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Yamaguchi T, Hoshizaki M, Imai Y, Yamamoto T, Kuba K. Cnot4 heterozygosity attenuates high fat diet-induced obesity in mice and impairs PPARγ-mediated adipocyte differentiation. PLoS One 2025; 20:e0316417. [PMID: 40424271 DOI: 10.1371/journal.pone.0316417] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2024] [Accepted: 04/24/2025] [Indexed: 05/29/2025] Open
Abstract
Adipocyte differentiation is crucial for formation and expansion of white adipose tissue and is also associated with the pathologies of obesity. CNOT4 is an E3 ubiquitin ligase and also contains RNA binding domain. In mammals CNOT4 has been suggested to interact with CCR4-NOT complex, a major executor of mRNA poly(A) shortening. While several subunits within the CCR4-NOT complex were shown to be involved in obesity and energy metabolism, the roles of CNOT4 in obesity remain unexplored. In this study, we generated and analyzed Cnot4 knockout mice and found that Cnot4 heterozygous (Cnot4 Het) mice exhibit resistance to high fat diet-induced obesity, including significant reduction in adipose tissue mass and hepatic lipid depots. However, Cnot4 Het did not affect mRNA expression of metabolic genes as well as serum lipid levels or glucose tolerance. On the other hand, Cnot4 Het fibroblasts significantly reduced the capability of differentiation into adipocytes and down-regulated adipogenic gene expression compared to wild type fibroblasts. Mechanistically, heterozygous deletion of Cnot4 down-regulated the transcriptional activity through decreased binding of PPARγ to promoter region of the target gene, thereby suppressing up-regulation of adipocyte marker gene expression in response to rosiglitazone, a PPARγ agonist. These results suggest that CNOT4 mediates adipocyte differentiation during formation and growth of adipose tissue partly through positively regulating transcriptional activity of PPARγ.
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Affiliation(s)
- Tomokazu Yamaguchi
- Department of Pharmacology, Kyushu University Graduate School of Medical Sciences, Fukuoka, Japan
| | - Midori Hoshizaki
- Department of Pharmacology, Kyushu University Graduate School of Medical Sciences, Fukuoka, Japan
| | - Yumiko Imai
- Department of Medical Infection System, Research Institute Nozaki Tokushukai Hospital, Osaka, Japan
| | - Tadashi Yamamoto
- Cell Signal Unit, Okinawa Institute of Science and Technology, Okinawa, Japan
| | - Keiji Kuba
- Department of Pharmacology, Kyushu University Graduate School of Medical Sciences, Fukuoka, Japan
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2
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Singh A, Chaudhary R. Potentials of peroxisome proliferator-activated receptor (PPAR) α, β/δ, and γ: An in-depth and comprehensive review of their molecular mechanisms, cellular Signalling, immune responses and therapeutic implications in multiple diseases. Int Immunopharmacol 2025; 155:114616. [PMID: 40222274 DOI: 10.1016/j.intimp.2025.114616] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2025] [Revised: 03/21/2025] [Accepted: 04/01/2025] [Indexed: 04/15/2025]
Abstract
Peroxisome proliferator-activated receptors (PPARs), ligand-activated transcription factors, have emerged as a key regulator of various biological processes, underscoring their relevance in the pathophysiology and treatment of numerous diseases. PPARs are primarily recognized for their critical role in lipid and glucose metabolism, which underpins their therapeutic applications in managing type 2 diabetes mellitus. Beyond metabolic disorders, they have gained attention for their involvement in immune modulation, making them potential targets for autoimmune-related inflammatory diseases. Furthermore, PPAR's ability to regulate proliferation, differentiation, and apoptosis has positioned them as promising candidates in oncology. Their anti-inflammatory and anti-fibrotic properties further highlight their potential in dermatological and cardiovascular conditions, where dysregulated inflammatory responses contribute to disease progression. Recent advancements have elucidated the molecular mechanisms of different PPAR isoforms, including their regulation of key signalling pathways such as NF-κB and MAPK, which are crucial in inflammation and cellular stress responses. Additionally, their interactions with co-factors and post-translational modifications further diversify their functional roles. The therapeutic potential of various PPAR agonists has been extensively explored, although challenges related to side effects and target specificity remain. This growing body of evidence underscores the significance of PPARs in understanding the molecular basis of diseases and advancing therapeutic interventions, paving way for targeted treatment approach across a wide spectrum of medical conditions. Here, we provide a comprehensive and detailed perspective of PPARs and their potential across different health conditions to advance our understanding, elucidate underlying mechanisms, and facilitate the development of potential treatment strategies.
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Affiliation(s)
- Alpana Singh
- Department of Pharmaceutical Sciences, Babasaheb Bhimrao Ambedkar University, Vidya Vihar, Raebareli Road, Lucknow 226025, U.P., India
| | - Rishabh Chaudhary
- Department of Pharmaceutical Sciences, Babasaheb Bhimrao Ambedkar University, Vidya Vihar, Raebareli Road, Lucknow 226025, U.P., India.
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3
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Lang A, Ildefeld N, Lillich FF, Kaiser A, Busch R, Marschner JA, Proschak E, Heering J, Schubert-Zsilavecz M, Merk D. Fragment-Based Discovery of Drug-like LRH-1 Agonists. ACS Med Chem Lett 2025; 16:575-582. [PMID: 40236550 PMCID: PMC11995229 DOI: 10.1021/acsmedchemlett.4c00604] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2024] [Revised: 03/13/2025] [Accepted: 03/14/2025] [Indexed: 04/17/2025] Open
Abstract
The phospholipid sensing transcription factor liver receptor homologue 1 (LRH-1) participates in the transcriptional regulation of metabolic balance and inflammation in liver, pancreas, and other tissues. It is an emerging target for metabolic dysfunction, fatty liver disease, and cancer, but LRH-1 modulators are rare and lack drug-like properties. We discovered new LRH-1 ligands with improved physicochemical features in a fragment-based approach and optimized a venlafaxine-related lead for LRH-1 activation. Despite a strict structure-activity relationship, systematic structural variation resulted in a new LRH-1 agonist scaffold with strong activation efficacy, validated direct and cellular target engagement, and anti-inflammatory and ER-stress-resolving properties in functional cellular settings.
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Affiliation(s)
- Alisa Lang
- Institute
of Pharmaceutical Chemistry, Goethe University
Frankfurt, 60438 Frankfurt, Germany
| | - Niklas Ildefeld
- Institute
of Pharmaceutical Chemistry, Goethe University
Frankfurt, 60438 Frankfurt, Germany
| | - Felix F. Lillich
- Fraunhofer
Institute for Translational Medicine and Pharmacology ITMP, 60596 Frankfurt, Germany
| | - Astrid Kaiser
- Institute
of Pharmaceutical Chemistry, Goethe University
Frankfurt, 60438 Frankfurt, Germany
| | - Romy Busch
- Department
of Pharmacy, Ludwig-Maximilians-Universität
(LMU) München, 81377 Munich, Germany
| | - Julian A. Marschner
- Department
of Pharmacy, Ludwig-Maximilians-Universität
(LMU) München, 81377 Munich, Germany
| | - Ewgenij Proschak
- Institute
of Pharmaceutical Chemistry, Goethe University
Frankfurt, 60438 Frankfurt, Germany
| | - Jan Heering
- Fraunhofer
Institute for Translational Medicine and Pharmacology ITMP, 60596 Frankfurt, Germany
| | | | - Daniel Merk
- Institute
of Pharmaceutical Chemistry, Goethe University
Frankfurt, 60438 Frankfurt, Germany
- Department
of Pharmacy, Ludwig-Maximilians-Universität
(LMU) München, 81377 Munich, Germany
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Pan J, Liang J, Xue Z, Meng X, Jia L. Effect of dietary anthocyanins on the risk factors related to metabolic syndrome: A systematic review and meta-analysis. PLoS One 2025; 20:e0315504. [PMID: 39928643 PMCID: PMC11809928 DOI: 10.1371/journal.pone.0315504] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2024] [Accepted: 11/25/2024] [Indexed: 02/12/2025] Open
Abstract
OBJECTIVE This meta-analysis aims to systematically investigate whether dietary anthocyanin supplementation can reduce metabolic syndrome (MetS)-related risk factors: abdominal obesity, dyslipidemia (low high-density lipoprotein cholesterol (HDL-C) and hypertriglyceridemia), hypertension, and hyperglycemia by conducting a meta-analysis of randomized controlled trials (RCTs). METHODS A systematic search of 5 electronic databases (PubMed, Web of Science, Scopus, Cochrane Library, and Embase) was conducted from inception until April 25, 2024. A total of 1213 studies were identified, of which randomized controlled trials involving subjects with MetS-related factors, comparing dietary anthocyanin supplementation with placebo, and reporting results on anthropometric, physiological, and metabolic markers relevant to this study were selected. Depending on the heterogeneity of the included studies, a fixed-effect model was applied for low heterogeneity (I2 < 50%), whereas a random-effects model was employed when substantial heterogeneity was present (I2 ≥ 50%). The weighted mean difference (WMD) and 95% confidence intervals (CI) were calculated. RESULTS This meta-analysis included 29 randomized controlled trials with 2006 participants. The results showed that dietary anthocyanins significantly improved various lipid and glycemic markers: HDL-C: increased by 0.05 mmol/L (95% CI: 0.01 to 0.10, p = 0.026), LDL-C: decreased by 0.18 mmol/L (95% CI: -0.28 to -0.08, p = 0.000), Triglycerides (TGs): reduced by 0.11 mmol/L (95% CI: -0.20 to -0.02, p = 0.021), Total cholesterol (TC): lowered by 0.34 mmol/L (95% CI: -0.49 to -0.18, p = 0.000), Fasting blood glucose (FBG): reduced by 0.29 mmol/L (95% CI: -0.46 to -0.12, p = 0.001), Glycated hemoglobin (HbA1c): decreased by 0.43% (95% CI: -0.74 to -0.13, p = 0.005). Weight: (WMD: -0.12 kg, 95% CI: -0.45 to 0.21, p = 0.473), Body mass index (BMI): (WMD: -0.12 kg/m2, 95% CI: -0.26 to 0.03, p = 0.12), Overall WC: (WMD: 0.18 cm, 95% CI: -0.51 to 0.87, p = 0.613), Systolic blood pressure (SBP): (WMD: -0.12 mmHg, 95% CI: -1.06 to 0.82, p = 0.801), Diastolic blood pressure (DBP): (WMD: 0.61 mmHg, 95% CI: -0.03 to 1.25, p = 0.061), Insulin levels: (WMD: -0.02 mU/L, 95% CI: -0.44 to 0.40, p = 0.932), HOMA-IR: (WMD: -0.11, 95% CI: -0.51 to 0.28, p = 0.573). Additionally, a 100 mg/day dosage of anthocyanins significantly reduced: Waist circumference (WC): by 0.55 cm (95% CI: -1.09 to -0.01, p = 0.047). Subgroup analyses based on intervention duration, anthocyanin dosage, health status, formulation, dosage frequency, physical activity levels, and baseline levels of corresponding markers revealed varying significances, particularly in relation to blood pressure. CONCLUSION Dietary anthocyanins effectively improve low HDL cholesterol, hypertriglyceridemia, and hyperglycemia, making them a promising adjunct for managing MetS. However, it is important to note that dietary anthocyanin interventions may raise systolic blood pressure (SBP) and diastolic blood pressure (DBP) depending on intervention dose, duration, participant health status, and formulation. Clinicians should fully consider these effects when recommending anthocyanin supplementation. Further long-term, well-designed, large-scale clinical trials are needed to draw definitive conclusions.
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Affiliation(s)
- Junyin Pan
- School of Pharmacy of Heilongjiang University of Chinese Medicine, Harbin, Heilongjiang, China
| | - Jingwen Liang
- School of Pharmacy of Heilongjiang University of Chinese Medicine, Harbin, Heilongjiang, China
| | - Zhantu Xue
- Foshan Clinical Medical School of Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, China
| | - Xin Meng
- School of Pharmacy of Heilongjiang University of Chinese Medicine, Harbin, Heilongjiang, China
| | - Liwei Jia
- School of Pharmacy of Heilongjiang University of Chinese Medicine, Harbin, Heilongjiang, China
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5
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Beigoli S, Kiani S, Asgharzadeh F, Memarzia A, Boskabady MH. Promising role of peroxisome proliferator-activated receptors in respiratory disorders, a review. Drug Metab Rev 2025; 57:26-50. [PMID: 39726246 DOI: 10.1080/03602532.2024.2442012] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2024] [Accepted: 12/09/2024] [Indexed: 12/28/2024]
Abstract
Several studies indicate various pharmacological and therapeutic effects of peroxisome proliferator-activated receptors (PPARs) in different disorders. The current review describes the influences of PPARs on respiratory, allergic, and immunologic diseases. Various databases, including PubMed, Science Direct, and Scopus, were searched regarding the effect of PPARs on respiratory and allergic disorders from 1990 to 2024. The effects of PPARs stimulation on experimental animal models of respiratory diseases such as asthma, chronic obstructive pulmonary diseases (COPD), pulmonary fibrosis (PF), and lung infections were shown. Therapeutic potential mediated through PPARs has also been demonstrated in lung cancer, lung infections, and allergic and immunologic disorders. However, few clinical studies showed PPARs mediated therapeutic effects on asthma and COPD. The PPARs-mediated effects on various respiratory disorders were shown through antioxidant, immunomodulatory, anti-inflammatory, and other mechanisms. Therefore, this review indicated possible remedy effects mediated by these receptors in treating respiratory, allergic, and immunologic diseases. Moreover, this mechanistic review paves the way for researchers to consider further experimental and clinical studies.
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Affiliation(s)
- Sima Beigoli
- Applied Biomedical Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Sahar Kiani
- Department of Stem Cell and Developmental Biology, Cell Science Research Center, ROYAN Institute for Stem Cell Biology and Technology, ACECR, Tehran, Iran
- Department of Brain and Cognitive Sciences, Cell Science Research Center, ROYAN Institute for Stem Cell Biology and Technology, ACECR, Tehran, Iran
| | - Fereshteh Asgharzadeh
- Department of Physiology, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Arghavan Memarzia
- Applied Biomedical Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
- Department of Physiology, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Mohammad Hossein Boskabady
- Applied Biomedical Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
- Department of Physiology, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
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Gianopoulos I, Mantzoros CS, Daskalopoulou SS. Adiponectin and Adiponectin Receptors in Atherosclerosis. Endocr Rev 2025; 46:1-25. [PMID: 39106421 PMCID: PMC11720176 DOI: 10.1210/endrev/bnae021] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/20/2023] [Revised: 05/14/2024] [Accepted: 08/02/2024] [Indexed: 08/09/2024]
Abstract
Adiponectin is an abundantly secreted hormone that communicates information between the adipose tissue, and the immune and cardiovascular systems. In metabolically healthy individuals, adiponectin is usually found at high levels and helps improve insulin responsiveness of peripheral tissues, glucose tolerance, and fatty acid oxidation. Beyond its metabolic functions in insulin-sensitive tissues, adiponectin plays a prominent role in attenuating the development of atherosclerotic plaques, partially through regulating macrophage-mediated responses. In this context, adiponectin binds to its receptors, adiponectin receptor 1 (AdipoR1) and AdipoR2 on the cell surface of macrophages to activate a downstream signaling cascade and induce specific atheroprotective functions. Notably, macrophages modulate the stability of the plaque through their ability to switch between proinflammatory responders, and anti-inflammatory proresolving mediators. Traditionally, the extremes of the macrophage polarization spectrum span from M1 proinflammatory and M2 anti-inflammatory phenotypes. Previous evidence has demonstrated that the adiponectin-AdipoR pathway influences M1-M2 macrophage polarization; adiponectin promotes a shift toward an M2-like state, whereas AdipoR1- and AdipoR2-specific contributions are more nuanced. To explore these concepts in depth, we discuss in this review the effect of adiponectin and AdipoR1/R2 on 1) metabolic and immune responses, and 2) M1-M2 macrophage polarization, including their ability to attenuate atherosclerotic plaque inflammation, and their potential as therapeutic targets for clinical applications.
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Affiliation(s)
- Ioanna Gianopoulos
- Division of Experimental Medicine, Department of Medicine, Faculty of Medicine, Research Institute of the McGill University Health Centre, McGill University, Montreal, Quebec H4A 3J1, Canada
| | - Christos S Mantzoros
- Division of Endocrinology, Diabetes and Metabolism, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA
- Section of Endocrinology, Diabetes and Metabolism, Boston VA Healthcare System, Boston, MA 02130, USA
| | - Stella S Daskalopoulou
- Division of Experimental Medicine, Department of Medicine, Faculty of Medicine, Research Institute of the McGill University Health Centre, McGill University, Montreal, Quebec H4A 3J1, Canada
- Division of Internal Medicine, Department of Medicine, Faculty of Medicine, McGill University Health Centre, McGill University, Montreal, Quebec H4A 3J1, Canada
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7
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Ganbold M, Takahashi S, Kakui O, Nakajima M, Isoda H. Inhibitory effects of cashew Anacardium occidentale L. kernel, apple, and shell extracts on lipid accumulation and adipogenesis in 3T3-L1 adipocytes. Sci Rep 2025; 15:1644. [PMID: 39794379 PMCID: PMC11723992 DOI: 10.1038/s41598-025-85727-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2024] [Accepted: 01/06/2025] [Indexed: 01/13/2025] Open
Abstract
Obesity, a major risk factor for various metabolic diseases, often results in dysfunctional white adipose tissue and altered adipogenesis leading to ectopic fat accumulation, inflammation, and insulin resistance. On the other hand, cashew (Anacardium occidentale L.) nut worldwide consumption and production is increasing steadily, which augments the mass of byproducts to be discarded. Indeed, cashew apples and cashew shells have shown potent effects to lower adiposity weight in human and animal models. However, the direct effect on adipocyte differentiation still remains unexplored. Therefore, this study aimed to investigate the biological effect of cashew nut or kernel (CK), dried cashew apple (DA), and cashew shell (SH) ethanolic extracts on 3T3-L1 adipocyte differentiation and lipid accumulation. SH showed strong inhibition on adipocyte differentiation by downregulating transcription factors, PPARγ, C/EBPα, and SREBP-1. DA also inhibited the transcription factors accompanied by reduced lipid accumulation, while proteins for de novo lipogenesis were unchanged. Finally, CK did not alter any markers in adipocyte differentiation, however, interestingly adiponectin level was significantly increased. Concisely, our findings showed that CK ameliorates adiponectin production without interfering adipogenesis, while DA lowers lipid accumulation and SH suppresses adipogenesis.
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Affiliation(s)
- Munkhzul Ganbold
- Open Innovation Laboratory for Food and Medicinal Resource Engineering (FoodMed-OIL), National Institute of Advanced Science and Technology (AIST), Tsukuba, Japan
| | - Shinya Takahashi
- Institute of Life and Environmental Sciences, University of Tsukuba, Tsukuba, Japan
- Alliance for Research on the Mediterranean and North Africa (ARENA), University of Tsukuba, Tsukuba, Japan
| | - Osamu Kakui
- Biotechnical Create Co.Ltd, Hatchobori 4-12-20, Chuo-ku, Tokyo, Japan
| | - Mitsutoshi Nakajima
- Institute of Life and Environmental Sciences, University of Tsukuba, Tsukuba, Japan
- Alliance for Research on the Mediterranean and North Africa (ARENA), University of Tsukuba, Tsukuba, Japan
| | - Hiroko Isoda
- Open Innovation Laboratory for Food and Medicinal Resource Engineering (FoodMed-OIL), National Institute of Advanced Science and Technology (AIST), Tsukuba, Japan.
- Institute of Life and Environmental Sciences, University of Tsukuba, Tsukuba, Japan.
- Alliance for Research on the Mediterranean and North Africa (ARENA), University of Tsukuba, Tsukuba, Japan.
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8
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Nhoek P, Hwang S, Huh J, Pel P, Park CW, Khiev P, Kim HW, Noh M, Chin YW. Butanolides and clerodane diterpenes from the twigs of Casearia grewiifolia and their effects on adiponectin secretion. Bioorg Chem 2024; 153:107890. [PMID: 39427630 DOI: 10.1016/j.bioorg.2024.107890] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2024] [Revised: 10/07/2024] [Accepted: 10/12/2024] [Indexed: 10/22/2024]
Abstract
Three butanolides derivatives, grewiifolides A-C, and nine clerodane diterpenes, grewiifolins M-U, as well as a known sterol were isolated from the twigs of Casearia grewiifolia. The chemical structures and configurations of all isolates were established by various spectroscopic means and chemical derivatization. In a cell-based phenotypic assay using the adipogenesis model of human bone marrow mesenchymal stem cells (hBM-MSCs), grewiifolide B significantly promoted adiponectin-secretion with EC50 value of 24.8 µM. In target identification studies, butanolide derivatives were selectively bound to PPARγ with Ki values of 4.65, 0.55, and 17.8 µM, respectively. Further functional analysis and molecular modeling revealed that grewiifolide B promotes adiponectin-secretion through PPARγ full agonism.
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Affiliation(s)
- Piseth Nhoek
- Natural Product Research Institute and Research Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University, Seoul 08826, Republic of Korea
| | - Seokyoung Hwang
- Natural Product Research Institute and Research Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University, Seoul 08826, Republic of Korea
| | - Jungmoo Huh
- Natural Product Research Institute and Research Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University, Seoul 08826, Republic of Korea
| | - Pisey Pel
- Natural Product Research Institute and Research Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University, Seoul 08826, Republic of Korea
| | - Chan-Woong Park
- Natural Product Research Institute and Research Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University, Seoul 08826, Republic of Korea
| | - Piseth Khiev
- Royal University of Phnom Penh, Department of Biology, Russian Federation Boulevard, Khan Toul Kork, Phnom Penh 12156, Cambodia
| | - Hyun Woo Kim
- College of Pharmacy and Integrated Research Institute for Drug Development, Dongguk University-Seoul, Gyeonggi-do 04620, Republic of Korea
| | - Minsoo Noh
- Natural Product Research Institute and Research Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University, Seoul 08826, Republic of Korea.
| | - Young-Won Chin
- Natural Product Research Institute and Research Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University, Seoul 08826, Republic of Korea.
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Jackson KH, Harris WS, Belury MA, Kris-Etherton PM, Calder PC. Beneficial effects of linoleic acid on cardiometabolic health: an update. Lipids Health Dis 2024; 23:296. [PMID: 39267068 PMCID: PMC11391774 DOI: 10.1186/s12944-024-02246-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2024] [Accepted: 08/09/2024] [Indexed: 09/14/2024] Open
Abstract
Linoleic acid (LA), as a part of the wider debate about saturated, omega-6 and omega-3 fatty acids (FAs) and health, continues to be at the center of controversy in the world of fatty acid research. A robust evidence base, however, demonstrates that higher intakes and blood levels of LA are associated with improved cardiometabolic health outcomes. LA lowers total and low-density lipoprotein cholesterol when compared with saturated fatty acids and carbohydrates. Using large prospective datasets, higher blood levels of LA were associated with lower risk of coronary heart disease, stroke and incident type-2 diabetes mellitus compared with lower levels, suggesting that, across the range of typical dietary intakes, higher LA is beneficial. Recent trials of LA-rich oils report favorable outcomes in people with common lipid disorders. However, an LA intake that is too high can impair endogenous synthesis of eicosapentaenoic acid (EPA) from alpha-linolenic acid (ALA), but the threshold at which this becomes clinically relevant is not known. In the absence of a significant intake of EPA and docosahexaenoic acid, an ideal dietary ratio of LA and ALA may be theoretically useful as it provides insight into the likely extent of endogenous EPA synthesis from ALA. Updating dietary reference intakes (DRIs) for LA and ALA is needed; however, there are insufficient data to establish RDAs for these fatty acids. The omega-6 (n-6) to omega-3 (n-3) PUFA ratio is not informative and does not shed meaningful insight about the amount of individual fatty acids in each class needed to confer health benefits.
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Affiliation(s)
- Kristina H Jackson
- OmegaQuant Analytics, 5009 W. 12th St, Suite 8, Sioux Falls, Sioux Falls, SD, 57106, USA.
- Fatty Acid Research Institute, Sioux Falls, SD, USA.
- Sanford School of Medicine, University of South Dakota, Sioux Falls, SD, USA.
| | - William S Harris
- OmegaQuant Analytics, 5009 W. 12th St, Suite 8, Sioux Falls, Sioux Falls, SD, 57106, USA
- Fatty Acid Research Institute, Sioux Falls, SD, USA
- Sanford School of Medicine, University of South Dakota, Sioux Falls, SD, USA
| | - Martha A Belury
- Department of Food Science and Technology, The Ohio State University, Columbus, OH, USA
| | - Penny M Kris-Etherton
- Department of Nutritional Sciences, The Pennsylvania State University, University Park, PA, USA
| | - Philip C Calder
- School of Human Development and Health, Faculty of Medicine, University of Southampton, Southampton, UK
- NIHR Southampton Biomedical Research Centre, University Hospital Southampton NHS Foundation Trust and University of Southampton, Southampton, UK
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10
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Rapuano R, Mercuri A, Dallavalle S, Moricca S, Lavecchia A, Lupo A. Cladosporols and PPARγ: Same Gun, Same Bullet, More Targets. Biomolecules 2024; 14:998. [PMID: 39199386 PMCID: PMC11353246 DOI: 10.3390/biom14080998] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2024] [Revised: 07/26/2024] [Accepted: 08/02/2024] [Indexed: 09/01/2024] Open
Abstract
Several natural compounds have been found to act as PPARγ agonists, thus regulating numerous biological processes, including the metabolism of carbohydrates and lipids, cell proliferation and differentiation, angiogenesis, and inflammation. Recently, Cladosporols, secondary metabolites purified from the fungus Cladosporium tenuissimum, have been demonstrated to display an efficient ability to control cell proliferation in human colorectal and prostate cancer cells through a PPARγ-mediated modulation of gene expression. In addition, Cladosporols exhibited a strong anti-adipogenetic activity in 3T3-L1 murine preadipocytes, preventing their in vitro differentiation into mature adipocytes. These data interestingly point out that the interaction between Cladosporols and PPARγ, in the milieu of different cells or tissues, might generate a wide range of beneficial effects for the entire organism affected by diabetes, obesity, inflammation, and cancer. This review explores the molecular mechanisms by which the Cladosporol/PPARγ complex may simultaneously interfere with a dysregulated lipid metabolism and cancer promotion and progression, highlighting the potential therapeutic benefits of Cladosporols for human health.
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Affiliation(s)
- Roberta Rapuano
- Dipartimento di Scienze e Tecnologie, Università del Sannio, Via dei Mulini, 82100 Benevento, Italy; (R.R.); (A.M.)
| | - Antonella Mercuri
- Dipartimento di Scienze e Tecnologie, Università del Sannio, Via dei Mulini, 82100 Benevento, Italy; (R.R.); (A.M.)
| | - Sabrina Dallavalle
- Dipartimento di Scienze per gli Alimenti, la Nutrizione e l’Ambiente, Università degli Studi di Milano, Via Celoria 2, 20133 Milano, Italy;
| | - Salvatore Moricca
- Dipartimento di Scienze e Tecnologie Agrarie, Alimentari, Ambientali e Forestali (DAGRI), Università degli Studi di Firenze, Piazzale delle Cascine 28, 50144 Firenze, Italy;
| | - Antonio Lavecchia
- Dipartimento di Farmacia “Drug Discovery Laboratory”, Università di Napoli “Federico II”, Via D. Montesano 49, 80131 Napoli, Italy
| | - Angelo Lupo
- Dipartimento di Scienze e Tecnologie, Università del Sannio, Via dei Mulini, 82100 Benevento, Italy; (R.R.); (A.M.)
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Katahira S, Barth M, Döpp R, Sugimura Y, Schmidt V, Selig JI, Saiki Y, Jankowski J, Marx N, Jahnen-Dechent W, Lichtenberg A, Akhyari P. Pioglitazone treatment mitigates cardiovascular bioprosthetic degeneration in a chronic kidney disease model. Front Pharmacol 2024; 15:1412169. [PMID: 39175545 PMCID: PMC11338925 DOI: 10.3389/fphar.2024.1412169] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2024] [Accepted: 07/25/2024] [Indexed: 08/24/2024] Open
Abstract
Aims Chronic kidney disease (CKD) is a risk factor for the development of cardiovascular diseases, e.g., atherosclerosis and calcific aortic valve disease, leading inevitably to valve replacement surgery. CKD patients with bioprosthetic cardiovascular grafts, in turn, have a higher risk of premature graft degeneration. Peroxisome proliferator-activated receptor gamma (PPARγ) activation by pioglitazone has cardio-renal protective properties, and research using a heterotopic valve implantation model has shown anti-degenerative effects of PPARγ activation on bioprosthetic valved grafts (BVG) in rats. The present work aims to analyze a potential protective effect of pioglitazone treatment on BVG in an adenine-induced rat model of CKD. Methods and Results BVG of Sprague Dawley rats were heterotopically implanted in Wistar rats in an infrarenal position for 4 and 8 weeks. Animals were distributed into three groups for each time point: 1) control group receiving standard chow, 2) CKD group receiving 0.25% adenine and 3) CKD + pioglitazone group (300 mg per kg of 0.25% adenine chow). BVG function was analyzed by echocardiography. Plasma analytes were determined and explanted grafts were analyzed by semi-quantitative real-time PCR, Western blot analysis, histology and immunohistology.PPARγ activation significantly reduced CKD-induced calcification of aortic and valvular segments of BVG by 44% and 53%, respectively. Pioglitazone treatment significantly also reduced CKD-induced intima hyperplasia by 60%. Plasma analysis revealed significantly attenuated potassium and phosphate levels after pioglitazone treatment. Moreover, PPARγ activation led to significantly decreased interleukin-6 gene expression (by 57%) in BVG compared to CKD animals. Pioglitazone treatment leads to functional improvement of BVG. Conclusion This study broadens the understanding of the potential value of PPARγ activation in cardio-renal diseases and delineates pioglitazone treatment as a valuable option to prevent bioprosthetic graft failure in CKD. Further mechanistic studies, e.g., using small molecules activating PPARγ signaling pathways, are necessary for the evaluation of involved mechanisms. Additionally, the translation into pre-clinical studies using large animals is intended as the next research project.
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Affiliation(s)
- Shintaro Katahira
- Department of Cardiovascular Surgery, Medical Faculty, University Hospital Düsseldorf, Heinrich Heine University Düsseldorf, Dusseldorf, Germany
- Division of Cardiovascular Surgery, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Mareike Barth
- Department of Cardiovascular Surgery, Medical Faculty, University Hospital Düsseldorf, Heinrich Heine University Düsseldorf, Dusseldorf, Germany
- Department of Cardiac Surgery, Medical Faculty, University Hospital RWTH Aachen, Aachen, Germany
| | - Robin Döpp
- Department of Cardiovascular Surgery, Medical Faculty, University Hospital Düsseldorf, Heinrich Heine University Düsseldorf, Dusseldorf, Germany
| | - Yukiharu Sugimura
- Department of Cardiovascular Surgery, Medical Faculty, University Hospital Düsseldorf, Heinrich Heine University Düsseldorf, Dusseldorf, Germany
- Department of Thoracic and Cardiovascular Surgery, West German Heart and Vascular Center, University of Duisburg-Essen, Essen, Germany
| | - Vera Schmidt
- Department of Cardiovascular Surgery, Medical Faculty, University Hospital Düsseldorf, Heinrich Heine University Düsseldorf, Dusseldorf, Germany
| | - Jessica Isabel Selig
- Department of Cardiovascular Surgery, Medical Faculty, University Hospital Düsseldorf, Heinrich Heine University Düsseldorf, Dusseldorf, Germany
| | - Yoshikatsu Saiki
- Division of Cardiovascular Surgery, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Joachim Jankowski
- Institute of Molecular Cardiovascular Research, Medical Faculty, RWTH Aachen University, Aachen, Germany
| | - Nikolaus Marx
- Department of Internal Medicine I (Cardiology), University Hospital RWTH Aachen University, Aachen, Germany
| | - Willi Jahnen-Dechent
- Helmholtz-Institute for Biomedical Engineering, University Hospital RWTH Aachen, Aachen, Germany
| | - Artur Lichtenberg
- Department of Cardiovascular Surgery, Medical Faculty, University Hospital Düsseldorf, Heinrich Heine University Düsseldorf, Dusseldorf, Germany
| | - Payam Akhyari
- Department of Cardiovascular Surgery, Medical Faculty, University Hospital Düsseldorf, Heinrich Heine University Düsseldorf, Dusseldorf, Germany
- Department of Thoracic and Cardiovascular Surgery, West German Heart and Vascular Center, University of Duisburg-Essen, Essen, Germany
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Yang YH, Fan XX, Ye L, Huang WJ, Ko CY. Examining the molecular mechanisms of topiramate in alleviating insulin resistance: A study on C2C12 myocytes and 3T3L-1 adipocytes. Endocrine 2024; 85:168-180. [PMID: 38308786 DOI: 10.1007/s12020-024-03706-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/04/2023] [Accepted: 01/17/2024] [Indexed: 02/05/2024]
Abstract
PURPOSE Migraine, a severely debilitating condition, may be effectively managed with topiramate, known for its migraine prevention and weight loss properties due to changes in body muscle and fat composition and improved insulin sensitivity. However, the mechanism of topiramate in modulating insulin response in adipocytes and myocytes remains elusive. This study aims to elucidate these molecular mechanisms, offering insights into its role in weight management for migraine sufferers and underpinning its clinical application. METHODS Insulin resistance improvements were evaluated through glucose uptake measurements in C2C12 muscle cells and 3T3L-1 adipocytes, with Oil red O staining conducted on adipocytes. RNA-seq transcriptome analysis was used to identify the regulatory target genes of topiramate in these cells. The involvement of key genes and pathways was further validated through western blot analysis. RESULTS Topiramate effectively reduced insulin resistance in C2C12 and 3T3L-1 cells. In C2C12 cells, it significantly lowered SORBS1 gene and protein levels. In 3T3L-1 cells, topiramate upregulated CTGF and downregulated MAPK8 and KPNA1 genes. Changes were notable in nuclear cytoplasmic transport and circadian signaling pathways. Furthermore, it caused downregulation of MKK7, pJNK1/ JNK1, BMAL1, and CLOCK proteins compared to the insulin-resistant model. CONCLUSION This study provides preliminary insights into the mechanisms through which topiramate modulates insulin resistance in C2C12 myocytes and 3T3L-1 adipocytes, enhancing our understanding of its therapeutic potential in managing weight and insulin sensitivity in migraine patients.
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Affiliation(s)
- Ya-Hui Yang
- The School of Public Health, Fujian Medical University, Fuzhou, Fujian, 350122, China
- Department of Clinical Nutrition, the Second Affiliated Hospital of Fujian Medical University, Quanzhou, 362000, China
| | - Xi-Xin Fan
- The School of Public Health, Fujian Medical University, Fuzhou, Fujian, 350122, China
- Department of Clinical Nutrition, the Second Affiliated Hospital of Fujian Medical University, Quanzhou, 362000, China
| | - Lichao Ye
- Department of Neurology, the Second Affiliated Hospital of Fujian Medical University, Quanzhou, Fujian, 3620000, China
| | - Wen-Jian Huang
- Department of Clinical Nutrition, the Second Affiliated Hospital of Fujian Medical University, Quanzhou, 362000, China
- Huidong Center for Chronic Disease Control, Huizhou, Guangdong Province, 516300, China
| | - Chih-Yuan Ko
- The School of Public Health, Fujian Medical University, Fuzhou, Fujian, 350122, China.
- Department of Clinical Nutrition, the Second Affiliated Hospital of Fujian Medical University, Quanzhou, 362000, China.
- The School of Medical Technology and Engineering, Fujian Medical University, Fuzhou, Fujian, 350122, China.
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13
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Afzal S, Sattar MA, Albokhadaim I, Attiq A, Kandeel M, Manap ASA, Alhojaily SM. Interaction between Nuclear Receptor and Alpha-Adrenergic Agonist Subtypes in Metabolism and Systemic Hemodynamics of Spontaneously Hypertensive Rats. PPAR Res 2024; 2024:5868010. [PMID: 38899161 PMCID: PMC11186691 DOI: 10.1155/2024/5868010] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2023] [Revised: 11/22/2023] [Accepted: 05/03/2024] [Indexed: 06/21/2024] Open
Abstract
Partial and full PPAR-γ agonists have shown promising effects and antihypertensive and antidiabetic agents through increased plasma adiponectin concentration. This study is aimed at examining the role of PPAR-γ, alpha-adrenoceptors, and adiponectin receptors in the modulation of vasopressor responses to angiotensin II (Ang II) and adrenergic agonists, after a subset treatment of partial and full PPAR-γ agonists, each individually, and also when coupled with adiponectin in SHRs. The antioxidant potential and metabolic indices for these animals were also determined. Group I (WKY) and group II (SHR) were designated as normotensive control and hypertensive control, respectively. Groups III (SHR) and IV (SHR) received irbesartan (30 mg/kg) and pioglitazone (10 mg/kg) orally for 28 days, and groups V (SHR), VI (SHR), and VII (SHR) were treated with adiponectin (2.5 μg/kg) intraperitoneally alone, in combination with irbesartan, and in combination with pioglitazone, respectively, from days 21 to 28 only. On day 29, sodium pentobarbitone (60 mg/kg) was used to anesthetize all test animals, and systemic hemodynamic and plasma adiponectin concentrations and in vitro and in vivo antioxidant potential were measured. As compared to the WKY control, the SHR control group's noninvasive blood pressure and basal mean arterial pressure were significantly greater, along with increased arterial stiffness, lower plasma nitric oxide, adiponectin concentration, and antioxidant enzyme levels (all P < 0.05). However, they were gradually normalized by single drug treatments in all groups, and to a greater extent in the SHR + Irb + Adp group (P < 0.05). In the acute study, the dose dependant mean arterial pressure responses to intravenously administered adrenergic agonists and angiotensin-II were significantly larger in SHRs as compared to WKY by 20-25%. Adiponectin alone and in combination significantly blunted vasopressor responses to these alpha-adrenergic agonists in the SHR + Pio + Adp group by 63%, whereas attenuated responses to ANG-II administration to 70% in SHR + Irb + Adp. In conclusion, the combined treatment of adiponectin with PPAR-agonists reduced the systemic vascular responses to adrenergic agonists and improved arterial stiffness. This an evidence of the interaction of adiponectin receptors, PPAR-γ, alpha-adrenoceptors, and ANG-II in the systemic vasculature of SHRs. A significant level of synergism has also been proved among full PPAR-γ agonists and adiponectin receptors.
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Affiliation(s)
- Sheryar Afzal
- Department of Biomedical ScienceCollege of Veterinary MedicineKing Faisal University, Al Hofuf, Saudi Arabia
- Discipline of PharmacologySchool of Pharmaceutical SciencesUniversiti Sains Malaysia, Gelugor 11800, Penang, Malaysia
| | - Munavvar Abdul Sattar
- Discipline of PharmacologySchool of Pharmaceutical SciencesUniversiti Sains Malaysia, Gelugor 11800, Penang, Malaysia
| | - Ibrahim Albokhadaim
- Department of Biomedical ScienceCollege of Veterinary MedicineKing Faisal University, Al Hofuf, Saudi Arabia
| | - Ali Attiq
- Discipline of PharmacologySchool of Pharmaceutical SciencesUniversiti Sains Malaysia, Gelugor 11800, Penang, Malaysia
| | - Mahmoud Kandeel
- Department of Biomedical ScienceCollege of Veterinary MedicineKing Faisal University, Al Hofuf, Saudi Arabia
| | - Aimi Syamima Abdul Manap
- Department of Biomedical ScienceCollege of Veterinary MedicineKing Faisal University, Al Hofuf, Saudi Arabia
| | - Sameer M. Alhojaily
- Department of Biomedical ScienceCollege of Veterinary MedicineKing Faisal University, Al Hofuf, Saudi Arabia
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Ozawa R, Iwata H, Kuwayama T, Shirasuna K. Maternal hypertensive condition alters adipose tissue function and blood pressure sensitivity in offspring. Biochem Biophys Res Commun 2024; 707:149617. [PMID: 38520942 DOI: 10.1016/j.bbrc.2024.149617] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2024] [Revised: 01/25/2024] [Accepted: 01/31/2024] [Indexed: 03/25/2024]
Abstract
Preeclampsia (PE) is characterized by hypertension, proteinuria, and fetal growth restriction during pregnancy, suggesting that the preeclamptic intrauterine environment may affect the growth and health of the offspring. This study aimed to how maternal hypertension affects male offspring growth, focusing on lipid metabolism and blood pressure in mice. Female mice were infused with angiotensin II (Ang II) on gestational day 12. Dysregulation and accumulation of lipid were observed in the placenta of Ang II-induced maternal hypertensive dams, associating with fetal growth restriction. Ang II-offspring showed lower birth weight than in the control-offspring. Isolated and differentiated adipocyte from neonatal mice of Ang II-dams showed higher Pparγ mRNA expression compared with the control group. Lower body weight tendency had continued in Ang II-offspring during long period, body weight of Ang II-offspring caught up the control-offspring at 16 weeks of age. The adipose tissue of Ang II-offspring in adult also showed higher Pparγ mRNA expression with the accumulation of neutrophils and inflammatory monocytes than in those control. In addition, Ang II-offspring had higher basal blood pressure and higher sensitivity to hypertensive stimuli than in the control-offspring. Taken together, maternal hypertension induced by Ang II changes placental function, causing a lower birth weight. These changes in the intrauterine environment may affect adipocyte function and blood pressure of offspring after growth.
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Affiliation(s)
- Ren Ozawa
- Laboratory of Animal Reproduction, Department of Animal Science, Tokyo University of Agriculture, 1737 Funako, Atsugi, Kanagawa, 234-0034, Japan
| | - Hisataka Iwata
- Laboratory of Animal Reproduction, Department of Animal Science, Tokyo University of Agriculture, 1737 Funako, Atsugi, Kanagawa, 234-0034, Japan
| | - Takehito Kuwayama
- Laboratory of Animal Reproduction, Department of Animal Science, Tokyo University of Agriculture, 1737 Funako, Atsugi, Kanagawa, 234-0034, Japan
| | - Koumei Shirasuna
- Laboratory of Animal Reproduction, Department of Animal Science, Tokyo University of Agriculture, 1737 Funako, Atsugi, Kanagawa, 234-0034, Japan.
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15
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Han Y, Sun Q, Chen W, Gao Y, Ye J, Chen Y, Wang T, Gao L, Liu Y, Yang Y. New advances of adiponectin in regulating obesity and related metabolic syndromes. J Pharm Anal 2024; 14:100913. [PMID: 38799237 PMCID: PMC11127227 DOI: 10.1016/j.jpha.2023.12.003] [Citation(s) in RCA: 11] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2023] [Revised: 11/18/2023] [Accepted: 12/07/2023] [Indexed: 05/29/2024] Open
Abstract
Obesity and related metabolic syndromes have been recognized as important disease risks, in which the role of adipokines cannot be ignored. Adiponectin (ADP) is one of the key adipokines with various beneficial effects, including improving glucose and lipid metabolism, enhancing insulin sensitivity, reducing oxidative stress and inflammation, promoting ceramides degradation, and stimulating adipose tissue vascularity. Based on those, it can serve as a positive regulator in many metabolic syndromes, such as type 2 diabetes (T2D), cardiovascular diseases, non-alcoholic fatty liver disease (NAFLD), sarcopenia, neurodegenerative diseases, and certain cancers. Therefore, a promising therapeutic approach for treating various metabolic diseases may involve elevating ADP levels or activating ADP receptors. The modulation of ADP genes, multimerization, and secretion covers the main processes of ADP generation, providing a comprehensive orientation for the development of more appropriate therapeutic strategies. In order to have a deeper understanding of ADP, this paper will provide an all-encompassing review of ADP.
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Affiliation(s)
- Yanqi Han
- State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, 100050, China
- Beijing Key laboratory of Drug Delivery Technology and Novel Formulation, Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, 100050, China
| | - Qianwen Sun
- State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, 100050, China
- Beijing Key laboratory of Drug Delivery Technology and Novel Formulation, Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, 100050, China
| | - Wei Chen
- State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, 100050, China
- Beijing Key laboratory of Drug Delivery Technology and Novel Formulation, Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, 100050, China
| | - Yue Gao
- State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, 100050, China
- Beijing Key laboratory of Drug Delivery Technology and Novel Formulation, Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, 100050, China
| | - Jun Ye
- State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, 100050, China
- Beijing Key laboratory of Drug Delivery Technology and Novel Formulation, Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, 100050, China
| | - Yanmin Chen
- State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, 100050, China
- Beijing Key laboratory of Drug Delivery Technology and Novel Formulation, Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, 100050, China
| | - Tingting Wang
- State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, 100050, China
- Beijing Key laboratory of Drug Delivery Technology and Novel Formulation, Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, 100050, China
| | - Lili Gao
- State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, 100050, China
- Beijing Key laboratory of Drug Delivery Technology and Novel Formulation, Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, 100050, China
| | - Yuling Liu
- State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, 100050, China
- Beijing Key laboratory of Drug Delivery Technology and Novel Formulation, Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, 100050, China
| | - Yanfang Yang
- State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, 100050, China
- Beijing Key laboratory of Drug Delivery Technology and Novel Formulation, Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, 100050, China
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16
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Fleishman JS, Kumar S. Bile acid metabolism and signaling in health and disease: molecular mechanisms and therapeutic targets. Signal Transduct Target Ther 2024; 9:97. [PMID: 38664391 PMCID: PMC11045871 DOI: 10.1038/s41392-024-01811-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2023] [Revised: 03/06/2024] [Accepted: 03/17/2024] [Indexed: 04/28/2024] Open
Abstract
Bile acids, once considered mere dietary surfactants, now emerge as critical modulators of macronutrient (lipid, carbohydrate, protein) metabolism and the systemic pro-inflammatory/anti-inflammatory balance. Bile acid metabolism and signaling pathways play a crucial role in protecting against, or if aberrant, inducing cardiometabolic, inflammatory, and neoplastic conditions, strongly influencing health and disease. No curative treatment exists for any bile acid influenced disease, while the most promising and well-developed bile acid therapeutic was recently rejected by the FDA. Here, we provide a bottom-up approach on bile acids, mechanistically explaining their biochemistry, physiology, and pharmacology at canonical and non-canonical receptors. Using this mechanistic model of bile acids, we explain how abnormal bile acid physiology drives disease pathogenesis, emphasizing how ceramide synthesis may serve as a unifying pathogenic feature for cardiometabolic diseases. We provide an in-depth summary on pre-existing bile acid receptor modulators, explain their shortcomings, and propose solutions for how they may be remedied. Lastly, we rationalize novel targets for further translational drug discovery and provide future perspectives. Rather than dismissing bile acid therapeutics due to recent setbacks, we believe that there is immense clinical potential and a high likelihood for the future success of bile acid therapeutics.
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Affiliation(s)
- Joshua S Fleishman
- Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, St. John's University, Queens, NY, USA
| | - Sunil Kumar
- Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, St. John's University, Queens, NY, USA.
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17
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Liu C, Sun X, Peng J, Yu H, Lu J, Feng Y. Association between dietary vitamin A intake from different sources and non-alcoholic fatty liver disease among adults. Sci Rep 2024; 14:1851. [PMID: 38253816 PMCID: PMC10803811 DOI: 10.1038/s41598-024-52077-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2023] [Accepted: 01/12/2024] [Indexed: 01/24/2024] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD) has become an urgent public health issue with high global prevalence, but data on NAFLD are inconsistent. The association of total dietary vitamin A intake with the NAFLD risk was not well documented in previous studies. To explore the relationship between dietary vitamin A intake from different sources and NAFLD risk among American adults. Data were collected from the National Health and Nutrition Examination Survey (NHANES) from 2007 to 2014. Logistic regression and restricted cubic spline models were used to estimate the relationship between total dietary vitamin A intake and NAFLD risk. 6,613 adult participants were included. After adjusting potential confounders, the odds ratios (ORs) with 95% confidence intervals (CIs) of NAFLD for the highest quartile intake of total vitamin A, preformed vitamin A, provitamin A carotenoids were respectively 0.86 (0.69-1.06), 0.97 (0.74-1.28), and 0.78 (0.61-0.99), compared to the lowest quartile. Stratifying gender and age, provitamin A carotenoids intake was inversely associated with NAFLD risk in females and participants aged < 45 years. Dose-response analysis indicated a linear negative relationship between provitamin A carotenoids intake and NAFLD risk. Provitamin A carotenoids intake was inversely associated with NAFLD, especially in women and those aged < 45 years among adult American.
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Affiliation(s)
- Can Liu
- School of Public Health, Shanxi Medical University, Taiyuan, China
- School of Management, Shanxi Medical University, Taiyuan, China
| | - Xiaona Sun
- Department of Respiratory and Critical Care Medicine, Qingdao Central Hospital, University of Health and Rehabilitation Sciences, Qingdao, China
| | - Jing Peng
- Department of Pediatrics, Qingdao Central Hospital, University of Health and Rehabilitation Sciences, Qingdao, China
| | - Haiqing Yu
- Shenzhen Maternity and Child Healthcare Hospital, Shenzhen, China
| | - Jiao Lu
- School of Public Policy and Administration, Xi'an Jiaotong University, Xi'an, China
| | - Yihui Feng
- School of Rehabilitation Science and Engineering, University of Health and Rehabilitation Sciences, Qingdao, China.
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Pradhan G, Kulkarni YA. Diabetes and its Complications: Role of Luteolin, A Wonder Chemical from the Natural Source. Curr Diabetes Rev 2024; 21:e290224227537. [PMID: 38425118 DOI: 10.2174/0115733998285798240217084632] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/06/2023] [Revised: 01/22/2024] [Accepted: 01/31/2024] [Indexed: 03/02/2024]
Abstract
Flavonoids have been reported to be vital in treating various chronic disorders. Luteolin (3',4',5,7-tetrahydroxyflavone) is a flavonoid present in a variety of plant sources such as celery, green pepper, olive oil, peppermint, thyme, rosemary, oregano, etc. It has been reported to have various pharmacological activities such as antioxidant, anti-inflammatory, anticancer, antidiabetic, anti-Alzheimer, antimicrobial, etc. Many scientific studies have been carried out on luteolin for its possible effects on diabetes and its associated complications. The present review focuses on the role of luteolin in diabetes mellitus and the associated complications. The antidiabetic impact of luteolin is linked with the increased expression of PPARγ and GLUT. Various in vitro and in vivo studies have been performed to explore the effects of luteolin on diabetic complications, and it has shown a significant impact in the management of the same.
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Affiliation(s)
- Gandhar Pradhan
- Shobhaben Pratapbhai Patel School of Pharmacy & Technology Management, SVKM's Narsee Monjee Institute of Management Studies (NMIMS), V.L. Mehta Road, Vile Parle (W), Mumbai 400 056, India
| | - Yogesh A Kulkarni
- Shobhaben Pratapbhai Patel School of Pharmacy & Technology Management, SVKM's Narsee Monjee Institute of Management Studies (NMIMS), V.L. Mehta Road, Vile Parle (W), Mumbai 400 056, India
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19
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Reza-López SA, González-Gurrola S, Morales-Morales OO, Moreno-González JG, Rivas-Gómez AM, González-Rodríguez E, Moreno-Brito V, Licón-Trillo A, Leal-Berumen I. Metabolic Biomarkers in Adults with Type 2 Diabetes: The Role of PPAR-γ2 and PPAR-β/δ Polymorphisms. Biomolecules 2023; 13:1791. [PMID: 38136661 PMCID: PMC10741495 DOI: 10.3390/biom13121791] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2023] [Revised: 11/27/2023] [Accepted: 12/02/2023] [Indexed: 12/24/2023] Open
Abstract
Glucose and lipid metabolism regulation by the peroxisome proliferator-activated receptors (PPARs) has been extensively reported. However, the role of their polymorphisms remains unclear. OBJECTIVE To determine the relation between PPAR-γ2 rs1801282 (Pro12Ala) and PPAR-β/δ rs2016520 (+294T/C) polymorphisms and metabolic biomarkers in adults with type 2 diabetes (T2D). MATERIALS AND METHODS We included 314 patients with T2D. Information on anthropometric, fasting plasma glucose (FPG), HbA1c and lipid profile measurements was taken from clinical records. Genomic DNA was obtained from peripheral blood. End-point PCR was used for PPAR-γ2 rs1801282, while for PPAR-β/δ rs2016520 the PCR product was digested with Bsl-I enzyme. Data were compared with parametric or non-parametric tests. Multivariate models were used to adjust for covariates and interaction effects. RESULTS minor allele frequency was 12.42% for PPAR-γ2 rs1801282-G and 13.85% for PPAR-β/δ rs2016520-C. Both polymorphisms were related to waist circumference; they showed independent effects on HbA1c, while they interacted for FPG; carriers of both PPAR minor alleles had the highest values. Interactions between FPG and polymorphisms were identified in their relation to triglyceride level. CONCLUSIONS PPAR-γ2 rs1801282 and PPAR-β/δ rs2016520 polymorphisms are associated with anthropometric, glucose, and lipid metabolism biomarkers in T2D patients. Further research is required on the molecular mechanisms involved.
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Affiliation(s)
- Sandra A. Reza-López
- Facultad de Medicina y Ciencias Biomédicas, Universidad Autónoma de Chihuahua, Campus II. Circuito Universitario S/N, Chihuahua 31109, CP, Mexico; (S.A.R.-L.); (O.O.M.-M.); (J.G.M.-G.); (E.G.-R.); (V.M.-B.); (A.L.-T.)
| | - Susana González-Gurrola
- Instituto Mexicano del Seguro Social UMF 33, Avenida Melchor Ocampo y Arroyo de los Perros S/N, Col. El Palomar, Chihuahua 31204, CP, Mexico; (S.G.-G.); or (A.M.R.-G.)
| | - Oscar O. Morales-Morales
- Facultad de Medicina y Ciencias Biomédicas, Universidad Autónoma de Chihuahua, Campus II. Circuito Universitario S/N, Chihuahua 31109, CP, Mexico; (S.A.R.-L.); (O.O.M.-M.); (J.G.M.-G.); (E.G.-R.); (V.M.-B.); (A.L.-T.)
| | - Janette G. Moreno-González
- Facultad de Medicina y Ciencias Biomédicas, Universidad Autónoma de Chihuahua, Campus II. Circuito Universitario S/N, Chihuahua 31109, CP, Mexico; (S.A.R.-L.); (O.O.M.-M.); (J.G.M.-G.); (E.G.-R.); (V.M.-B.); (A.L.-T.)
| | - Ana M. Rivas-Gómez
- Instituto Mexicano del Seguro Social UMF 33, Avenida Melchor Ocampo y Arroyo de los Perros S/N, Col. El Palomar, Chihuahua 31204, CP, Mexico; (S.G.-G.); or (A.M.R.-G.)
| | - Everardo González-Rodríguez
- Facultad de Medicina y Ciencias Biomédicas, Universidad Autónoma de Chihuahua, Campus II. Circuito Universitario S/N, Chihuahua 31109, CP, Mexico; (S.A.R.-L.); (O.O.M.-M.); (J.G.M.-G.); (E.G.-R.); (V.M.-B.); (A.L.-T.)
| | - Verónica Moreno-Brito
- Facultad de Medicina y Ciencias Biomédicas, Universidad Autónoma de Chihuahua, Campus II. Circuito Universitario S/N, Chihuahua 31109, CP, Mexico; (S.A.R.-L.); (O.O.M.-M.); (J.G.M.-G.); (E.G.-R.); (V.M.-B.); (A.L.-T.)
| | - Angel Licón-Trillo
- Facultad de Medicina y Ciencias Biomédicas, Universidad Autónoma de Chihuahua, Campus II. Circuito Universitario S/N, Chihuahua 31109, CP, Mexico; (S.A.R.-L.); (O.O.M.-M.); (J.G.M.-G.); (E.G.-R.); (V.M.-B.); (A.L.-T.)
| | - Irene Leal-Berumen
- Facultad de Medicina y Ciencias Biomédicas, Universidad Autónoma de Chihuahua, Campus II. Circuito Universitario S/N, Chihuahua 31109, CP, Mexico; (S.A.R.-L.); (O.O.M.-M.); (J.G.M.-G.); (E.G.-R.); (V.M.-B.); (A.L.-T.)
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20
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Mao T, Akshit FNU, Mohan MS. Effects of anthocyanin supplementation in diet on glycemic and related cardiovascular biomarkers in patients with type 2 diabetes: a systematic review and meta-analysis of randomized controlled trials. Front Nutr 2023; 10:1199815. [PMID: 37810926 PMCID: PMC10556752 DOI: 10.3389/fnut.2023.1199815] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2023] [Accepted: 09/01/2023] [Indexed: 10/10/2023] Open
Abstract
Purpose This study is the first systematic review and meta-analysis based on RCTs on the effects of anthocyanins on patients with type 2 diabetes mellitus (T2DM) and the effect on T2DM-related cardiovascular disease. Methods RCTs published in English from five electronic databases were evaluated for glycated hemoglobin (HbA1c), fasting blood glucose (FBG), 2-h postprandial blood glucose, fasting insulin, model assessment for insulin resistance, triglycerides (TG), total cholesterol (TC), high-density lipoprotein (HDL) cholesterol, low-density lipoprotein (LDL) cholesterol, systolic blood pressure, and diastolic blood pressure. The quality of the studies was rated (Cochrane Risk of Bias tool) and weighted mean differences were calculated (DerSimonian-Laird model with random effects). Leave-one-out sensitivity, subgroup, and publication bias analyses were conducted. The strength of the evidence was rated according to the GRADE guidelines. Results In all, 13 RCTs were analyzed out of the 239 identified studies, with a duration longer than 4 weeks (703 participants with T2DM). Our findings indicate that a median dose of 320 mg/day anthocyanins, either from fruit extracts or pure supplements, for a median intervention length of 8 weeks significantly reduced HbA1c [Weighted Mean Difference (WMD) -0.31, p = 0.00], FBG (WMD -0.63, p = 0.00), 2-h postprandial glucose (WMD -1.60, p = 0.00), TG (WMD -0.45, p = 0.01), and LDL (WMD -0.26 p = 0.02). However, the effects of anthocyanins on fasting insulin, HOMA-IR, TC, HDL cholesterol, systolic blood pressure, and diastolic blood pressure in patients with T2DM were not statistically significant. Anthocyanins from fruit extracts or powder exhibited a higher reduction of HbA1c compared to pure anthocyanin supplements. Conclusion The significant improvements in glycemic parameters and lipid profile, suggest the benefits of anthocyanins, especially from fruit extract or powder, in the management of T2DM, and their ability to delay the onset of lipid disorder-related diseases such as cardiovascular disease associated with T2DM. The mechanism behind this reduction in glycemic markers could be attributed to the antioxidant and anti-inflammatory activity of anthocyanins. Further research with well-designed RCTs is required to determine the optimal dosage of anthocyanins for the treatment of T2DM and to comprehend the consequences.
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Affiliation(s)
| | | | - Maneesha S. Mohan
- Alfred Dairy Science Laboratory, Department of Dairy and Food Science, South Dakota State University, Brookings, SD, United States
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21
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Putera HD, Doewes RI, Shalaby MN, Ramírez-Coronel AA, Clayton ZS, Abdelbasset WK, Murtazaev SS, Jalil AT, Rahimi P, Nattagh-Eshtivani E, Malekahmadi M, Pahlavani N. The effect of conjugated linoleic acids on inflammation, oxidative stress, body composition and physical performance: a comprehensive review of putative molecular mechanisms. Nutr Metab (Lond) 2023; 20:35. [PMID: 37644566 PMCID: PMC10466845 DOI: 10.1186/s12986-023-00758-9] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2023] [Accepted: 08/25/2023] [Indexed: 08/31/2023] Open
Abstract
Conjugated linoleic acids (CLAs) are polyunsaturated fatty acids primarily found in dairy products and ruminant animal products such as beef, lamb, and butter. Supplementation of CLAs has recently become popular among athletes due to the variety of health-promoting effects, including improvements in physical performance. Preclinical and some clinical studies have shown that CLAs can reduce inflammation and oxidative stress and favorably modulate body composition and physical performance; however, the results of previously published clinical trials are mixed. Here, we performed a comprehensive review of previously published clinical trials that assessed the role of CLAs in modulating inflammation, oxidative stress, body composition, and select indices of physical performance, emphasizing the molecular mechanisms governing these changes. The findings of our review demonstrate that the effect of supplementation with CLAs on inflammation and oxidative stress is controversial, but this supplement can decrease body fat mass and increase physical performance. Future well-designed randomized clinical trials are warranted to determine the effectiveness of (1) specific doses of CLAs; (2) different dosing durations of CLAs; (3) various CLA isomers, and the exact molecular mechanisms by which CLAs positively influence oxidative stress, inflammation, body composition, and physical performance.
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Affiliation(s)
- Husna Dharma Putera
- Department of Surgery, Faculty of Medicine, Lambung Mangkurat University, Banjarmasin, South Kalimantan, Indonesia
| | - Rumi Iqbal Doewes
- Faculty of Sport, Universitas Sebelas Maret, Jl. Ir. Sutami, 36A, Kentingan, Surakarta, Indonesia
| | - Mohammed Nader Shalaby
- Biological Sciences and Sports Health Department, Faculty of Physical Education, Suez Canal University, Ismailia, Egypt
| | - Andrés Alexis Ramírez-Coronel
- Azogues Campus Nursing Career, Health and Behavior Research Group (HBR), Psychometry and Ethology Laboratory, Catholic University of Cuenca, Azogues, Ecuador
| | - Zachary S Clayton
- Department of Integrative Physiology, University of Colorado Boulder, Boulder, CO, USA
| | - Walid Kamal Abdelbasset
- Department of Health and Rehabilitation Sciences, College of Applied Medical Sciences, Prince Sattam Bin Abdulaziz University, Al Kharj, Saudi Arabia
- Department of Physical Therapy, Kasr Al-Aini Hospital, Cairo University, Giza, Egypt
| | - Saidmurodkhon S Murtazaev
- Department of Therapeutic Pediatric Dentistry, Dean of the Faculty of International Education, Tashkent State Dental Institute, Tashkent, Uzbekistan
- Department of Scientific Affairs, Samarkand State Medical University, Amir Temur Street 18, Samarkand, Uzbekistan
| | - Abduladheem Turki Jalil
- Medical Laboratories Techniques Department, Al-Mustaqbal University College, Hilla, Babylon, 51001, Iraq
| | - Pegah Rahimi
- Department of Clinical Pharmacy, Faculty of Pharmacy, Kerman University of Medical Sciences, Kerman, Iran
| | - Elyas Nattagh-Eshtivani
- Social Development and Health Promotion Research Center, Gonabad University of Medical Sciences, Gonabad, Iran
| | - Mahsa Malekahmadi
- Department of Clinical Nutrition, School of Nutritional Sciences and Dietetics, Tehran University of Medical Sciences, Tehran, Iran
| | - Naseh Pahlavani
- Health Sciences Research Center, Torbat Heydariyeh University of Medical Sciences, Torbat-e Heydariyeh, Iran.
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22
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Salem MA, Aborehab NM, Abdelhafez MM, Ismail SH, Maurice NW, Azzam MA, Alseekh S, Fernie AR, Salama MM, Ezzat SM. Anti-Obesity Effect of a Tea Mixture Nano-Formulation on Rats Occurs via the Upregulation of AMP-Activated Protein Kinase/Sirtuin-1/Glucose Transporter Type 4 and Peroxisome Proliferator-Activated Receptor Gamma Pathways. Metabolites 2023; 13:871. [PMID: 37512578 PMCID: PMC10385210 DOI: 10.3390/metabo13070871] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2023] [Revised: 07/12/2023] [Accepted: 07/18/2023] [Indexed: 07/30/2023] Open
Abstract
White, green, and oolong teas are produced from the tea plant (Camellia sinensis (L.) Kuntze) and are reported to have anti-obesity and hypolipidemic effects. The current study aims to investigate the anti-obesity effects of a tea mixture nano-formulation by targeting the AMPK/Sirt-1/GLUT-4 axis in rats. In vitro lipase and α-amylase inhibition assays were used to determine the active sample, which was then incorporated into a nanoparticle formulation subjected to in vivo anti-obesity testing in rats by measuring the expression level of different genes implicated in adipogenesis and inflammation using qRT-PCR. Moreover, metabolomic analysis was performed for each tea extract using LC/ESI MS/MS coupled to chemometrics in an attempt to find a correlation between the constituents of the extracts and their biological activity. The in vitro pancreatic lipase and α-amylase inhibition assays demonstrated more effective activity in the tea mixture than the standards, orlistat and acarbose, respectively, and each tea alone. Thus, the herbal tea mixture and its nanoparticle formulation were evaluated for their in vivo anti-obesity activity. Intriguingly, the tea mixture significantly decreased the serum levels of glucose and triglycerides and increased the mRNA expression of GLUT-4, P-AMPK, Sirt-1, and PPAR-γ, which induce lipolysis while also decreasing the mRNA expression of TNF-α and ADD1/SREBP-1c, thereby inhibiting the inflammation associated with obesity. Our study suggests that the tea mixture nano-formulation is a promising therapeutic agent in the treatment of obesity and may also be beneficial in other metabolic disorders by targeting the AMPK/Sirt-1/Glut-4 pathway.
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Affiliation(s)
- Mohamed A Salem
- Department of Pharmacognosy and Natural Products, Faculty of Pharmacy, Menoufia University, Gamal Abd El Nasr Street, Shibin Elkom 32511, Menoufia, Egypt
| | - Nora M Aborehab
- Department of Biochemistry, Faculty of Pharmacy, October University for Modern Sciences and Arts (MSA), Giza 12451, Egypt
| | - Mai M Abdelhafez
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, October University for Modern Sciences and Arts (MSA), Giza 12451, Egypt
| | - Sameh H Ismail
- Faculty of Nanotechnology for Postgraduate Studies, Sheikh Zayed Branch Campus, Cairo University, Sheikh Zayed, Giza 12588, Egypt
| | - Nadine W Maurice
- Department of Biochemistry, Faculty of Pharmacy, Cairo University, Kasr El-Aini Street, Cairo 11562, Egypt
| | - May A Azzam
- Department of Biochemistry, Faculty of Pharmacy, Cairo University, Kasr El-Aini Street, Cairo 11562, Egypt
| | - Saleh Alseekh
- Max Planck Institute of Molecular Plant Physiology, Am Mühlenberg 1, 14476 Potsdam-Golm, Germany
- Center for Plant Systems Biology and Biotechnology, 4000 Plovdiv, Bulgaria
| | - Alisdair R Fernie
- Max Planck Institute of Molecular Plant Physiology, Am Mühlenberg 1, 14476 Potsdam-Golm, Germany
- Center for Plant Systems Biology and Biotechnology, 4000 Plovdiv, Bulgaria
| | - Maha M Salama
- Pharmacognosy Department, Faculty of Pharmacy, Cairo University, Kasr El-Ainy Street, Cairo 11562, Egypt
- Department of Pharmacognosy, Faculty of Pharmacy, The British University in Egypt, Suez Desert Road, El Sherouk City, Cairo 11837, Egypt
| | - Shahira M Ezzat
- Pharmacognosy Department, Faculty of Pharmacy, Cairo University, Kasr El-Ainy Street, Cairo 11562, Egypt
- Department of Pharmacognosy, Faculty of Pharmacy, October University for Modern Sciences and Arts (MSA), Giza 12451, Egypt
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23
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Yu H, Gao X, Ge Q, Tai W, Hao X, Shao Q, Fang Z, Chen M, Song Y, Gao W, Liu G, Du X, Li X. Tumor necrosis factor-α reduces adiponectin production by decreasing transcriptional activity of peroxisome proliferator-activated receptor-γ in calf adipocytes. J Dairy Sci 2023; 106:5182-5195. [PMID: 37268580 DOI: 10.3168/jds.2022-22919] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2022] [Accepted: 01/24/2023] [Indexed: 06/04/2023]
Abstract
Adiponectin (encoded by ADIPOQ) is an adipokine that orchestrates energy homeostasis by modulating glucose and fatty acid metabolism in peripheral tissues. During the periparturient period, dairy cows often develop adipose tissue inflammation and decreased plasma adiponectin levels. Proinflammatory cytokine tumor necrosis factor-α (TNF-α) plays a pivotal role in regulating the endocrine functions of adipocytes, but whether it affects adiponectin production in calf adipocytes remains obscure. Thus, the present study aimed to determine whether TNF-α could affect adiponectin production in calf adipocytes and to identify the underlying mechanism. Adipocytes isolated from Holstein calves were differentiated and used for (1) BODIPY493/503 staining; (2) treatment with 0.1 ng/mL TNF-α for different times (0, 8, 16, 24, or 48 h); (3) transfection with peroxisome proliferator-activated receptor-γ (PPARG) small interfering RNA for 48 h followed by treatment with or without 0.1 ng/mL TNF-α for 24 h; and (4) overexpression of PPARG for 48 h followed by treatment with or without 0.1 ng/mL TNF-α for 24 h. After differentiation, obvious lipid droplets and secretion of adiponectin were observed in adipocytes. Treatment with TNF-α did not alter mRNA abundance of ADIPOQ but reduced the total and high molecular weight (HMW) adiponectin content in the supernatant of adipocytes. Quantification of mRNA abundance of endoplasmic reticulum (ER)/Golgi resident chaperones involved in adiponectin assembly revealed that ER protein 44 (ERP44), ER oxidoreductase 1α (ERO1A), and disulfide bond-forming oxidoreductase A-like protein (GSTK1) were downregulated in TNF-α-treated adipocytes, while 78-kDa glucose-regulated protein and Golgi-localizing γ-adaptin ear homology domain ARF binding protein-1 were unaltered. Moreover, TNF-α diminished nuclear translocation of PPARγ and downregulated mRNA abundance of PPARG and its downstream target gene fatty acid synthase, suggesting that TNF-α suppressed the transcriptional activity of PPARγ. In the absence of TNF-α, overexpression of PPARG enhanced the total and HMW adiponectin content in supernatant and upregulated the mRNA abundance of ADIPOQ, ERP44, ERO1A, and GSTK1 in adipocytes. However, knockdown of PPARG reduced the total and HMW adiponectin content in supernatant and downregulated the mRNA abundance of ADIPOQ, ERP44, ERO1A, and GSTK1 in adipocytes. In the presence of TNF-α, overexpression of PPARG decreased, while knockdown of PPARG further exacerbated TNF-α-induced reductions in total and HMW adiponectin secretion and gene expression of ERP44, ERO1A, and GSTK1. Overall, TNF-α reduces adiponectin assembly in the calf adipocyte, which may be partly mediated by attenuation of PPARγ transcriptional activity. Thus, locally elevated levels of TNF-α in adipose tissue may be one reason for the decrease in circulating adiponectin in periparturient dairy cows.
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Affiliation(s)
- Hao Yu
- State Key Laboratory for Zoonotic Diseases, Key Laboratory of Zoonosis Research, Ministry of Education, College of Veterinary Medicine, Jilin University, 5333 Xi'an Road, Changchun, 130062, Jilin, China
| | - Xinxing Gao
- State Key Laboratory for Zoonotic Diseases, Key Laboratory of Zoonosis Research, Ministry of Education, College of Veterinary Medicine, Jilin University, 5333 Xi'an Road, Changchun, 130062, Jilin, China
| | - Qilai Ge
- State Key Laboratory for Zoonotic Diseases, Key Laboratory of Zoonosis Research, Ministry of Education, College of Veterinary Medicine, Jilin University, 5333 Xi'an Road, Changchun, 130062, Jilin, China
| | - Wenjun Tai
- State Key Laboratory for Zoonotic Diseases, Key Laboratory of Zoonosis Research, Ministry of Education, College of Veterinary Medicine, Jilin University, 5333 Xi'an Road, Changchun, 130062, Jilin, China
| | - Xue Hao
- State Key Laboratory for Zoonotic Diseases, Key Laboratory of Zoonosis Research, Ministry of Education, College of Veterinary Medicine, Jilin University, 5333 Xi'an Road, Changchun, 130062, Jilin, China
| | - Qi Shao
- State Key Laboratory for Zoonotic Diseases, Key Laboratory of Zoonosis Research, Ministry of Education, College of Veterinary Medicine, Jilin University, 5333 Xi'an Road, Changchun, 130062, Jilin, China
| | - Zhiyuan Fang
- State Key Laboratory for Zoonotic Diseases, Key Laboratory of Zoonosis Research, Ministry of Education, College of Veterinary Medicine, Jilin University, 5333 Xi'an Road, Changchun, 130062, Jilin, China
| | - Meng Chen
- State Key Laboratory for Zoonotic Diseases, Key Laboratory of Zoonosis Research, Ministry of Education, College of Veterinary Medicine, Jilin University, 5333 Xi'an Road, Changchun, 130062, Jilin, China
| | - Yuxiang Song
- State Key Laboratory for Zoonotic Diseases, Key Laboratory of Zoonosis Research, Ministry of Education, College of Veterinary Medicine, Jilin University, 5333 Xi'an Road, Changchun, 130062, Jilin, China
| | - Wenwen Gao
- State Key Laboratory for Zoonotic Diseases, Key Laboratory of Zoonosis Research, Ministry of Education, College of Veterinary Medicine, Jilin University, 5333 Xi'an Road, Changchun, 130062, Jilin, China
| | - Guowen Liu
- State Key Laboratory for Zoonotic Diseases, Key Laboratory of Zoonosis Research, Ministry of Education, College of Veterinary Medicine, Jilin University, 5333 Xi'an Road, Changchun, 130062, Jilin, China
| | - Xiliang Du
- State Key Laboratory for Zoonotic Diseases, Key Laboratory of Zoonosis Research, Ministry of Education, College of Veterinary Medicine, Jilin University, 5333 Xi'an Road, Changchun, 130062, Jilin, China.
| | - Xinwei Li
- State Key Laboratory for Zoonotic Diseases, Key Laboratory of Zoonosis Research, Ministry of Education, College of Veterinary Medicine, Jilin University, 5333 Xi'an Road, Changchun, 130062, Jilin, China.
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24
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Bellavite P, Fazio S, Affuso F. A Descriptive Review of the Action Mechanisms of Berberine, Quercetin and Silymarin on Insulin Resistance/Hyperinsulinemia and Cardiovascular Prevention. Molecules 2023; 28:4491. [PMID: 37298967 PMCID: PMC10254920 DOI: 10.3390/molecules28114491] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2023] [Revised: 05/26/2023] [Accepted: 05/30/2023] [Indexed: 06/12/2023] Open
Abstract
Insulin resistance (IR) and the associated hyperinsulinemia are early pathophysiological changes which, if not well treated, can lead to type 2 diabetes, endothelial dysfunction and cardiovascular disease. While diabetes care is fairly well standardized, the prevention and treatment of IR lacks a single pharmaceutical approach and many lifestyle and dietary interventions have been proposed, including a wide range of food supplements. Among the most interesting and well-known natural remedies, alkaloid berberine and the flavonol quercetin have particular relevance in the literature, while silymarin-the active principle of the Silybum marianum thistle-was traditionally used for lipid metabolism disorders and to sustain liver function. This review describes the major defects of insulin signaling leading to IR and the main properties of the three mentioned natural substances, their molecular targets and synergistic action mechanisms. The actions of berberine, quercetin and silymarin are partially superimposable as remedies against reactive oxygen intermediates generated by a high-lipid diet and by NADPH oxidase, which is triggered by phagocyte activation. Furthermore, these compounds inhibit the secretion of a battery of pro-inflammatory cytokines, modulate intestinal microbiota and are especially able to control the various disorders of the insulin receptor and post-receptor signaling systems. Although most of the evidence on the effects of berberine, quercetin and silymarin in modulating insulin resistance and preventing cardiovascular disease derive from experimental studies on animals, the amount of pre-clinical knowledge strongly suggests the need to investigate the therapeutic potential of these substances in human pathology.
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Affiliation(s)
- Paolo Bellavite
- Pathophysiology Chair, Homeopathic Medical School of Verona, 37121 Verona, Italy
| | - Serafino Fazio
- Department of Internal Medicine, University of Naples Federico II, 80138 Naples, Italy;
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25
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Sun Z, Wang M, Xu L, Li Q, Zhao Z, Liu X, Meng F, Liu J, Wang W, Li C, Jiang S. PPARγ/Adiponectin axis attenuates methamphetamine-induced conditional place preference via the hippocampal AdipoR1 signaling pathway. Prog Neuropsychopharmacol Biol Psychiatry 2023; 125:110758. [PMID: 36972780 DOI: 10.1016/j.pnpbp.2023.110758] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/09/2023] [Revised: 03/21/2023] [Accepted: 03/24/2023] [Indexed: 03/29/2023]
Abstract
Methamphetamine (METH) is a highly addictive psychostimulant. The adipocyte-derived hormone adiponectin has a broad spectrum of functions in the brain. However, limited research has been conducted on the effect of adiponectin signaling on METH-induced conditioned place preference (CPP) and knowledge of the underlying neural mechanisms is scarce. The METH induced adult male C57/BL6J mice model were used for testing the therapeutic activities of intraperitoneal injection of AdipoRon or Rosiglitazone, and AdipoR1 overexpression in hippocampal dentate gyrus (DG), and chemogenetic inhibiting the neural activity of DG, and the changes of neurotrophic factors, synaptic molecules, and glutamate receptors, and inflammatory cytokines were also measured. We found that adiponectin expression was significantly reduced in METH addicted patients and mice. Our findings also showed that injection of AdipoRon or Rosiglitazone alleviated the METH-induced CPP behavior. Moreover, the expression of AdipoR1 in the hippocampus was also reduced, and AdipoR1 overexpression blocked the development of METH-induced CPP behavior through regulatory effects on neurotrophic factors, synaptic molecules, and glutamate receptors. The observed inhibitory neural activity of the hippocampal dentate gyrus (DG) induced via a chemogenetic approach produced a therapeutic effect on the METH-induced CPP behavior. Finally, we identified an abnormal expression of some key inflammatory cytokines through the PPARγ/Adiponectin/AdipoR1 axis. This study demonstrates that adiponectin signaling is a promising diagnostic and therapeutic target for METH addiction.
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Affiliation(s)
- Zongyue Sun
- Department of Physiology, Binzhou Medical University, Shandong 264003, China; Medical Research Center, Binzhou Medical University Hospital, Binzhou, Shandong 256603, China; Institute for Metabolic & Neuropsychiatric Disorders, Binzhou Medical University Hospital, Binzhou, Shandong 256603, China
| | - Meiqin Wang
- Department of Physiology, Binzhou Medical University, Shandong 264003, China; Medical Research Center, Binzhou Medical University Hospital, Binzhou, Shandong 256603, China; Institute for Metabolic & Neuropsychiatric Disorders, Binzhou Medical University Hospital, Binzhou, Shandong 256603, China
| | - Lei Xu
- Department of Physiology, Binzhou Medical University, Shandong 264003, China; Medical Research Center, Binzhou Medical University Hospital, Binzhou, Shandong 256603, China; Institute for Metabolic & Neuropsychiatric Disorders, Binzhou Medical University Hospital, Binzhou, Shandong 256603, China
| | - Qiongyu Li
- Department of Gastroenterology, Binzhou Medical University Hospital, Binzhou, Shandong 256603, China; Medical Research Center, Binzhou Medical University Hospital, Binzhou, Shandong 256603, China; Institute for Metabolic & Neuropsychiatric Disorders, Binzhou Medical University Hospital, Binzhou, Shandong 256603, China
| | - Zhongyi Zhao
- Department of Physiology, Binzhou Medical University, Shandong 264003, China
| | - Xuehao Liu
- Department of Physiology, Binzhou Medical University, Shandong 264003, China
| | - Fantao Meng
- Medical Research Center, Binzhou Medical University Hospital, Binzhou, Shandong 256603, China; Institute for Metabolic & Neuropsychiatric Disorders, Binzhou Medical University Hospital, Binzhou, Shandong 256603, China
| | - Jing Liu
- Medical Research Center, Binzhou Medical University Hospital, Binzhou, Shandong 256603, China; Institute for Metabolic & Neuropsychiatric Disorders, Binzhou Medical University Hospital, Binzhou, Shandong 256603, China
| | - Wentao Wang
- Medical Research Center, Binzhou Medical University Hospital, Binzhou, Shandong 256603, China; Institute for Metabolic & Neuropsychiatric Disorders, Binzhou Medical University Hospital, Binzhou, Shandong 256603, China
| | - Chen Li
- Medical Research Center, Binzhou Medical University Hospital, Binzhou, Shandong 256603, China; Institute for Metabolic & Neuropsychiatric Disorders, Binzhou Medical University Hospital, Binzhou, Shandong 256603, China.
| | - Shujun Jiang
- Department of Physiology, Binzhou Medical University, Shandong 264003, China.
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26
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The Role of Dietary Fats in the Development and Treatment of Endometriosis. Life (Basel) 2023; 13:life13030654. [PMID: 36983810 PMCID: PMC10058497 DOI: 10.3390/life13030654] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2023] [Revised: 02/24/2023] [Accepted: 02/25/2023] [Indexed: 03/02/2023] Open
Abstract
Endometriosis is an estrogen-dependent disease in women of childbearing age that affects approximately 5–15% of the female population. The etiology of endometriosis is complex, multifaceted, and not fully understood. In endometriosis, which is an estrogen-related chronic inflammatory condition, estrogen plays a major role in endometrial cellular growth. High estrogen levels could be another risk factor for developing endometriosis. The aim of this review is to update knowledge on the impact of dietary fats on the development of endometriosis and chronic inflammation in women with endometriosis and diet therapy. Dietary fat may be linked with the progression and development of endometriosis, but studies have been contradictory due to various issues including sample size, different study designs, and different methodological aspects. Results have shown that the risk of endometriosis may increase with a higher consumption of products rich in saturated fats, especially palmitic acid and trans-unsaturated fatty acids. Monounsaturated fats and omega-3 polyunsaturated fatty acids may likely be connected with a lower risk of developing endometriosis and with reductions in the severity of disease. Monounsaturated fats, omega-3 polyunsaturated fatty acids, and a suitable eicosapentaenoic acid to arachidonic acid ratio can be used in diet therapy to improve quality of life by reducing pain and inflammation. Further research is needed in order to fully understand the influence of dietary fats on the risk of development of this disease.
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27
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Zhao Y, Zhao W, Bu H, Toshiyoshi M, Zhao Y. Liraglutide on type 2 diabetes mellitus with nonalcoholic fatty liver disease: A systematic review and meta-analysis of 16 RCTs. Medicine (Baltimore) 2023; 102:e32892. [PMID: 36820578 PMCID: PMC9907937 DOI: 10.1097/md.0000000000032892] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/12/2023] Open
Abstract
BACKGROUND Nonalcoholic fatty liver disease (NAFLD) is a common comorbidity of type 2 diabetes mellitus (T2DM). Our aim is to investigate the effects of liraglutide on T2DM with NAFLD. METHODS Relevant articles published from the earliest publication to March 2022 were selected from several databases. The Cochrane Collaboration's RevMan software was used for the analysis. RESULTS Sixteen studies are selected for this meta-analysis, which includes totally 634 patients in the treatment group and 630 patients in the control group. As a result, 14 studies show that fasting plasma glucose levels of the experimental group are lower than that of the control group; 15 studies show that glycosylated hemoglobin A1c levels of the experimental group are lower than that of the control group; 13 studies show that triglyceride levels of the experimental group are lower than that of the control group; twelve studies show that total cholesterol levels of the experimental group are lower than that of the control group; 10 studies show that alanine aminotransferase levels of the experimental group is lower than that of the control group; 10 studies show that no significant difference in changes in aspartate transaminase between 2 groups; 13 studies show that low density lipoprotein cholesterol levels of the experimental group is lower than that of the control group; 9 studies show that no significant difference in changes in high density lipoprotein cholesterol between 2 groups; 7 studies mentioned adverse effects and the difference is significant. CONCLUSION Liraglutide is potentially curative for T2DM with NAFLD.
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Affiliation(s)
- Yan Zhao
- Graduate School, Tianjin University of Traditional Chinese Medicine, Tianjin, China
| | - Wenli Zhao
- Department of Public Health, International College, Krirk University, Bangkok, Thailand
- Liver Center, Saga University Hospital, Saga University, Saga, Japan
| | - Huaien Bu
- School of Health Science and Engineering, Tianjin University of Traditional Chinese Medicine, Tianjin, China
| | - Maeda Toshiyoshi
- International Education College, Shandong University of Traditional Chinese Medicine, Jinan, China
| | - Ye Zhao
- Department of Public Health, International College, Krirk University, Bangkok, Thailand
- * Correspondence: Ye Zhao, Department of Public Health, International College, Krirk University, Bangkok 10220, Thailand (e-mail: )
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Nartey MNN, Jisaka M, Syeda PK, Nishimura K, Shimizu H, Yokota K. Prostaglandin D 2 Added during the Differentiation of 3T3-L1 Cells Suppresses Adipogenesis via Dysfunction of D-Prostanoid Receptor P1 and P2. Life (Basel) 2023; 13:life13020370. [PMID: 36836727 PMCID: PMC9963520 DOI: 10.3390/life13020370] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2022] [Revised: 01/20/2023] [Accepted: 01/27/2023] [Indexed: 01/31/2023] Open
Abstract
We previously reported that the addition of prostaglandin, (PG)D2, and its chemically stable analog, 11-deoxy-11-methylene-PGD2 (11d-11m-PGD2), during the maturation phase of 3T3-L1 cells promotes adipogenesis. In the present study, we aimed to elucidate the effects of the addition of PGD2 or 11d-11m-PGD2 to 3T3-L1 cells during the differentiation phase on adipogenesis. We found that both PGD2 and 11d-11m-PGD2 suppressed adipogenesis through the downregulation of peroxisome proliferator-activated receptor gamma (PPARγ) expression. However, the latter suppressed adipogenesis more potently than PGD2, most likely because of its higher resistance to spontaneous transformation into PGJ2 derivatives. In addition, this anti-adipogenic effect was attenuated by the coexistence of an IP receptor agonist, suggesting that the effect depends on the intensity of the signaling from the IP receptor. The D-prostanoid receptors 1 (DP1) and 2 (DP2, also known as a chemoattractant receptor-homologous molecule expressed on Th2 cells) are receptors for PGD2. The inhibitory effects of PGD2 and 11d-11m-PGD2 on adipogenesis were slightly attenuated by a DP2 agonist. Furthermore, the addition of PGD2 and 11d-11m-PGD2 during the differentiation phase reduced the DP1 and DP2 expression during the maturation phase. Overall, these results indicated that the addition of PGD2 or 11d-11m-PGD2 during the differentiation phase suppresses adipogenesis via the dysfunction of DP1 and DP2. Therefore, unidentified receptor(s) for both molecules may be involved in the suppression of adipogenesis.
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Affiliation(s)
- Michael N. N. Nartey
- The United Graduate School of Agricultural Sciences, Tottori University, 4-101 Koyama-Minami, Tottori 680-8553, Japan
- Council for Scientific and Industrial Research-Animal Research Institute, Achimota, Accra P.O. Box AH20, Ghana
| | - Mitsuo Jisaka
- The United Graduate School of Agricultural Sciences, Tottori University, 4-101 Koyama-Minami, Tottori 680-8553, Japan
- Department of Life Science and Biotechnology, Shimane University, 1060 Nishikawatsu-Cho, Matsue 690-8504, Japan
- Institute of Agricultural and Life Sciences, Academic Assembly, Shimane University, 1060 Nishikawatsu-Cho, Matsue 690-8504, Japan
- Correspondence:
| | - Pinky Karim Syeda
- Department of Life Science and Biotechnology, Shimane University, 1060 Nishikawatsu-Cho, Matsue 690-8504, Japan
| | - Kohji Nishimura
- The United Graduate School of Agricultural Sciences, Tottori University, 4-101 Koyama-Minami, Tottori 680-8553, Japan
- Department of Life Science and Biotechnology, Shimane University, 1060 Nishikawatsu-Cho, Matsue 690-8504, Japan
- Institute of Agricultural and Life Sciences, Academic Assembly, Shimane University, 1060 Nishikawatsu-Cho, Matsue 690-8504, Japan
- Interdisciplinary Center for Science Research, Shimane University, 1060 Nishikawatsu-Cho, Matsue 690-8504, Japan
| | - Hidehisa Shimizu
- The United Graduate School of Agricultural Sciences, Tottori University, 4-101 Koyama-Minami, Tottori 680-8553, Japan
- Department of Life Science and Biotechnology, Shimane University, 1060 Nishikawatsu-Cho, Matsue 690-8504, Japan
- Institute of Agricultural and Life Sciences, Academic Assembly, Shimane University, 1060 Nishikawatsu-Cho, Matsue 690-8504, Japan
- Interdisciplinary Center for Science Research, Shimane University, 1060 Nishikawatsu-Cho, Matsue 690-8504, Japan
| | - Kazushige Yokota
- The United Graduate School of Agricultural Sciences, Tottori University, 4-101 Koyama-Minami, Tottori 680-8553, Japan
- Department of Life Science and Biotechnology, Shimane University, 1060 Nishikawatsu-Cho, Matsue 690-8504, Japan
- Institute of Agricultural and Life Sciences, Academic Assembly, Shimane University, 1060 Nishikawatsu-Cho, Matsue 690-8504, Japan
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Vasu K, Ramachandiran I, Chechi A, Khan K, Khan D, Kaufman R, Fox PL. Translational control of murine adiponectin expression by an upstream open reading frame element. RNA Biol 2023; 20:737-749. [PMID: 37702393 PMCID: PMC10501164 DOI: 10.1080/15476286.2023.2256094] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Revised: 06/13/2023] [Accepted: 06/19/2023] [Indexed: 09/14/2023] Open
Abstract
Adiponectin, an adipocyte-specific secretory protein encoded by the ADIPOQ gene has a causal role in insulin resistance. Anti-diabetic drugs increase plasma adiponectin by a poorly understood, post-transcriptional mechanism enhancing insulin sensitivity. Deletion analysis of a reporter bearing the mouse Adipoq mRNA 5'-leader identified an inhibitory cis-regulatory sequence. The 5'-leader harbours two potential upstream open reading frames (uORFs) overlapping the principal downstream ORF. Mutation of the uORF ATGs increased reporter translation ~3-fold, indicative of a functional uORF. uORFs are common in mammalian mRNAs; however, only a select group resist translational repression by the integrated stress response (ISR). Thapsigargin (TG), which induces endoplasmic reticulum (ER) stress and the ISR, enhanced expression of a reporter bearing the Adipoq 5'-leader; polysome profiling verified translation-stimulation. TG-stimulated translation was absent in cells defective in Ser51 phosphorylation of eukaryotic initiation factor 2α (eIF2α), required for the ISR. To determine its role in expression and function of endogenous adiponectin, the upstream uORF was disrupted by CRISPR-Cas9-mediated mutagenesis of differentiated mouse 3T3-L1 adipocytes. uORF disruption in adipocytes increased adiponectin expression, triacylglycerol accumulation, and glucose uptake, and inhibited paracrine muscle and liver cell expression of gluconeogenic enzymes, establishing an important role of the uORF in adiponectin-mediated responses to stress.
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Affiliation(s)
- Kommireddy Vasu
- Department of Cardiovascular and Metabolic Sciences, Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, OH, USA
| | - Iyappan Ramachandiran
- Department of Cardiovascular and Metabolic Sciences, Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, OH, USA
| | - Aayushi Chechi
- Department of Cardiovascular and Metabolic Sciences, Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, OH, USA
| | - Krishnendu Khan
- Department of Cardiovascular and Metabolic Sciences, Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, OH, USA
| | - Debjit Khan
- Department of Cardiovascular and Metabolic Sciences, Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, OH, USA
| | - Randall Kaufman
- Degenerative Diseases Program, Center for Genetic Disorders and Aging Research, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA, USA
| | - Paul L. Fox
- Department of Cardiovascular and Metabolic Sciences, Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, OH, USA
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Tea Plant ( Camellia sinensis): A Current Update on Use in Diabetes, Obesity, and Cardiovascular Disease. Nutrients 2022; 15:nu15010037. [PMID: 36615695 PMCID: PMC9823498 DOI: 10.3390/nu15010037] [Citation(s) in RCA: 19] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/27/2022] [Revised: 12/14/2022] [Accepted: 12/19/2022] [Indexed: 12/24/2022] Open
Abstract
The tea plant (C. sinensis) has traditionally been consumed worldwide as "tea" for its many health benefits, with the potential for the prevention and therapy of various conditions. Regardless of its long history, the use of tea plants in modern times seems not to have changed much, as the beverage remains the most popular form. This review aimed to compile scientific information about the role and action of tea plants, as well as their status concerning clinical applications, based on the currently available evidence, with a focus on metabolic syndrome, mainly covering obesity, diabetes, and cardiovascular disease. It has been recognized that these diseases pose a significant threat to public health, and the development of effective treatment and prevention strategies is necessary but still challenging. In this article, the potential benefits of tea plants and their derived bioactive components (such as epigallocatechin-3-gallate) as anti-obesity, anti-diabetic, and anti-cardiovascular agents are clearly shown and emphasized, along with their mechanisms of action. However, according to the status of the clinical translation of tea plants, particularly in drug development, more substantial efforts in well-designed, randomized, controlled trials are required to expand their applications in treating the three major metabolic disorders and avoiding the toxicity caused by overconsumption.
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Activation of PPARγ Protects Obese Mice from Acute Lung Injury by Inhibiting Endoplasmic Reticulum Stress and Promoting Mitochondrial Biogenesis. PPAR Res 2022; 2022:7888937. [PMID: 36213491 PMCID: PMC9534695 DOI: 10.1155/2022/7888937] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/10/2022] [Revised: 08/20/2022] [Accepted: 09/06/2022] [Indexed: 11/17/2022] Open
Abstract
Objective Obesity-induced endoplasmic reticulum (ER) stress plays a role in increased susceptibility to acute lung injury (ALI)/acute respiratory distress syndrome (ARDS). The activation of peroxisome proliferator-activated receptor-γ (PPARγ) is associated with lung protection and is effective in ameliorating ER stress and mitochondrial dysfunction. The aim of this study was to investigate the expression of PPARγ in the lung tissues of obese mice and explore whether the PPARγ-dependent pathway could mediate decreased ALI/ARDS by regulating ER stress and mitochondrial biogenesis. Methods We determined PPARγ expression in the lung tissues of normal and obese mice. ALI models of alveolar epithelial cells and of obese mice were used and treated with either PPARγ activator rosiglitazone (RSG) or PPARγ inhibitor GW9662. Lung tissue and cell samples were collected to assess lung inflammation and apoptosis, and ER stress and mitochondrial biogenesis were detected. Results PPARγ expression was significantly decreased in the lung tissue of obese mice compared with that in normal mice. Both in vivo and in vitro studies have shown that activation of PPARγ leads to reduced expression of the ER stress marker proteins 78-kDa glucose-regulated protein (GRP78), C/EBP homologous protein (CHOP), and Caspase12. Conversely, expression of the mitochondrial biogenesis-related proteins peroxisome proliferator-activated receptor γ coactivator 1 (PGC-1α), nuclear respiratory factor-1 (NRF-1), and mitochondrial transcription factor A (TFAM) increased. Furthermore, activation of PPARγ is associated with decreased levels of lung inflammation and epithelial apoptosis and increased expression of adiponectin (APN) and mitofusin2 (MFN2). GW9662 bound to PPARγ and blocked its transcriptional activity and then diminished the protective effect of PPARγ on lung tissues. Conclusions PPARγ activation exerts anti-inflammation effects in alveolar epithelia by alleviating ER stress and promoting mitochondrial biogenesis. Therefore, lower levels of PPARγ in the lung tissues of obese mice may lead to an increased susceptibility to ALI.
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Altuna-Coy A, Ruiz-Plazas X, Sánchez-Martin S, Ascaso-Til H, Prados-Saavedra M, Alves-Santiago M, Bernal-Escoté X, Segarra-Tomás J, R Chacón M. The lipidomic profile of the tumoral periprostatic adipose tissue reveals alterations in tumor cell's metabolic crosstalk. BMC Med 2022; 20:255. [PMID: 35978404 PMCID: PMC9386931 DOI: 10.1186/s12916-022-02457-3] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/03/2022] [Accepted: 06/30/2022] [Indexed: 12/15/2022] Open
Abstract
BACKGROUND Periprostatic adipose tissue (PPAT) plays a role in prostate cancer (PCa) progression. PPAT lipidomic composition study may allow us to understand the tumor metabolic microenvironment and provide new stratification factors. METHODS We used ultra-high-performance liquid chromatography-mass spectrometry-based non-targeted lipidomics to profile lipids in the PPAT of 40 patients with PCa (n = 20 with low-risk and n = 20 high-risk). Partial least squares-discriminant analysis (PLS-DA) and variable importance in projection (VIP) analysis were used to identify the most relevant features of PPAT between low- and high-risk PCa, and metabolite set enrichment analysis was used to detect disrupted metabolic pathways. Metabolic crosstalk between PPAT and PCa cell lines (PC-3 and LNCaP) was studied using ex vivo experiments. Lipid uptake and lipid accumulation were measured. Lipid metabolic-related genes (SREBP1, FASN, ACACA, LIPE, PPARG, CD36, PNPLA2, FABP4, CPT1A, FATP5, ADIPOQ), inflammatory markers (IL-6, IL-1B, TNFα), and tumor-related markers (ESRRA, MMP-9, TWIST1) were measured by RT-qPCR. RESULTS Significant differences in the content of 67 lipid species were identified in PPAT samples between high- and low-risk PCa. PLS-DA and VIP analyses revealed a discriminating lipidomic panel between low- and high-risk PCa, suggesting the occurrence of disordered lipid metabolism in patients related to PCa aggressiveness. Functional analysis revealed that alterations in fatty acid biosynthesis, linoleic acid metabolism, and β-oxidation of very long-chain fatty acids had the greatest impact in the PPAT lipidome. Gene analyses of PPAT samples demonstrated that the expression of genes associated with de novo fatty acid synthesis such as FASN and ACACA were significantly lower in PPAT from high-risk PCa than in low-risk counterparts. This was accompanied by the overexpression of inflammatory markers (IL-6, IL-1B, and TNFα). Co-culture of PPAT explants with PCa cell lines revealed a reduced gene expression of lipid metabolic-related genes (CD36, FASN, PPARG, and CPT1A), contrary to that observed in co-cultured PCa cell lines. This was followed by an increase in lipid uptake and lipid accumulation in PCa cells. Tumor-related genes were increased in co-cultured PCa cell lines. CONCLUSIONS Disturbances in PPAT lipid metabolism of patients with high-risk PCa are associated with tumor cell metabolic changes.
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Affiliation(s)
- Antonio Altuna-Coy
- Disease Biomarkers and Molecular Mechanisms Group, Institut d'Investigació Sanitària Pere Virgilii, Joan XXIII University Hospital, Universitat Rovira i Virgili, C/ Dr. Mallafré Guasch, 4. 43007, Tarragona, Spain
| | - Xavier Ruiz-Plazas
- Disease Biomarkers and Molecular Mechanisms Group, Institut d'Investigació Sanitària Pere Virgilii, Joan XXIII University Hospital, Universitat Rovira i Virgili, C/ Dr. Mallafré Guasch, 4. 43007, Tarragona, Spain.,Urology Unit, Joan XXIII University Hospital, Tarragona, Spain
| | - Silvia Sánchez-Martin
- Disease Biomarkers and Molecular Mechanisms Group, Institut d'Investigació Sanitària Pere Virgilii, Joan XXIII University Hospital, Universitat Rovira i Virgili, C/ Dr. Mallafré Guasch, 4. 43007, Tarragona, Spain
| | | | | | - Marta Alves-Santiago
- Disease Biomarkers and Molecular Mechanisms Group, Institut d'Investigació Sanitària Pere Virgilii, Joan XXIII University Hospital, Universitat Rovira i Virgili, C/ Dr. Mallafré Guasch, 4. 43007, Tarragona, Spain.,Urology Unit, Joan XXIII University Hospital, Tarragona, Spain
| | | | - José Segarra-Tomás
- Disease Biomarkers and Molecular Mechanisms Group, Institut d'Investigació Sanitària Pere Virgilii, Joan XXIII University Hospital, Universitat Rovira i Virgili, C/ Dr. Mallafré Guasch, 4. 43007, Tarragona, Spain. .,Urology Unit, Joan XXIII University Hospital, Tarragona, Spain.
| | - Matilde R Chacón
- Disease Biomarkers and Molecular Mechanisms Group, Institut d'Investigació Sanitària Pere Virgilii, Joan XXIII University Hospital, Universitat Rovira i Virgili, C/ Dr. Mallafré Guasch, 4. 43007, Tarragona, Spain.
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Ryan AS, Li G. Adipose and Skeletal Muscle Expression of Adiponectin and Liver Receptor Homolog-1 With Weight Loss and Aerobic Exercise. J Endocr Soc 2022; 6:bvac095. [PMID: 35854979 PMCID: PMC9281870 DOI: 10.1210/jendso/bvac095] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/29/2021] [Indexed: 11/19/2022] Open
Abstract
Context Adiponectin is an adipokine mainly secreted by adipocytes that regulates the metabolism of lipids and glucose. Liver receptor homolog-1 (LRH-1), also named NR5A2, is a nuclear receptor that regulates lipid metabolism and homeostasis. Objective The purpose of this study was to compare adiponectin and LRH-1 messenger RNA (mRNA) expression in adipose tissue and LRH-1 expression in skeletal muscle between men and women at baseline and to study the effects of aerobic exercise (AEX) training or weight loss (WL) on their expression. Methods This hospital and university setting study included 62 overweight and obese men (n = 23) and women (n = 39) older than 45 years, of whom 41 completed 6 months of WL (n = 21) or AEX (n = 20). Outcomes included abdominal and gluteal adipose tissue and skeletal muscle gene expression. Results Adiponectin and LRH-1 mRNA expression in adipose tissue and LRH-1 mRNA expression in skeletal muscle is higher in women than in men (P < .05). Adiponectin mRNA expression in gluteal and abdominal adipose tissue did not change significantly after AEX or WL. LRH-1 mRNA expression increased both in adipose tissue and skeletal muscle after AEX (P < .05) and the change in muscle LRH-1 was different between the groups (P < .05). Adiponectin was positively correlated to LRH-1 in adipose tissue (P < .001). The change in maximal oxygen consumption related to the change in LRH-1 mRNA (r = 0.43; P = .01). Conclusion LRH-1, as a nuclear reporter, may activate adiponectin mRNA expression in adipose tissue and increases after AEX.
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Affiliation(s)
- Alice S Ryan
- VA Research Service, VA Maryland Health Care System, Baltimore, Maryland 21201, USA
| | - Guoyan Li
- Department of Medicine, Division of Geriatric and Palliative Medicine, University of Maryland School of Medicine, Baltimore, Maryland 21201, USA
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Chekol Abebe E, Tilahun Muche Z, Behaile T/Mariam A, Mengie Ayele T, Mekonnen Agidew M, Teshome Azezew M, Abebe Zewde E, Asmamaw Dejenie T, Asmamaw Mengstie M. The structure, biosynthesis, and biological roles of fetuin-A: A review. Front Cell Dev Biol 2022; 10:945287. [PMID: 35923855 PMCID: PMC9340150 DOI: 10.3389/fcell.2022.945287] [Citation(s) in RCA: 50] [Impact Index Per Article: 16.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2022] [Accepted: 06/28/2022] [Indexed: 11/21/2022] Open
Abstract
Fetuin-A is a heterodimeric plasma glycoprotein containing an A-chain of 282 amino acids and a B-chain of 27 amino acid residues linked by a single inter-disulfide bond. It is predominantly expressed in embryonic cells and adult hepatocytes, and to a lesser extent in adipocytes and monocytes. Fetuin-A binds with a plethora of receptors and exhibits multifaceted physiological and pathological functions. It is involved in the regulation of calcium metabolism, osteogenesis, and the insulin signaling pathway. It also acts as an ectopic calcification inhibitor, protease inhibitor, inflammatory mediator, anti-inflammatory partner, atherogenic factor, and adipogenic factor, among other several moonlighting functions. Fetuin-A has also been demonstrated to play a crucial role in the pathogenesis of several disorders. This review mainly focuses on the structure, synthesis, and biological roles of fetuin-A. Information was gathered manually from various journals via electronic searches using PubMed, Google Scholar, HINARI, and Cochrane Library from inception to 2022. Studies written in English and cohort, case-control, cross-sectional, or experimental studies were considered in the review, otherwise excluded.
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Affiliation(s)
- Endeshaw Chekol Abebe
- Department of Medical Biochemistry, College of Health Sciences, Debre Tabor University, Debre Tabor, Ethiopia
| | - Zelalem Tilahun Muche
- Department of Physiology, College of Health Sciences, Debre Tabor University, Debre Tabor, Ethiopia
| | - Awigchew Behaile T/Mariam
- Department of Medical Biochemistry, College of Health Sciences, Debre Tabor University, Debre Tabor, Ethiopia
| | - Teklie Mengie Ayele
- Department of Pharmacy, College of Health Sciences, Debre Tabor University, Debre Tabor, Ethiopia
| | - Melaku Mekonnen Agidew
- Department of Medical Biochemistry, College of Health Sciences, Debre Tabor University, Debre Tabor, Ethiopia
| | - Muluken Teshome Azezew
- Department of Physiology, College of Health Sciences, Debre Tabor University, Debre Tabor, Ethiopia
| | - Edgeit Abebe Zewde
- Department of Physiology, College of Health Sciences, Debre Tabor University, Debre Tabor, Ethiopia
| | - Tadesse Asmamaw Dejenie
- Department of Medical Biochemistry, College of Medicine and Health Sciences, University of Gondar, Gondar, Ethiopia
| | - Misganaw Asmamaw Mengstie
- Department of Medical Biochemistry, College of Health Sciences, Debre Tabor University, Debre Tabor, Ethiopia
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Lin WS, Lin SJ, Liao PY, Suresh D, Hsu TR, Wang PY. Role of Ketogenic Diets in Multiple Sclerosis and Related Animal Models: An Updated Review. Adv Nutr 2022; 13:2002-2014. [PMID: 35679067 PMCID: PMC9526852 DOI: 10.1093/advances/nmac065] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/21/2022] [Revised: 04/25/2022] [Accepted: 06/02/2022] [Indexed: 01/28/2023] Open
Abstract
Prescribing a ketogenic diet (KD) is a century-old dietary intervention mainly used in the context of intractable epilepsy. The classic KD and its variants regained popularity in recent decades, and they are considered potentially beneficial in a variety of neurological conditions other than epilepsy. Many patients with multiple sclerosis (MS) have attempted diet modification for better control of their disease, although evidence thus far remains insufficient to recommend a specific diet for these patients. The results of 3 pilot clinical trials of KD therapy for MS, as well as several related studies, have been reported in recent years. The preliminary findings suggest that KD is safe, feasible, and potentially neuroprotective and disease-modifying for patients with MS. Research on corresponding rodent models has also lent support to the efficacy of KD in the prevention and treatment of experimental autoimmune encephalomyelitis and toxin-induced inflammatory demyelinating conditions in the brain. Furthermore, the animal studies have yielded mechanistic insights into the molecular mechanisms of KD action in relevant situations, paving the way for precision nutrition. Herein we review and synthesize recent advances and also identify unresolved issues, such as the roles of adipokines and gut microbiota, in this field. Hopefully this panoramic view of current understanding can inform future research directions and clinical practice with regard to KD in MS and related conditions.
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Affiliation(s)
| | - Shan-Ju Lin
- Department of Physical Medicine and Rehabilitation, National Taiwan University Hospital Yunlin Branch, Yunlin, Taiwan
| | - Pei-Yin Liao
- Department of Dietetics, National Taiwan University Hospital Yunlin Branch, Yunlin, Taiwan
| | - Divya Suresh
- Department of Pediatrics, National Taiwan University Hospital Yunlin Branch, Yunlin, Taiwan
| | - Ting-Rong Hsu
- Department of Pediatrics, Taipei Veterans General Hospital, Taipei, Taiwan,School of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan
| | - Pei-Yu Wang
- Graduate Institute of Brain and Mind Sciences, College of Medicine, National Taiwan University, Taipei, Taiwan,Neurobiology and Cognitive Science Center, National Taiwan University, Taipei, Taiwan,Program in Translational Medicine, National Taiwan University and Academia Sinica, Taipei, Taiwan,Taiwan International Graduate Program in Interdisciplinary Neuroscience, National Taiwan University and Academia Sinica, Taipei, Taiwan,Graduate Institute of Neural Regenerative Medicine, College of Medical Science and Technology, Taipei Medical University, Taipei, Taiwan
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Nuclear Receptors in Energy Metabolism. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2022; 1390:61-82. [DOI: 10.1007/978-3-031-11836-4_4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
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Okuro K, Fukuhara A, Minemura T, Hayakawa T, Nishitani S, Okuno Y, Otsuki M, Shimomura I. Glutamine deficiency induces lipolysis in adipocytes. Biochem Biophys Res Commun 2021; 585:155-161. [PMID: 34801935 DOI: 10.1016/j.bbrc.2021.11.043] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2021] [Accepted: 11/11/2021] [Indexed: 10/19/2022]
Abstract
Glutamine is the most abundant amino acid in the body, and adipose tissue is one of the glutamine-producing organs. Glutamine has important and unique metabolic functions; however, its effects in adipocytes are still unclear. 3T3-L1 adipocytes produced and secreted glutamine dependent on glutamine synthetase, but preadipocytes did not. The inhibition of glutamine synthetase by l-methionine sulfoximine (MSO) impaired the differentiation of preadipocytes to mature adipocytes, and this inhibitory effect of MSO was rescued by exogenous glutamine supplementation. Glutamine concentrations were low, and Atgl gene expression was high in epididymal white adipose tissues of fasting mice in vivo. In 3T3-L1 adipocytes, glutamine deprivation induced Atgl expression and increased glycerol concentration in culture medium. Atgl expression is regulated by FoxO1, and glutamine deprivation reduced FoxO1 phosphorylation (Ser256), indicating the activation of FoxO1. These results demonstrate that glutamine is necessary for the differentiation of preadipocytes and regulates lipolysis through FoxO1 in mature adipocytes.
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Affiliation(s)
- Kenta Okuro
- Department of Metabolic Medicine, Osaka University Graduate School of Medicine, Suita, Osaka, Japan
| | - Atsunori Fukuhara
- Department of Metabolic Medicine, Osaka University Graduate School of Medicine, Suita, Osaka, Japan; Department of Adipose Management, Osaka University Graduate School of Medicine, Suita, Osaka, Japan.
| | - Tomomi Minemura
- Department of Metabolic Medicine, Osaka University Graduate School of Medicine, Suita, Osaka, Japan
| | - Tomoaki Hayakawa
- Department of Metabolic Medicine, Osaka University Graduate School of Medicine, Suita, Osaka, Japan
| | - Shigeki Nishitani
- Department of Metabolic Medicine, Osaka University Graduate School of Medicine, Suita, Osaka, Japan
| | - Yosuke Okuno
- Department of Metabolic Medicine, Osaka University Graduate School of Medicine, Suita, Osaka, Japan
| | - Michio Otsuki
- Department of Metabolic Medicine, Osaka University Graduate School of Medicine, Suita, Osaka, Japan
| | - Iichiro Shimomura
- Department of Metabolic Medicine, Osaka University Graduate School of Medicine, Suita, Osaka, Japan
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Ertuglu LA, Elijovich F, Laffer CL, Kirabo A. Salt-Sensitivity of Blood Pressure and Insulin Resistance. Front Physiol 2021; 12:793924. [PMID: 34966295 PMCID: PMC8711096 DOI: 10.3389/fphys.2021.793924] [Citation(s) in RCA: 25] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2021] [Accepted: 11/18/2021] [Indexed: 12/20/2022] Open
Abstract
Salt sensitivity of blood pressure (SSBP) is an independent risk factor for cardiovascular morbidity and mortality that is seen in both hypertensive and normotensive populations. Insulin resistance (IR) strongly correlates with SSBP and affects nearly 50% of salt sensitive people. While the precise mechanism by which IR and SSBP relate remains elusive, several common pathways are involved in the genesis of both processes, including vascular dysfunction and immune activation. Vascular dysfunction associated with insulin resistance is characterized by loss of nitric oxide (NO)-mediated vasodilation and heightened endothelin-1 induced vasoconstriction, as well as capillary rarefaction. It manifests with increased blood pressure (BP) in salt sensitive murine models. Another common denominator in the pathogenesis of insulin resistance, hypertension, and salt sensitivity (SS) is immune activation involving pro-inflammatory cytokines like tumor necrosis factor (TNF)-α, IL-1β, and IL-6. In the last decade, a new understanding of interstitial sodium storage in tissues such as skin and muscle has revolutionized traditional concepts of body sodium handling and pathogenesis of SS. We have shown that interstitial Na+ can trigger a T cell mediated inflammatory response through formation of isolevuglandin protein adducts in antigen presenting cells (APCs), and that this response is implicated in salt sensitive hypertension. The peroxisome proliferator-activated receptor γ (PPARγ) is a transcription factor that modulates both insulin sensitivity and BP. PPARγ agonists increase insulin sensitivity and ameliorate salt sensitivity, whereas deficiency of PPARγ results in severe insulin resistance and hypertension. These findings suggest that PPARγ plays a role in the common pathogenesis of insulin sensitivity and salt sensitivity, perhaps via effects on the immune system and vascular function. The goal of this review is to discuss those mechanisms that may play a role in both SSBP and in insulin resistance.
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Affiliation(s)
- Lale A Ertuglu
- Division of Nephrology, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, United States
| | - Fernando Elijovich
- Division of Clinical Pharmacology, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, United States
| | - Cheryl L Laffer
- Division of Clinical Pharmacology, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, United States
| | - Annet Kirabo
- Division of Clinical Pharmacology, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, United States
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Lang A, Isigkeit L, Schubert-Zsilavecz M, Merk D. The Medicinal Chemistry and Therapeutic Potential of LRH-1 Modulators. J Med Chem 2021; 64:16956-16973. [PMID: 34839661 DOI: 10.1021/acs.jmedchem.1c01663] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
The ligand-activated transcription factor liver receptor homologue 1 (LRH-1, NR5A2) is involved in the regulation of metabolic homeostasis, including cholesterol and glucose balance. Preliminary evidence points to therapeutic potential of LRH-1 modulation in diabetes, hepatic diseases, inflammatory bowel diseases, atherosclerosis, and certain cancers, but because of a lack of suitable ligands, pharmacological control of LRH-1 has been insufficiently studied. Despite the availability of considerable structural knowledge on LRH-1, only a few ligand chemotypes have been developed, and potent, selective, and bioavailable tools to explore LRH-1 modulation in vivo are lacking. In view of the therapeutic potential of LRH-1 in prevalent diseases, improved chemical tools are needed to probe the beneficial and adverse effects of pharmacological LRH-1 modulation in sophisticated preclinical models and to further elucidate the receptor's molecular function.
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Affiliation(s)
- Alisa Lang
- Institute of Pharmaceutical Chemistry, Goethe University Frankfurt, D-60438 Frankfurt, Germany
| | - Laura Isigkeit
- Institute of Pharmaceutical Chemistry, Goethe University Frankfurt, D-60438 Frankfurt, Germany
| | | | - Daniel Merk
- Institute of Pharmaceutical Chemistry, Goethe University Frankfurt, D-60438 Frankfurt, Germany.,Department of Pharmacy, Ludwig-Maximilians-Universität München, Butenandtstr. 5-13, D-81377 Munich, Germany
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Jokioja J, Yang B, Linderborg KM. Acylated anthocyanins: A review on their bioavailability and effects on postprandial carbohydrate metabolism and inflammation. Compr Rev Food Sci Food Saf 2021; 20:5570-5615. [PMID: 34611984 DOI: 10.1111/1541-4337.12836] [Citation(s) in RCA: 61] [Impact Index Per Article: 15.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2021] [Revised: 08/13/2021] [Accepted: 08/14/2021] [Indexed: 12/31/2022]
Abstract
Anthocyanins, the natural red and purple colorants of berries, fruits, vegetables, and tubers, improve carbohydrate metabolism and decrease the risk factors of metabolic disorders, but their industrial use is limited by their chemical instability. Acylation of the glycosyl moieties of anthocyanins, however, changes the chemical properties of anthocyanins and provides enhanced stability. Thus, acylated anthocyanins are more usable as natural colorants and bioactive components of innovative functional foods. Acylated anthocyanins are common in pigmented vegetables and tubers, the consumption of which has the potential to increase the intake of health-promoting anthocyanins as part of the daily diet. For the first time, this review presents the current findings on bioavailability, absorption, metabolism, and health effects of acylated anthocyanins with comparison to more extensively investigated nonacylated anthocyanins. The structural differences between nonacylated and acylated anthocyanins lead to enhanced color stability, altered absorption, bioavailability, in vivo stability, and colonic degradation. The impact of phenolic metabolites and their potential health effects regardless of the low bioavailability of the parent anthocyanins as such is discussed. Here, purple-fleshed potatoes are presented as a globally available, eco-friendly model food rich in acylated anthocyanins, which further highlights the industrial possibilities and nutritional relevance of acylated anthocyanins. This work supports the academic community and industry in food research and development by reviewing the current literature and highlighting gaps of knowledge.
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Affiliation(s)
- Johanna Jokioja
- Food Chemistry and Food Development, Department of Life Technologies, University of Turku, Turku, Finland
| | - Baoru Yang
- Food Chemistry and Food Development, Department of Life Technologies, University of Turku, Turku, Finland
| | - Kaisa M Linderborg
- Food Chemistry and Food Development, Department of Life Technologies, University of Turku, Turku, Finland
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41
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Sharma A, Mah M, Ritchie RH, De Blasio MJ. The adiponectin signalling pathway - A therapeutic target for the cardiac complications of type 2 diabetes? Pharmacol Ther 2021; 232:108008. [PMID: 34610378 DOI: 10.1016/j.pharmthera.2021.108008] [Citation(s) in RCA: 27] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2021] [Revised: 08/17/2021] [Accepted: 09/23/2021] [Indexed: 12/11/2022]
Abstract
Diabetes is associated with an increased risk of heart failure (HF). This is commonly termed diabetic cardiomyopathy and is often characterised by increased cardiac fibrosis, pathological hypertrophy, increased oxidative and endoplasmic reticulum stress as well as diastolic dysfunction. Adiponectin is a cardioprotective adipokine that is downregulated in settings of type 2 diabetes (T2D) and obesity. Furthermore, both adiponectin receptors (AdipoR1 and R2) are also downregulated in these settings which further results in impaired cardiac adiponectin signalling and reduced cardioprotection. In many cardiac pathologies, adiponectin signalling has been shown to protect against cardiac remodelling and lipotoxicity, however its cardioprotective actions in T2D-induced cardiomyopathy remain unresolved. Diabetic cardiomyopathy has historically lacked effective treatment options. In this review, we summarise the current evidence for links between the suppressed adiponectin signalling pathway and cardiac dysfunction, in diabetes. We describe adiponectin receptor-mediated signalling pathways that are normally associated with cardioprotection, as well as current and potential future therapeutic approaches that could target this pathway as possible interventions for diabetic cardiomyopathy.
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Affiliation(s)
- Abhipree Sharma
- Heart Failure Pharmacology, Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, VIC 3052, Australia
| | - Michael Mah
- Heart Failure Pharmacology, Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, VIC 3052, Australia
| | - Rebecca H Ritchie
- Heart Failure Pharmacology, Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, VIC 3052, Australia; Department of Pharmacology, Monash University, Clayton, VIC 3800, Australia; Department of Medicine, Monash University, Clayton, VIC 3800, Australia
| | - Miles J De Blasio
- Heart Failure Pharmacology, Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, VIC 3052, Australia; Department of Pharmacology, Monash University, Clayton, VIC 3800, Australia.
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Gopal T, Ai W, Casey CA, Donohue TM, Saraswathi V. A review of the role of ethanol-induced adipose tissue dysfunction in alcohol-associated liver disease. Alcohol Clin Exp Res 2021; 45:1927-1939. [PMID: 34558087 PMCID: PMC9153937 DOI: 10.1111/acer.14698] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2021] [Revised: 08/10/2021] [Accepted: 08/13/2021] [Indexed: 12/14/2022]
Abstract
Alcohol-associated liver disease (AALD) encompasses a spectrum of liver diseases that includes simple steatosis, steatohepatitis, fibrosis, and cirrhosis. The adverse effects of alcohol in liver and the mechanisms by which ethanol (EtOH) promotes liver injury are well studied. Although liver is known to be the primary organ affected by EtOH exposure, alcohol's effects on other organs are also known to contribute significantly to the development of liver injury. It is becoming increasingly evident that adipose tissue (AT) is an important site of EtOH action. Both AT storage and secretory functions are altered by EtOH. For example, AT lipolysis, stimulated by EtOH, contributes to chronic alcohol-induced hepatic steatosis. Adipocytes secrete a wide variety of biologically active molecules known as adipokines. EtOH alters the secretion of these adipokines from AT, which include cytokines and chemokines that exert paracrine effects in liver. In addition, the level of EtOH-metabolizing enzymes, in particular, CYP2E1, rises in the AT of EtOH-fed mice, which promotes oxidative stress and/or inflammation in AT. Thus, AT dysfunction characterized by increased AT lipolysis and free fatty acid mobilization and altered secretion of adipokines can contribute to the severity of AALD. Of note, moderate EtOH exposure results in AT browning and activation of brown adipose tissue which, in turn, can promote thermogenesis. In this review article, we discuss the direct effects of EtOH consumption in AT and the mechanisms by which EtOH impacts the functions of AT, which, in turn, increases the severity of AALD in animal models and humans.
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Affiliation(s)
- Thiyagarajan Gopal
- Department of Internal Medicine, Divisions of Diabetes, Endocrinology, and Metabolism
- VA Nebraska-Western Iowa Health Care System, Omaha, NE
| | - Weilun Ai
- Department of Internal Medicine, Divisions of Diabetes, Endocrinology, and Metabolism
- VA Nebraska-Western Iowa Health Care System, Omaha, NE
| | - Carol A. Casey
- Gastroenterology and Hepatology, University of Nebraska Medical Center, Omaha, NE
- VA Nebraska-Western Iowa Health Care System, Omaha, NE
| | - Terrence M. Donohue
- Gastroenterology and Hepatology, University of Nebraska Medical Center, Omaha, NE
- VA Nebraska-Western Iowa Health Care System, Omaha, NE
| | - Viswanathan Saraswathi
- Department of Internal Medicine, Divisions of Diabetes, Endocrinology, and Metabolism
- VA Nebraska-Western Iowa Health Care System, Omaha, NE
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Cheng C, Xue F, Sui W, Meng L, Xie L, Zhang C, Yang J, Zhang Y. Deletion of natriuretic peptide receptor C alleviates adipose tissue inflammation in hypercholesterolemic Apolipoprotein E knockout mice. J Cell Mol Med 2021; 25:9837-9850. [PMID: 34528389 PMCID: PMC8505842 DOI: 10.1111/jcmm.16931] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/17/2021] [Revised: 08/24/2021] [Accepted: 09/01/2021] [Indexed: 12/16/2022] Open
Abstract
The inflammation of adipose tissue is one of the most common secondary pathological changes in atherosclerosis, which in turn influences the process of atherosclerosis. Natriuretic peptides have been revealed important effect in regulating adipose metabolism. However, the relationship between natriuretic peptide receptor C and inflammation of adipose tissue in atherosclerosis remains unknown. This study aims to explore the effect natriuretic peptide receptor C exerts on the regulation of the adipose inflammation in atherosclerotic mice induced by western-type diet and its overlying mechanisms. To clarify the importance of NPRC of adipose inflammation in atherosclerotic mice, NPRC expression was measured in mice fed with chow diet and western-type diet for 12 weeks and we found a considerable increase in adipose tissue of atherosclerotic mice. Global NPRC knockout in mice was bred onto ApoE-/- mice to generate NPRC-/- ApoE-/- mice, which displayed remarked increase in browning of white adipose tissue and lipolysis of adipose tissue and decrease in adipose inflammation manifested by decreased macrophage invasion to form less CLS (crown-like structure), reduced oxidative stress and alleviated expression of TNFα, IL-6, IL-1β and MCP1, but increased expression of adiponectin in adipose tissue. Moreover, our study showed that white adipose tissue browning in NPRC-/- ApoE-/- atherosclerotic mice was associated with decreased inflammatory response through cAMP/PKA signalling activation. These results identify NPRC as a novel regulator for adipose inflammation in atherosclerotic mice by modulating white adipose tissue browning.
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Affiliation(s)
- Cheng Cheng
- Department of CardiologyThe Key Laboratory of Cardiovascular Remodeling and Function ResearchChinese Ministry of EducationChinese National Health Commission and Chinese Academy of Medical SciencesThe State and Shandong Province Joint Key Laboratory of Translational Cardiovascular MedicineQilu HospitalCheeloo College of MedicineShandong UniversityJinanChina
| | - Fei Xue
- Department of CardiologyThe Key Laboratory of Cardiovascular Remodeling and Function ResearchChinese Ministry of EducationChinese National Health Commission and Chinese Academy of Medical SciencesThe State and Shandong Province Joint Key Laboratory of Translational Cardiovascular MedicineQilu HospitalCheeloo College of MedicineShandong UniversityJinanChina
| | - Wenhai Sui
- Department of CardiologyThe Key Laboratory of Cardiovascular Remodeling and Function ResearchChinese Ministry of EducationChinese National Health Commission and Chinese Academy of Medical SciencesThe State and Shandong Province Joint Key Laboratory of Translational Cardiovascular MedicineQilu HospitalCheeloo College of MedicineShandong UniversityJinanChina
| | - Linlin Meng
- Department of CardiologyThe Key Laboratory of Cardiovascular Remodeling and Function ResearchChinese Ministry of EducationChinese National Health Commission and Chinese Academy of Medical SciencesThe State and Shandong Province Joint Key Laboratory of Translational Cardiovascular MedicineQilu HospitalCheeloo College of MedicineShandong UniversityJinanChina
| | - Lin Xie
- Department of CardiologyThe Key Laboratory of Cardiovascular Remodeling and Function ResearchChinese Ministry of EducationChinese National Health Commission and Chinese Academy of Medical SciencesThe State and Shandong Province Joint Key Laboratory of Translational Cardiovascular MedicineQilu HospitalCheeloo College of MedicineShandong UniversityJinanChina
| | - Cheng Zhang
- Department of CardiologyThe Key Laboratory of Cardiovascular Remodeling and Function ResearchChinese Ministry of EducationChinese National Health Commission and Chinese Academy of Medical SciencesThe State and Shandong Province Joint Key Laboratory of Translational Cardiovascular MedicineQilu HospitalCheeloo College of MedicineShandong UniversityJinanChina
| | - Jianmin Yang
- Department of CardiologyThe Key Laboratory of Cardiovascular Remodeling and Function ResearchChinese Ministry of EducationChinese National Health Commission and Chinese Academy of Medical SciencesThe State and Shandong Province Joint Key Laboratory of Translational Cardiovascular MedicineQilu HospitalCheeloo College of MedicineShandong UniversityJinanChina
| | - Yun Zhang
- Department of CardiologyThe Key Laboratory of Cardiovascular Remodeling and Function ResearchChinese Ministry of EducationChinese National Health Commission and Chinese Academy of Medical SciencesThe State and Shandong Province Joint Key Laboratory of Translational Cardiovascular MedicineQilu HospitalCheeloo College of MedicineShandong UniversityJinanChina
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Influence of Single Nucleotide Polymorphism of ENPP1 and ADIPOQ on Insulin Resistance and Obesity: A Case-Control Study in a Javanese Population. Life (Basel) 2021; 11:life11060552. [PMID: 34208364 PMCID: PMC8231196 DOI: 10.3390/life11060552] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2021] [Revised: 06/07/2021] [Accepted: 06/09/2021] [Indexed: 11/17/2022] Open
Abstract
Single nucleotide polymorphisms (SNPs) in obesity-related genes, such as ectonucleotide pyrophosphatase phosphodiesterase 1 (ENPP1) and adiponectin (ADIPOQ), potentially increase the risk of insulin resistance, the most common metabolic dysregulation related to obesity. We investigated the association of ENPP1 SNP K121Q (rs1044498) with insulin resistance and ADIPOQ SNP + 267G > T (rs1501299) with circulating adiponectin levels in a case–control study involving 55 obese and 55 lean Javanese people residing in Yogyakarta, Indonesia. Allele frequency was determined by a chi squared test or Fisher’s exact test with an expected value less than 0.05. Odds ratios and 95% confidence intervals were estimated by regression logistic analysis. The presence of the Q121 allele of ENPP1 resulted in significantly higher fasting glucose, fasting insulin levels, and HOMA-IR, as compared to homozygous K121 carriers. The risk of insulin resistance was elevated in obese individuals carrying Q121 instead of homozygous K121. Adiponectin level was significantly lower in the obese group as compared to the lean group. Obese individuals carrying homozygous protective alleles (TT) of ADIPOQ tended to have lower adiponectin levels as compared to GT and GG carriers, however, we did not find statistically significant effects of the +276G > T SNP of the ADIPOQ gene on the plasma adiponectin levels or on the development of obesity.
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de Luis Roman DA, Primo D, IZaola O, Gómez E, López JJ. Adiponectin Gene Variant rs3774261, Effects on Lipid Profile and Adiponectin Levels after a High Polyunsaturated Fat Hypocaloric Diet with Mediterranean Pattern. Nutrients 2021; 13:nu13061811. [PMID: 34073587 PMCID: PMC8229318 DOI: 10.3390/nu13061811] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/08/2021] [Revised: 05/21/2021] [Accepted: 05/24/2021] [Indexed: 11/16/2022] Open
Abstract
The role of ADIPOQ gene variants on metabolic improvements after weight change secondary to different hypocaloric diets remained unclear. We evaluate the effect of rs3774261 of ADIPOQ gene polymorphism on biochemical improvements and weight change after high polyunsaturated fat hypocaloric diet with a Mediterranean dietary pattern for 12 weeks. A population of 361 obese subjects was enrolled in an intervention trial with a calorie restriction of 500 calories over the usual intake and 45.7% of carbohydrates, 34.4% of fats, and 19.9% of proteins. The percentages of different fats was; 21.8% of monounsaturated fats, 55.5% of saturated fats, and 22.7% of polyunsaturated fats. Before and after intervention, an anthropometric study, an evaluation of nutritional intake and a biochemical evaluation were realized. All patients lost weight regardless of genotype and diet used. After 12 weeks with a similar improvement in weight loss (AA vs. AG vs. GG); total cholesterol (delta: −28.1 ± 2.1 mg/dL vs. −14.2 ± 4.1 mg/dL vs. −11.0 ± 3.9 mg/dL; p = 0.02), LDL cholesterol (delta: −17.1 ± 2.1 mg/dL vs. −6.1 ± 1.9 mg/dL vs. −6.0 ± 2.3 mg/dL; p = 0.01), triglyceride levels (delta: −35.0 ± 3.6 mg/dL vs. 10.1 ± 3.2 mg/dL vs. −9.7 ± 3.1 mg/dL; p = 0.02), C reactive protein (CRP) (delta: −2.3 ± 0.1 mg/dL vs. −0.2 ± 0.1 mg/dL vs. −0.2 ± 0.1 mg/dL; p = 0.02), serum adiponectin (delta: 11.6 ± 2.9 ng/dL vs. 2.1 ± 1.3 ng/dL vs. 3.3 ± 1.1 ng/dL; p = 0.02) and adiponectin/leptin ratio (delta: 1.5 ± 0.1 ng/dL vs. 0.3 ± 0.2 ng/dL vs. 0.4 ± 0.3 ng/dL; p = 0.03), improved only in AA group. AA genotype of ADIPOQ variant (rs3774261) is related with a significant increase in serum levels of adiponectin and ratio adiponectin/leptin and decrease on lipid profile and C-reactive protein (CRP).
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Madel MB, Fu H, Pierroz DD, Schiffrin M, Winkler C, Wilson A, Pochon C, Toffoli B, Taïeb M, Jouzeau JY, Gilardi F, Ferrari S, Bonnet N, Blin-Wakkach C, Desvergne B, Moulin D. Lack of Adiponectin Drives Hyperosteoclastogenesis in Lipoatrophic Mice. Front Cell Dev Biol 2021; 9:627153. [PMID: 33869176 PMCID: PMC8047205 DOI: 10.3389/fcell.2021.627153] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2020] [Accepted: 02/22/2021] [Indexed: 11/13/2022] Open
Abstract
Long bones from mammals host blood cell formation and contain multiple cell types, including adipocytes. Physiological functions of bone marrow adipocytes are poorly documented. Herein, we used adipocyte-deficient PPARγ-whole body null mice to investigate the consequence of total adipocyte deficiency on bone homeostasis in mice. We first highlighted the dual bone phenotype of PPARγ null mice: one the one hand, the increased bone formation and subsequent trabecularization extending in the long bone diaphysis, due to the well-known impact of PPARγ deficiency on osteoblasts formation and activity; on the other hand, an increased osteoclastogenesis in the cortical bone. We then further explored the cause of this unexpected increased osteoclastogenesis using two independent models of lipoatrophy, which recapitulated this phenotype. This demonstrates that hyperosteoclastogenesis is not intrinsically linked to PPARγ deficiency, but is a consequence of the total lipodystrophy. We further showed that adiponectin, a cytokine produced by adipocytes and mesenchymal stromal cells is a potent inhibitor of osteoclastogenesis in vitro and in vivo. Moreover, pharmacological activation of adiponectin receptors by the synthetic agonist AdipoRon inhibited mature osteoclast activity both in mouse and human cells by blocking podosome formation through AMPK activation. Finally, we demonstrated that AdipoRon treatment blocks bone erosion in vivo in a murine model of inflammatory bone loss, providing potential new approaches to treat osteoporosis.
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Affiliation(s)
- Maria-Bernadette Madel
- Université Côte d'Azur, CNRS, UMR 7370, Laboratoire de PhysioMédecine Moléculaire, Nice, France
| | - He Fu
- Center for Integrative Genomics, Genopode, Lausanne Faculty of Biology and Medicine, Lausanne, Switzerland
| | | | - Mariano Schiffrin
- Center for Integrative Genomics, Genopode, Lausanne Faculty of Biology and Medicine, Lausanne, Switzerland
| | - Carine Winkler
- Center for Integrative Genomics, Genopode, Lausanne Faculty of Biology and Medicine, Lausanne, Switzerland
| | - Anne Wilson
- Department of Oncology, University of Lausanne, Epalinges, Switzerland
| | | | - Barbara Toffoli
- Center for Integrative Genomics, Genopode, Lausanne Faculty of Biology and Medicine, Lausanne, Switzerland
| | - Mahdia Taïeb
- Université Côte d'Azur, CNRS, UMR 7370, Laboratoire de PhysioMédecine Moléculaire, Nice, France
| | | | - Federica Gilardi
- Center for Integrative Genomics, Genopode, Lausanne Faculty of Biology and Medicine, Lausanne, Switzerland
| | - Serge Ferrari
- Division of Bone Diseases, Department of Internal Medicine Specialties, Geneva University Hospital, Faculty of Medicine, Geneva, Switzerland
| | | | - Claudine Blin-Wakkach
- Université Côte d'Azur, CNRS, UMR 7370, Laboratoire de PhysioMédecine Moléculaire, Nice, France
| | - Béatrice Desvergne
- Center for Integrative Genomics, Genopode, Lausanne Faculty of Biology and Medicine, Lausanne, Switzerland
| | - David Moulin
- Université de Lorraine, CNRS, IMoPA, Nancy, France
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Wang XQ, Tang YH, Zeng GR, Wu LF, Zhou YJ, Cheng ZN, Jiang DJ. Carnosic acid alleviates depression-like behaviors on chronic mild stressed mice via PPAR-γ-dependent regulation of ADPN/FGF9 pathway. Psychopharmacology (Berl) 2021; 238:501-516. [PMID: 33161473 DOI: 10.1007/s00213-020-05699-2] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/23/2020] [Accepted: 10/30/2020] [Indexed: 01/12/2023]
Abstract
RATIONALE The pathway of adiponectin (ADPN)/fibroblast growth factor 9 (FGF9) was recently thought as a key role in the development of depression. ADPN is crucially regulated by peroxisome proliferator-activated receptor-gamma (PPAR-γ). Natural material carnosic acid (CA) has been applied for therapeutics of mental disorders. OBJECTIVES To evaluate the antidepressive effect of CA in stress-treated mice and define whether its effects is involved in the regulation of ADPN/FGF9 pathway. METHODS In vivo study, the levels of ADPN and FGF9 in both serum and hippocampus tissues, the expressions of ADPN receptor 2 (AdipoR2) in hippocampus and PPAR-γ in abdominal adipose, as well as the pathological changes of hippocampus were determined in 28-day period of chronic unpredictable mild stress (CUMS)-induced depression model of male ICR (Institute of Cancer Research) mice or adipo-/- mice. In vitro study, the level of ADPN and the mRNA expressions of both ADPN and PPAR-γ were determined in mouse 3T3-L1 preadipocytes. RESULTS In vivo study, treatment with CA (50 or 100 mg/kg per day) for 21 days markedly suppressed depressive-like behaviors, the elevating levels of FGF9 and decreasing levels of ADPN in both serum and hippocampus tissues, the downregulating protein and mRNA expressions of AdipoR2 in hippocampus and PPAR-γ in abdominal adipose, as well as the pathological injury of hippocampus induced by CUMS in male ICR mice. The antidepressive effects of CA were markedly attenuated in male CUMS-treated adipo-/- mice. In vitro study, incubation with CA (3-30 μmol/L) for 24 h could concentration-dependently upregulate the mRNA expressions of both PPAR-γ and ADPN as well as increase the level of ADPN. The experiments using PPAR-γ-specific inhibitor GW9662 and transient transfection with mutated PPAR-γ-binding site promotor constructs showed that the activation of PPAR-γ mediated CA-induced ADPN expression in adipocytes. CONCLUSIONS CA could significantly improve stress-induced depressive disorder, which may be related to regulating the dysfunction of ADPN-FGF9 pathway via activating PPAR-γ in adipocytes.
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Affiliation(s)
- Xiao-Qing Wang
- XiangYa Pharmacy School, Central South University, Changsha, 410083, China.,Hunan Center for Safety Evaluation and Research of Drugs & Hunan Key Laboratory for Pharmacodynamics and Safety Evaluation of New Drugs, Changsha, 410013, China
| | - Ya-Hui Tang
- Hunan Center for Safety Evaluation and Research of Drugs & Hunan Key Laboratory for Pharmacodynamics and Safety Evaluation of New Drugs, Changsha, 410013, China
| | - Gui-Rong Zeng
- Hunan Center for Safety Evaluation and Research of Drugs & Hunan Key Laboratory for Pharmacodynamics and Safety Evaluation of New Drugs, Changsha, 410013, China
| | - Li-Feng Wu
- Hunan Center for Safety Evaluation and Research of Drugs & Hunan Key Laboratory for Pharmacodynamics and Safety Evaluation of New Drugs, Changsha, 410013, China
| | - Ying-Jun Zhou
- XiangYa Pharmacy School, Central South University, Changsha, 410083, China
| | - Ze-Neng Cheng
- XiangYa Pharmacy School, Central South University, Changsha, 410083, China.
| | - De-Jian Jiang
- Hunan Center for Safety Evaluation and Research of Drugs & Hunan Key Laboratory for Pharmacodynamics and Safety Evaluation of New Drugs, Changsha, 410013, China.
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Kupsco A, Wu H, Calafat AM, Kioumourtzoglou MA, Tamayo-Ortiz M, Pantic I, Cantoral A, Tolentino M, Oken E, Braun JM, Deierlein AL, Wright RO, Téllez-Rojo MM, Baccarelli AA, Just AC. Prenatal maternal phthalate exposures and child lipid and adipokine levels at age six: A study from the PROGRESS cohort of Mexico City. ENVIRONMENTAL RESEARCH 2021; 192:110341. [PMID: 33068586 PMCID: PMC7736226 DOI: 10.1016/j.envres.2020.110341] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/09/2020] [Revised: 09/30/2020] [Accepted: 10/11/2020] [Indexed: 05/13/2023]
Abstract
BACKGROUND Prenatal phthalate exposures may affect processes that underlie offspring cardiometabolic health, but findings from studies examining these associations are conflicting. We examined associations between biomarkers of phthalate exposures during pregnancy with child lipid and adipokine levels. METHODS Data were from 463 mother-child pairs in the PROGRESS cohort of Mexico City. We quantified 15 phthalate metabolites in 2nd and 3rd trimester maternal urine samples and created an average pregnancy measure using the geometric mean. We evaluated the 15 metabolites as nine biomarkers, including four metabolite molar sums. We measured fasting serum triglycerides, non-HDL cholesterol, leptin, and adiponectin in children at the six-year follow-up visit (mean = 6.8 years). We estimated associations using linear regression, Bayesian kernel machine regression (BKMR), and weighted quantile sum (WQS) and assessed effect modification by sex. RESULTS In BKMR and WQS models, higher concentrations of the total mixture of phthalate biomarkers were associated with lower triglycerides (β = -3.7% [-6.5, -0.78] per 1 unit increase in WQS biomarker index) and non-HDL cholesterol (β = -2.0 [-3.7, -0.25] ng/ml per increase in WQS biomarker index). Associations between individual biomarkers and child outcomes were largely null. We observed some evidence of effect modification by child sex for mono-3-carboxypropyl phthalate (β = 19.4% [1.26, 40.7] per doubling of phthalate) and monobenzyl phthalate (β = -7.6% [-14.4, -0.23]) in girls for adiponectin. CONCLUSIONS Individual prenatal phthalate biomarkers were not associated with child lipid or adipokine levels. Contrary to our hypothesis, the total phthalate mixture was associated with lower child triglycerides and non-HDL cholesterol.
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Affiliation(s)
- Allison Kupsco
- Department of Environmental Health Sciences, Mailman School of Public Health, Columbia University Medical Center, New York, NY, USA.
| | - Haotian Wu
- Department of Environmental Health Sciences, Mailman School of Public Health, Columbia University Medical Center, New York, NY, USA
| | - Antonia M Calafat
- National Center for Environmental Health, Centers for Disease Control and Prevention, Atlanta, GA, USA
| | - Marianthi-Anna Kioumourtzoglou
- Department of Environmental Health Sciences, Mailman School of Public Health, Columbia University Medical Center, New York, NY, USA
| | - Marcela Tamayo-Ortiz
- Center for Research on Nutrition and Health, National Institute of Public Health, Cuernavaca, Morelos, Mexico; National Council of Science and Technology, Mexico
| | - Ivan Pantic
- National Institute of Perinatology, Mexico City, Mexico
| | - Alejandra Cantoral
- Center for Research on Nutrition and Health, National Institute of Public Health, Cuernavaca, Morelos, Mexico
| | | | - Emily Oken
- Division of Chronic Disease Research Across the Lifecourse, Department of Population Medicine, Harvard Medical School and Harvard Pilgrim Health Care Institute, Boston, MA, USA
| | - Joseph M Braun
- Department of Epidemiology, Brown University, Providence, RI, USA
| | - Andrea L Deierlein
- Department of Epidemiology, School of Global Public Health, New York University, New York, NY, USA
| | - Robert O Wright
- Department of Environmental Medicine and Public Health, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Martha M Téllez-Rojo
- Center for Research on Nutrition and Health, National Institute of Public Health, Cuernavaca, Morelos, Mexico
| | - Andrea A Baccarelli
- Department of Environmental Health Sciences, Mailman School of Public Health, Columbia University Medical Center, New York, NY, USA
| | - Allan C Just
- Department of Environmental Medicine and Public Health, Icahn School of Medicine at Mount Sinai, New York, NY, USA
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Monounsaturated Fatty Acids in Obesity-Related Inflammation. Int J Mol Sci 2020; 22:ijms22010330. [PMID: 33396940 PMCID: PMC7795523 DOI: 10.3390/ijms22010330] [Citation(s) in RCA: 120] [Impact Index Per Article: 24.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/03/2020] [Revised: 12/23/2020] [Accepted: 12/25/2020] [Indexed: 12/14/2022] Open
Abstract
Obesity is an important aspect of the metabolic syndrome and is often associated with chronic inflammation. In this context, inflammation of organs participating in energy homeostasis (such as liver, adipose tissue, muscle and pancreas) leads to the recruitment and activation of macrophages, which secrete pro-inflammatory cytokines. Interleukin-1β secretion, sustained C-reactive protein plasma levels and activation of the NLRP3 inflammasome characterize this inflammation. The Stearoyl-CoA desaturase-1 (SCD1) enzyme is a central regulator of lipid metabolism and fat storage. This enzyme catalyzes the generation of monounsaturated fatty acids (MUFAs)-major components of triglycerides stored in lipid droplets-from saturated fatty acid (SFA) substrates. In this review, we describe the molecular effects of specific classes of fatty acids (saturated and unsaturated) to better understand the impact of different diets (Western versus Mediterranean) on inflammation in a metabolic context. Given the beneficial effects of a MUFA-rich Mediterranean diet, we also present the most recent data on the role of SCD1 activity in the modulation of SFA-induced chronic inflammation.
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Genistein Modulated Lipid Metabolism, Hepatic PPARγ, and Adiponectin Expression in Bilateral Ovariectomized Rats with Nonalcoholic Steatohepatitis (NASH). Antioxidants (Basel) 2020; 10:antiox10010024. [PMID: 33383845 PMCID: PMC7824652 DOI: 10.3390/antiox10010024] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2020] [Revised: 12/17/2020] [Accepted: 12/22/2020] [Indexed: 12/15/2022] Open
Abstract
The aim of this study was to evaluate the protective effects of genistein on lipid accumulation and apoptosis in estrogen deficient rats with NASH. Female Sprague-Dawley rats (n = 48) were divided into ovariectomized (OVX) and non-OVX groups. Each group was then sub-divided into 3 subgroups; control, NASH (rats fed with a high-fat, high-fructose (HFHF) diet), and NASH+Gen (rats fed with HFHF diet plus daily genistein at 16 mg/kg BW). Results showed that HFHF diet induced liver fat accumulation in both non-OVX and OVX rats, which was evidenced by hepatic steatosis on liver pathology and increased hepatic free fatty acid (FFA) and triglyceride levels. Hepatic fat accumulation was significantly more severe in NASH rats with OVX than non-OVX. Hepatocyte apoptosis was more severe in NASH groups compared with that in control groups. Genistein administration significantly improved histopathology of NASH in both non-OVX and OVX rats and attenuated hepatic lipid accumulation, oxidative stress, and hepatocyte apoptosis. Genistein also down-regulated PPARγ and up-regulated adiponectin expression. In summary, NASH could be worsened by estrogen deficiency, indicating the protective action of estrogen on NASH. Genistein administration alleviated hepatic steatosis and apoptosis through the down-regulation of PPARγ and up-regulation of adiponectin expression.
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