Research

16 pages, 2999 KiB

Open AccessArticle

Timosaponin A3 Induces Anti-Obesity and Anti-Diabetic Effects In Vitro and In Vivo

by Ji-Hyuk Park, Wona Jee, So-Mi Park, Ye-Rin Park, Seok Woo Kim, Hanbit Bae, Won-Suk Chung, Jae-Heung Cho, Hyungsuk Kim, Mi-Yeon Song and Hyeung-Jin Jang

Int. J. Mol. Sci. 2024, 25(5), 2914; https://doi.org/10.3390/ijms25052914 - 02 Mar 2024

Viewed by 622

Abstract

Obesity is a serious global health challenge, closely associated with numerous chronic conditions including type 2 diabetes. Anemarrhena asphodeloides Bunge (AA) known as Jimo has been used to address conditions associated with pathogenic heat such as wasting-thirst in Korean Medicine. Timosaponin A3 (TA3), [...] Read more.

Obesity is a serious global health challenge, closely associated with numerous chronic conditions including type 2 diabetes. Anemarrhena asphodeloides Bunge (AA) known as Jimo has been used to address conditions associated with pathogenic heat such as wasting-thirst in Korean Medicine. Timosaponin A3 (TA3), a natural compound extracted from AA, has demonstrated potential therapeutic effects in various disease models. However, its effects on diabetes and obesity remain largely unexplored. We investigated the anti-obesity and anti-diabetic properties of TA3 using in vitro and in vivo models. TA3 treatment in NCI-H716 cells stimulated the secretion of glucagon-like peptide 1 (GLP-1) through the activation of phosphorylation of protein kinase A catalytic subunit (PKAc) and 5′-AMP-activated protein kinase (AMPK). In 3T3-L1 adipocytes, TA3 effectively inhibited lipid accumulation by regulating adipogenesis and lipogenesis. In a high-fat diet (HFD)-induced mice model, TA3 administration significantly reduced body weight gain and food intake. Furthermore, TA3 improved glucose tolerance, lipid profiles, and mitigated hepatic steatosis in HFD-fed mice. Histological analysis revealed that TA3 reduced the size of white adipocytes and inhibited adipose tissue generation. Notably, TA3 downregulated the expression of lipogenic factor, including fatty-acid synthase (FAS) and sterol regulatory element-binding protein 1c (SREBP1c), emphasizing its potential as an anti-obesity agent. These findings revealed that TA3 may be efficiently used as a natural compound for tackling obesity, diabetes, and associated metabolic disorders, providing a novel approach for therapeutic intervention. Full article

(This article belongs to the Special Issue Obesity, Adipose Tissue, and Bioactive Natural Products)

► Show Figures

Figure 1

16 pages, 4166 KiB

Open AccessArticle

Graphislactone A, a Fungal Antioxidant Metabolite, Reduces Lipogenesis and Protects against Diet-Induced Hepatic Steatosis in Mice

by Yeonmi Lee, Hye-Rim Jang, Dongjin Lee, Jongjun Lee, Hae-Rim Jung, Sung-Yup Cho and Hui-Young Lee

Int. J. Mol. Sci. 2024, 25(2), 1096; https://doi.org/10.3390/ijms25021096 - 16 Jan 2024

Viewed by 778

Abstract

Graphislactone A (GPA), a secondary metabolite derived from a mycobiont found in the lichens of the genus Graphis, exhibits antioxidant properties. However, the potential biological functions and therapeutic applications of GPA at the cellular and animal levels have not yet been investigated. In [...] Read more.

Graphislactone A (GPA), a secondary metabolite derived from a mycobiont found in the lichens of the genus Graphis, exhibits antioxidant properties. However, the potential biological functions and therapeutic applications of GPA at the cellular and animal levels have not yet been investigated. In the present study, we explored the therapeutic potential of GPA in mitigating non-alcoholic fatty liver disease (NAFLD) and its underlying mechanisms through a series of experiments using various cell lines and animal models. GPA demonstrated antioxidant capacity on a par with that of vitamin C in cultured hepatocytes and reduced the inflammatory response induced by lipopolysaccharide in primary macrophages. However, in animal studies using an NAFLD mouse model, GPA had a milder impact on liver inflammation while markedly attenuating hepatic steatosis. This effect was confirmed in an animal model of early fatty liver disease without inflammation. Mechanistically, GPA inhibited lipogenesis rather than fat oxidation in cultured hepatocytes. Similarly, RNA sequencing data revealed intriguing associations between GPA and the adipogenic pathways during adipocyte differentiation. GPA effectively reduced lipid accumulation and suppressed lipogenic gene expression in AML12 hepatocytes and 3T3-L1 adipocytes. In summary, our study demonstrates the potential application of GPA to protect against hepatic steatosis in vivo and suggests a novel role for GPA as an underlying mechanism in lipogenesis, paving the way for future exploration of its therapeutic potential. Full article

(This article belongs to the Special Issue Obesity, Adipose Tissue, and Bioactive Natural Products)

► Show Figures

Figure 1

13 pages, 2145 KiB

Open AccessArticle

Inhibitory Effects of Sesquiterpenoids Isolated from Artemisia scoparia on Adipogenic Differentiation of 3T3-L1 Preadipocytes

by Jung Im Lee, Jung Hwan Oh, Fatih Karadeniz, Chang-Suk Kong and Youngwan Seo

Int. J. Mol. Sci. 2024, 25(1), 200; https://doi.org/10.3390/ijms25010200 - 22 Dec 2023

Viewed by 692

Abstract

Obesity and related complications are significant health issues in modern society, largely attributed to a sedentary lifestyle and a carbohydrate-rich diet. Since anti-obesity drugs often come with severe side effects, preventative measures are being sought globally, including dietary changes and functional foods that [...] Read more.

Obesity and related complications are significant health issues in modern society, largely attributed to a sedentary lifestyle and a carbohydrate-rich diet. Since anti-obesity drugs often come with severe side effects, preventative measures are being sought globally, including dietary changes and functional foods that can counteract weight gain. In this context, plant-based metabolites are extensively studied for their advantageous biological effects against obesity. Several plants within the Artemisia genus have been reported to possess anti-adipogenic properties, preventing adipocytes from maturing and accumulating lipids. The present study investigated the anti-adipogenic potential of two sesquiterpenoids, reynosin and santamarine, isolated from A. scoparia in adipose-induced 3T3-L1 preadipocytes. Differentiating 3T3-L1 adipocytes treated with these isolated compounds displayed fewer adipogenic characteristics compared to untreated mature adipocytes. The results indicated that cells treated with reynosin and santamarine accumulated 55.0% and 52.5% fewer intracellular lipids compared to untreated control adipocytes, respectively. Additionally, the mRNA expression of the key adipogenic marker, transcription factor PPARγ, was suppressed by 87.2% and 91.7% following 60 μM reynosin and santamarine treatment, respectively, in differentiated adipocytes. Protein expression was also suppressed in a similar manner, at 92.7% and 82.5% by 60 μM reynosin and santamarine treatment, respectively. Likewise, SERBP1c and C/EBPα were also downregulated at both gene and protein levels in adipocytes treated with samples during differentiation. Further analysis suggested that the anti-adipogenic effect of the compounds might be a result of AMPK activation and the subsequent suppression of MAPK phosphorylation. Overall, the present study suggested that sesquiterpenoids, reynosin, and santamarine were two potential bioactive compounds with anti-adipogenic properties. Further research is needed to explore other bioactive agents within A. scoparia and elucidate the in vivo action mechanisms of reynosin and santamarine. Full article

(This article belongs to the Special Issue Obesity, Adipose Tissue, and Bioactive Natural Products)

► Show Figures

Graphical abstract

13 pages, 1392 KiB

Open AccessArticle

Assessment of the Purity of IMM-H014 and Its Related Substances for the Treatment of Metabolic-Associated Fatty Liver Disease Using Quantitative Nuclear Magnetic Resonance Spectroscopy

by Hanyilan Zhang, Haowen Zhu, Song Wu, Haoyang Tang, Wenxuan Zhang, Xiaoliang Gong, Tiesong Wang, Yinghong Wang and Qingyun Yang

Int. J. Mol. Sci. 2023, 24(24), 17508; https://doi.org/10.3390/ijms242417508 - 15 Dec 2023

Viewed by 739

Abstract

An accurate, rapid, and selective quantitative nuclear magnetic resonance method was developed and validated to assess the purity of IMM-H014, a novel drug for the treatment of metabolic-associated fatty liver disease (MAFLD), and four related substances (impurities I, II, III, and IV). In [...] Read more.

An accurate, rapid, and selective quantitative nuclear magnetic resonance method was developed and validated to assess the purity of IMM-H014, a novel drug for the treatment of metabolic-associated fatty liver disease (MAFLD), and four related substances (impurities I, II, III, and IV). In this study, we obtained spectra of IMM--H014 and related substances in deuterated chloroform using dimethyl terephthalate (DMT) as the internal standard reference. Quantification was performed using the ¹H resonance signals at δ 8.13 ppm for DMT and δ 6.5–7.5 ppm for IMM-H014 and its related substances. Several key experimental parameters were investigated and optimized, such as pulse angle and relaxation delay. Methodology validation was conducted based on the International Council for Harmonization guidelines and verified with satisfactory specificity, precision, linearity, accuracy, robustness, and stability. In addition, the calibration results of the samples were consistent with those obtained from the mass balance method. Thus, this research provides a reliable and practical protocol for purity analysis of IMM-H014 and its critical impurities and contributes to subsequent clinical quality control research. Full article

(This article belongs to the Special Issue Obesity, Adipose Tissue, and Bioactive Natural Products)

► Show Figures

Graphical abstract

18 pages, 6865 KiB

Open AccessArticle

DHA-Provoked Reduction in Adipogenesis and Glucose Uptake Could Be Mediated by Gps2 Upregulation in Immature 3T3-L1 Cells

by Natalia Grigorova, Zhenya Ivanova, Ekaterina Vachkova, Valeria Petrova and Toncho Penev

Int. J. Mol. Sci. 2023, 24(17), 13325; https://doi.org/10.3390/ijms241713325 - 28 Aug 2023

Viewed by 948

Abstract

The signaling pathway of fatty acids in the context of obesity is an extensively explored topic, yet their primary mechanism of action remains incompletely understood. This study aims to examine the effect of docosahexaenoic acid (DHA) on some crucial aspects of adipogenesis in [...] Read more.

The signaling pathway of fatty acids in the context of obesity is an extensively explored topic, yet their primary mechanism of action remains incompletely understood. This study aims to examine the effect of docosahexaenoic acid (DHA) on some crucial aspects of adipogenesis in differentiating 3T3-L1 cells, using palmitic acid-treated (PA), standard differentiated, and undifferentiated adipocytes as controls. Employing 60 µM DHA or PA, 3T3-L1 preadipocytes were treated from the onset of adipogenesis, with negative and positive controls included. After eight days, we performed microscopic observations, cell viability assays, the determination of adiponectin concentration, intracellular lipid accumulation, and gene expression analysis. Our findings demonstrated that DHA inhibits adipogenesis, lipolysis, and glucose uptake by suppressing peroxisome proliferator-activated receptor gamma (Pparg) and G-protein coupled receptor 120 (Gpr120) gene expression. Cell cytotoxicity was ruled out as a causative factor, and β-oxidation involvement was suspected. These results challenge the conventional belief that omega-3 fatty acids, acting as Pparg and Gpr120 agonists, promote adipogenesis and enhance insulin-dependent glucose cell flux. Moreover, we propose a novel hypothesis suggesting the key role of the co-repressor G protein pathway suppressor 2 in mediating this process. Additional investigations are required to elucidate the molecular mechanisms driving DHA’s anti-adipogenic effect and its broader health implications. Full article

(This article belongs to the Special Issue Obesity, Adipose Tissue, and Bioactive Natural Products)

► Show Figures

Figure 1

15 pages, 2201 KiB

Open AccessArticle

Development and In Vitro–In Vivo Correlation Evaluation of IMM-H014 Extended-Release Tablets for the Treatment of Fatty Liver Disease

by Chi Zhang, Huihui Shao, Zunsheng Han, Bo Liu, Jing Feng, Jie Zhang, Wenxuan Zhang, Kun Zhang, Qingyun Yang and Song Wu

Int. J. Mol. Sci. 2023, 24(15), 12328; https://doi.org/10.3390/ijms241512328 - 02 Aug 2023

Cited by 1 | Viewed by 873

Abstract

This study aimed to develop extended-release tablets containing 25 mg IMM-H014, an original drug formulated by a direct powder pressing method based on pharmaceutical-grade hydrophilic matrix polymers such as hydroxypropyl methylcellulose, to establish an in vitro–in vivo correlation (IVIVC) to predict bioavailability. The [...] Read more.

This study aimed to develop extended-release tablets containing 25 mg IMM-H014, an original drug formulated by a direct powder pressing method based on pharmaceutical-grade hydrophilic matrix polymers such as hydroxypropyl methylcellulose, to establish an in vitro–in vivo correlation (IVIVC) to predict bioavailability. The tablets’ mechanical properties and in vitro and in vivo performance were studied. The formulation was optimized using a single-factor experiment and the reproducibility was confirmed. The in vitro dissolution profiles of the tablet were determined in five dissolution media, in which the drug released from the hydrophilic tablets followed the Ritger–Peppas model kinetics in 0.01 N HCl medium for the first 2 h, and in phosphate-buffered saline medium (pH 7.5) for a further 24 h. Accelerated stability studies (40 °C, 75% relative humidity) proved that the optimal formulation was stable for 6 months. The in vivo pharmacokinetics study in beagle dogs showed that compared to the IMM-H014 immediate release preparation, the maximum plasma concentration of the extended-release (ER) preparation was significantly decreased, while the maximum time to peak and mean residence time were significantly prolonged. The relative bioavailability was 97.9% based on the area under curve, indicating that the optimal formulation has an obvious ER profile, and a good IVIVC was established, which could be used to predict in vivo pharmacokinetics based on the formulation composition. Full article

(This article belongs to the Special Issue Obesity, Adipose Tissue, and Bioactive Natural Products)

► Show Figures

Graphical abstract

19 pages, 4237 KiB

Open AccessArticle

Lysine Deprivation Suppresses Adipogenesis in 3T3-L1 Cells: A Transcriptome Analysis

by Leo Man-Yuen Lee, Zhi-Qiang Lin, Lu-Xi Zheng, Yi-Fan Tu, Yik-Hing So, Xiu-Hua Zheng, Tie-Jun Feng, Xi-Yue Wang, Wai-Ting Wong and Yun-Chung Leung

Int. J. Mol. Sci. 2023, 24(11), 9402; https://doi.org/10.3390/ijms24119402 - 28 May 2023

Cited by 1 | Viewed by 1865

Abstract

Growing evidence proves that amino acid restriction can reverse obesity by reducing adipose tissue mass. Amino acids are not only the building blocks of proteins but also serve as signaling molecules in multiple biological pathways. The study of adipocytes’ response to amino acid [...] Read more.

Growing evidence proves that amino acid restriction can reverse obesity by reducing adipose tissue mass. Amino acids are not only the building blocks of proteins but also serve as signaling molecules in multiple biological pathways. The study of adipocytes’ response to amino acid level changes is crucial. It has been reported that a low concentration of lysine suppresses lipid accumulation and transcription of several adipogenic genes in 3T3-L1 preadipocytes. However, the detailed lysine-deprivation-induced cellular transcriptomic changes and the altered pathways have yet to be fully studied. Here, using 3T3-L1 cells, we performed RNA sequencing on undifferentiated and differentiated cells, and differentiated cells under a lysine-free environment, and the data were subjected to KEGG enrichment. We found that the differentiation process of 3T3-L1 cells to adipocytes required the large-scale upregulation of metabolic pathways, mainly on the mitochondrial TCA cycle, oxidative phosphorylation, and downregulation of the lysosomal pathway. Single amino acid lysine depletion suppressed differentiation dose dependently. It disrupted the metabolism of cellular amino acids, which could be partially reflected in the changes in amino acid levels in the culture medium. It inhibited the mitochondria respiratory chain and upregulated the lysosomal pathway, which are essential for adipocyte differentiation. We also noticed that cellular interleukin 6 (IL6) expression and medium IL6 level were dramatically increased, which was one of the targets for suppressing adipogenesis induced by lysine depletion. Moreover, we showed that the depletion of some essential amino acids such as methionine and cystine could induce similar phenomena. This suggests that individual amino acid deprivation may share some common pathways. This descriptive study dissects the pathways for adipogenesis and how the cellular transcriptome was altered under lysine depletion. Full article

(This article belongs to the Special Issue Obesity, Adipose Tissue, and Bioactive Natural Products)

► Show Figures

Figure 1

16 pages, 7825 KiB

Open AccessArticle

Different Fatty Acid Supplementation in Low-Protein Diets Regulate Nutrient Utilization and Lipid and Amino Acid Metabolism in Weaned Pigs Model

by Qingsong Tang, Wenxue Li, Zhongxiang Ren, Qi Ding, Xie Peng, Zhiru Tang, Jiaman Pang, Yetong Xu and Zhihong Sun

Int. J. Mol. Sci. 2023, 24(10), 8501; https://doi.org/10.3390/ijms24108501 - 09 May 2023

Viewed by 1633

Abstract

This study was conducted to evaluate the effects of a low-protein (LP) diet supplemented with sodium butyrate (SB), medium-chain fatty acids (MCFAs) and n-3 polyunsaturated fatty acids (PUFAs) on nutrient utilization and lipid and amino acid metabolism in weaned pigs. A total of [...] Read more.

This study was conducted to evaluate the effects of a low-protein (LP) diet supplemented with sodium butyrate (SB), medium-chain fatty acids (MCFAs) and n-3 polyunsaturated fatty acids (PUFAs) on nutrient utilization and lipid and amino acid metabolism in weaned pigs. A total of 120 Duroc × Landrace × Yorkshire pigs (initial body weight: 7.93 ± 0.65 kg) were randomly assigned to five dietary treatments, including the control diet (CON), LP diet, LP + 0.2% SB diet (LP + SB), LP + 0.2% MCFA diet (LP + MCFA) and LP + 0.2% n-3 PUFA diet (LP + PUFA). The results show that the LP + MCFA diet increased (p < 0.05) the digestibility of dry matter and total P in pigs compared with the CON and LP diets. In the liver of the pigs, the metabolites involved in sugar metabolism and oxidative phosphorylation significantly changed with the LP diet compared with the CON diet. Compared with the LP diet, the altered metabolites in the liver of the pigs fed with the LP + SB diet were mainly associated with sugar metabolism and pyrimidine metabolism; the altered metabolites in the liver of pigs fed with the LP + MCFA and LP + PUFA diets were mainly associated with lipid metabolism and amino acid metabolism. In addition, the LP + PUFA diet increased (p < 0.05) the concentration of glutamate dehydrogenase in the liver of pigs compared with the LP diet. Furthermore, the LP + MCFA and LP + PUFA diets increased (p < 0.05) the mRNA abundance of sterol regulatory element-binding protein 1 and acetyl-CoA carboxylase in the liver compared with the CON diet. The LP + PUFA diet increased (p < 0.05) mRNA abundances of fatty acid synthase in the liver compared with the CON and LP diets. Collectively, the LP diet supplemented with MCFAs improved nutrient digestibility, and the LP diet supplemented with MCFAs and n-3 PUFAs promoted lipid and amino acid metabolisms. Full article

(This article belongs to the Special Issue Obesity, Adipose Tissue, and Bioactive Natural Products)

► Show Figures

Figure 1

Journal Menu

Journal Browser

Obesity, Adipose Tissue, and Bioactive Natural Products

Share This Special Issue

Special Issue Editor

Special Issue Information

Published Papers (8 papers)

Research

Further Information

Guidelines

MDPI Initiatives

Follow MDPI