliferator‑activated receptor‑γ (PPAR-γ)/uncoupling protein 1 (UCP1) pathway. Human kidney-2 cells were used for in vitro validation.Results In this study, baicalin significantly ameliorated LPS-induced acute kidney injury by modulating the PPAR-γ/UCP1 signaling pathway. Both in vivo and in vitro experiments revealed that baicalin attenuates inflammation, oxidative stress, and apoptosis while restoring mitochondrial function. RNA sequencing analysis revealed significant upregulation of PPAR-γ/UCP1 in the baicalin-treated group. Further molecular docking and molecular dynamics simulations confirmed a stable interaction between baicalin and UCP1. Validation via small interfering RNA-mediated knockdown of PPAR-γ and UCP1 revealed that inhibition of the PPAR-γ/UCP1 pathway abrogated baicalin’s protective effects, highlighting the critical role of this pathway in mediating baicalin’s renoprotection.Conclusion Baicalin protects against SA-AKI by activating the PPAR-γ/UCP1 signaling pathway. This study provides new insights into the mechanisms through which baicalin mitigates kidney injury in sepsis, suggesting its potential as a therapeutic agent for SA-AKI.
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Journal of Advanced Research
·
2024
·
IF 11.4
Sijia Lu,Quanxin Jiang,Peihui Zhou,Limin Yin,Ning Wang,Junting Xu,Qiqi Qian,Mijia Tao,Hanrui Yin,Liu Han,Yunqing Gu,Fei Gao,Junli Liu,Suzhen Chen
Introduction Promoting adipose thermogenesis is considered as a promising therapeutic intervention in obesity. However, endeavors to develop anti-obesity medications by targeting the canonical thermogenesis regulatory pathway, particularly β3-adrenergic receptor (β3-AR)-dependent mechanism, have failed due to the off-target effects of β3-AR agonists, exacerbating the risk of cardiovascular disease. Hyperforin (HPF), a natural compound extracted from the traditional herbal St. John’s Wort, binds to Dihydrolipoamide s-acetyltransferase (Dlat) and exerts effective anti-obesity properties through promoting adipose thermogenesis. Objectives The objective of this study was to investigate the oral efficacy and pharmacokinetics profile of HPF, and explore the detailed mechanism by which Dlat modulates HPF-mediated adipose thermogenesis. Methods To assess the anti-obesity efficacy of orally administered HPF in vivo , Dlat heterozygous knockout (Dlat +/- ) mice and wild-type (WT) mice, both fed a high-fat diet (HFD), underwent a validation process that involved the use of metabolic cages, NMR analysis, and infrared imaging. Sprague Dawley rats were employed to determine the pharmacokinetic parameters of HPF. Seahorse assays, JC-1 staining, qPCR, and immunoblotting were performed to evaluate cellular thermogenic efficacy of HPF and Dlat in vitro . Results Our study uncovered a non-canonical thermogenesis pathway involving Dlat, transient receptor potential vanilloid 3 (Trpv3, a calcium channel) and AMPK. Dlat interacted with Trpv3 to activate it, resulting in an increase in intracellular calcium (Ca 2+ ) and the activation of Camkkβ. Camkkβ then stimulated AMPK, leading to elevated Ucp1 expression and initiating adipose thermogenesis. HPF promoted thermogenesis in adipose tissues through enhancing the Dlat-Trpv3 interaction independently of β3-AR, causing minimal cardiac side effects. Notably, HPF’s thermogenic effects were reduced in Dlat +/- mice. Moreover, HPF exerted favorable oral bioavailability, a relatively long half-life, and extensive distribution within adipose tissues. Conclusion In summary, our study demonstrates that HPF targets a novel mechanism for promoting adipose thermogenesis and exhibits potent and safe anti-obesity efficacy.
研究领域:
药理学
·
分子生物学
·
代谢
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Molecular Therapy-Methods & Clinical Development
·
2023
·
IF 4.7
Jiaqi Zeng,Jianing Liu,Haiya Ni,Ling Zhang,Jun Wang,Yazhou Li,Wentao Jiang,Ziyu Wu,Min Zhou
Recent studies have shown that mitochondrial transplantation can repair lower limb IRI, but the underlying mechanism of the repair effect remains unclear. In this study, we found that in addition to being taken up by skeletal muscle cells, human umbilical cord mesenchymal stem cells (hMSCs)-derived mitochondria were also taken up by adipocytes, which was accompanied by an increase in optic atrophy 1 (OPA1) and uncoupling protein 1. Transplantation of hMSCs-derived mitochondria could not only supplement the original damaged mitochondrial function of skeletal muscle, but also promote adipocyte browning by increasing the expression of OPA1. In this process, mitochondrial transplantation can reduce cell apoptosis and repair muscle tissue, which promotes the recovery of motor function in vivo . To the best of our knowledge, there is no study on the therapeutic mechanism of mitochondrial transplantation from this perspective, which could provide a theoretical basis.
研究领域:
医学
·
细胞生物学
✓ 已验证
DOI
PubMed
高影响因子
ACTA PHARMACOLOGICA SINICA
·
2023
·
IF 8.2
Li Yi-jie,Wu Rui-yu,Liu Run-ping,Wu Kai-yi,Ding Ming-ning,Sun Rong,Gu Yi-qing,Zhou Fei,Wu Jian-zhi,Zheng Qi,Duan Shu-ni,Li Rong-rong,Zhang Yin-hao,Li Fang-hong,Li Xiaojiaoyang
Obesity contributes to the progression of various chronic diseases, and shortens life expectancy. With abundant mitochondria, brown adipose tissue (BAT) dissipates energy through heat to limit weight gain and metabolic dysfunction in obesity. Our previous studies have shown that aurantio-obtusin (AO), a bioactive ingredient in Chinese traditional medicine Cassiae semen significantly improves hepatic lipid metabolism in a steatotic mouse model. In the current study we investigated the effects of AO on lipid metabolism in the BAT of diet-induced obesity mice and in oleic acid and palmitic acid (OAPA)-stimulated primary mature BAT adipocytes. Obese mice were established by feeding a HFHS diet for 4 weeks, and then administered AO (10 mg/kg, i.g.) for another 4 weeks. We showed that AO administration significantly increased the weight of BAT and accelerated energy expenditure to protect the weight increase in the obese mice. Using RNA sequencing and molecular biology analysis we found that AO significantly enhanced mitochondrial metabolism and UCP1 expression by activating PPARα both in vivo and in vitro in the primary BAT adipocytes. Interestingly, AO administration did not improve metabolic dysfunction in the liver and white adipose tissue of obese mice after interscapular BAT excision. We demonstrated that low temperature, a trigger of BAT thermogenesis, was not a decisive factor for AO to stimulate the growth and activation of BATs. This study uncovers a regulatory network of AO in activating BAT-dependent lipid consumption and brings up a new avenue for the pharmaceutical intervention in obesity and related comorbidities.
研究领域:
药理学
·
代谢学
·
内分泌学
·
分子生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
ACS Biomaterials Science & Engineering
·
2021
·
IF 4.749
Zhenhua Ding,Maohua Chen,Xinyan Tao,Yuan Liu,Jie He,Tao Wang,Xiaohong Li
Obesity is a primary risk factor for type 2 diabetes, cardiovascular diseases, cancer, and other chronic diseases. Current antiobesity medications need frequent administration and show limited efficacy with severe side effects. Herein, browning agent rosiglitazone (Rsg) and antioxidant manganese tetroxide nanoparticles (MnNPs, around 250 nm) are integrated into electrospun short fibers (SF@Rsg-Mn) with a 1.5 μm width and a 20 μm length. Upon injection into inguinal adipose tissues, SF@Rsg-Mn are well retained in the local depots to sustainably release Rsg in 30 days for adipose tissue browning, while MnNPs on the fiber surface continuously scavenge adipose reactive oxygen species (ROS) for an extended period of time. Synergistic inhibition of fat accumulation through ROS scavenging and white adipocyte browning has been demonstrated for the first time, and the optimal synergistic ratio of Rsg and MnNPs is determined to be 1/14 via combination index examination. SF@Rsg-Mn inhibit lipid accumulation through downregulation of adipogenic gene PPARγ while promoting energy expenditure through upregulation of brown-specific gene UCP1 and mitochondrial function gene COX7A1. In a diet-induced obesity mouse model, a single injection of SF@Rsg-Mn into inguinal adipose tissues has accomplished a synergistic effect on body weight loss, fat reduction, glucose, and lipid metabolic improvement while minimizing adverse effects on other tissues, thereby paving the way to efficacious, safe, and practical treatment of obesity.
研究领域:
药理学
·
代谢研究
·
纳米医学
·
肥胖研究
✓ 已验证
产品关联
DOI
PubMed
高影响因子
EUROPEAN JOURNAL OF PHARMACOLOGY
·
2024
·
IF 4.2
Yi Chu,Sisi Gui,Yazhen Zheng,Jingwu Zhao,Yaxiang Zhao,Yingying Li,Xiaodong Chen
Non-alcoholic fatty liver disease (NAFLD) is closely associated with the body's energy metabolism. A potential strategy to regulate energy metabolism, combat obesity, and reduce NAFLD is by enhancing adipocyte thermogenesis and increasing energy expenditure. In this study, our objective was to examine the effects of phenolic extracts derived from Magnolia officinalis on the regulation of NAFLD. Specifically, we investigated the impact of Magnolol or Honokiol treatment on high-fat diet (HFD)-induced obese C57BL6/J male mice. Firstly, we monitored energy metabolism, dissected tissues, and analyzed tissue sections. Additionally, we conducted experiments on HepG2 and primary adipocytes to gain insights into the roles of Magnolol or Honokiol. To further understand the effects of these compounds on related signaling pathways and marker genes, we performed molecular docking, dual-luciferase assays, and interfered with target genes. Our findings revealed that Magnolol or Honokiol activate the peroxisome proliferator activated receptor alpha (PPARα) signaling pathway, leading to the alleviation of NAFLD. This activation promotes fatty acid oxidation, reduces lipogenesis, and enhances the expression and secretion of FGF21. Notably, Fibroblast growth factor 21 (FGF21), secreted by the liver, plays a crucial role in improving communication between the liver and adipocytes while also promoting the browning of adipose tissue. Additionally, Magnolol or Honokiol activate the peroxisome proliferator activated receptor gamma (PPARγ) signaling pathway, resulting in increased uncoupling protein 1 (UCP1) expression, heightened heat production in adipose tissue, and anti-obesity. Therefore, Magnolol or Honokiol alleviate NAFLD, promote adipose tissue browning and resist obesity through dual activation of PPARα/γ.
研究领域:
药理学
·
代谢
·
分子生物学
·
营养学
✓ 已验证
DOI
PubMed
高影响因子
Food & Function
·
2017
·Vol. 8
·期 9
·3259-3270
·
IF 3.247
Xiaozhou Zhou,Shiguo Chen,Xingqian Ye
The anti-obesity effects of different proanthocyanidin extracts (PE) from Chinese bayberry (Myrica rubra Sieb.et Zucc.) leaves were evaluated in a high-fat (HF) diet-induced obese rat model. The leaves of Chinese bayberry (LCB), a non-desaccharified proanthocyanidin extract (NDPE), and a desaccharified proanthocyanidin extract (DPE) were compared with orlistat, a conventional anti-obesity drug used as a positive control. The rats from all of the PE-treated groups showed obvious weight loss, with the greatest weight loss in the DPE group (P < 0.05). Compared to the HF group, almost all of the PE-treated groups showed significantly reduced levels of serum TC, TG, AST, ALT, ALP, LDL-C, ADP and a LEP/ADP ratio, and increased levels of HDL-C and LEP. Furthermore, the expression levels of SIRT1, PPAR-γ, C/EBP-α, BMP4 and UCP1 were investigated in the liver, kidney, epididymis and abdominal adipose tissue. Compared to the HF group, PPAR-γ and C/EBP-α levels were significantly reduced and SIRT1, BMP4 and UCP1 levels were significantly upregulated in the DPE-treated group. Our results suggested that PE exerted its anti-obesity effects by upregulating the expression of SIRT1, thus inducing the deacetylation of PPAR-γ and downregulating the expression of C/EBP-α, and also upregulating the expression of BMP4 to boost the levels of brown fat.
研究领域:
药理学
·
营养学
·
分子生物学
·
生物化学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
STAR Protocols
·
2022
·
IF 0
Jingfei Yao,Dongmei Wu,Yifu Qiu
Summary The communication between macrophage and adipocyte plays a critical role in the initiation and development of metabolic inflammation, which is difficult to study in vivo . Here, we provide a step-by-step protocol using differentiated cells to investigate the paracrine effects of classically activated macrophage on beige adipocyte metabolism in vitro . This protocol uses bone-marrow-derived macrophage and SVF-derived UCP1 + beige adipocyte in a culture model to study immune regulation of adipocyte metabolism by western blot analyses. For complete details on the use and execution of this protocol, please refer to Yao et al. (2021) .
研究领域:
免疫学
·
细胞生物学
·
代谢
✓ 已验证
DOI
PubMed
Obesity
·
2015
·Vol. 24
·期 2
·368-378
·
IF 3.734
Ziquan Lv,Jinquan Cheng,Suli Huang,Yanwei Zhang,Shuang Wu,Yangshen Qiu,Yijie Geng,Qian Zhang,Guanqin Huang,Quan Ma,Xing Xie,Shiquan Zhou,Tangchun Wu,Yuebin Ke
Objective Di(2-ethylhexyl) phthalate (DEHP) is reported to cause obesity and hypothyroidism in both humans and rodents, but the underlying mechanisms were largely unknown. This study was designed to clarify the effects and the mechanisms of DEHP on the pathogenesis of obesity and hypothyroidism and to discover the relationship between them. Methods Male C3H/He mice were treated with DEHP for 5 weeks, and the body weight, food intake, and body temperature were recorded during the exposure. After exposure, key organs and serum were analyzed by Q-PCR, Western blot, and ELISA. Results DEHP induced significant body weight gain and adipogenesis in all exposure groups except for 0.05 mg/kg. Marked hyperphagia and daytime hypothermia were also observed, which were accompanied by disturbed hypothalamic neuropeptide expression and reduced BAT UCP1 expression. In addition, WAT lipid metabolism was significantly deceased at low dose (0.5 mg/kg) and increased at high dose (50 and 200 mg/kg). DEHP also induced hypothyroidism, which was probably attributed to the combined effects of hepatic CAR activation and hypothalamic TRH inhibition induced by hypothalamic leptin resistance. Conclusions Chronic DEHP exposure could induce obesity by interrupting energy homeostasis, which is probably due to the synergistic effects of hypothyroidism and hypothalamic leptin resistance.
研究领域:
毒理学
·
内分泌学
·
代谢
✓ 已验证
产品关联
DOI
PubMed
高影响因子
JOURNAL OF THERMAL BIOLOGY
·
2022
·
IF 3.189
Yan-Mei Zhang,Khas Erdene,Ya-Bo Zhao,Chang-Qing Li,Li Wang,Feng Tian,Chang-Jin Ao,Hai Jin
Mongolian sheep are characteristically cold-tolerant and thus can survive well and maintain genetic stability in the extremely cold environment of the Mongolian Plateau. However, the adaptive mechanism of Mongolian sheep during the cold season in the plateau environment remains unknown. Browning of white adipose tissues (WAT) can trigger nonshivering thermogenesis as a potential strategy to promote an animal's tolerance to cold environments. Thus, a comparative analysis of the genes and proteins of uncoupling protein 1 (UCP1)-dependent and UCP1-independent browning pathways, mitochondrial biogenesis , lipogenic and lipolytic processes of WAT from grazing Mongolian sheep in the cold and warm seasons was conducted. We found seasonal browning of both retroperitoneal WAT and perirenal WAT, and the signalling of the process was mainly transduced by the UCP1- dependent pathway, primarily reflected in the upregulated gene levels of UCP1 and peroxisome proliferative activated receptor gamma coactivator 1 alpha (PGC-1α). In addition, the mean adipocyte diameter and mRNA expression of lipogenic genes in both interscapular WAT and subcutaneous WAT were significantly elevated during the cold season. The findings of this study demonstrate that grazing Mongolian sheep could depend on seasonal browning of both retroperitoneal WAT and perirenal WAT together with the expansion of both interscapular WAT and subcutaneous WAT to acclimate to cold environments of the Mongolian Plateau.
研究领域:
动物科学
·
生理学
·
分子生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
危险品化学品经营许可证（带存储）