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Hoque K, Ali Z, Maliha A, Al-Ghouti MA, Cugno C, Rahman SM, Rahman MM. Enhancing Bone Health with Conjugated Linoleic Acid: Mechanisms, Challenges, and Innovative Strategies. Nutrients 2025; 17:1395. [PMID: 40284258 PMCID: PMC12030704 DOI: 10.3390/nu17081395] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2025] [Revised: 04/18/2025] [Accepted: 04/19/2025] [Indexed: 04/29/2025] Open
Abstract
Conjugated linoleic acid (CLA) is a bioactive compound known for its anti-inflammatory, anti-carcinogenic, and metabolic effects, with growing interest in its role in supporting bone health. Preclinical studies, particularly those involving the t10c12 isomer, have shown that CLA can enhance bone mineral density (BMD) by enhancing bone formation and reducing bone resorption, indicating its potential as a therapeutic agent to improve bone health. However, clinical trials have yielded inconsistent results, underscoring the difficulty in translating animal model successes to human applications. A major challenge is CLA's low water solubility, poor absorption, and limited bioavailability, which restrict its therapeutic effectiveness. To address these issues, nanoparticle-based delivery systems have been proposed to improve its solubility, stability, and resistance to oxidative damage, thereby enhancing its bioactivity. Recent studies also suggest that electrical stimulation can stimulate bone regeneration by promoting bone cell proliferation, differentiation, and adherence to scaffolds. This review explores the combined use of CLA supplementation and electrical stimulation as a novel approach to improving bone health, particularly in osteoporosis management. By integrating CLA's biological effects with the regenerative potential of electrical stimulation, this multimodal strategy offers a promising method for enhancing bone restoration, with significant implications for clinical applications in bone health.
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Affiliation(s)
- Khandoker Hoque
- Department of Electrical and Electronics Engineering, San Francisco Bay University, Fremont, CA 94539, USA;
| | - Zayana Ali
- Biological Program, Department of Biological and Environmental Sciences, College of Arts and Sciences, Qatar University, Doha P.O. Box 2713, Qatar;
| | - Asma Maliha
- Biomedical Sciences Department, College of Health Sciences, Qatar University, Doha P.O. Box 2713, Qatar;
| | - Mohammad A. Al-Ghouti
- Environmental Program, Department of Biological and Environmental Sciences, College of Arts and Sciences, Qatar University, Doha P.O. Box 2713, Qatar;
| | - Chiara Cugno
- Advanced Cell Therapy Core, Research Department, Sidra Medicine, Doha P.O. Box 26999, Qatar;
| | | | - Md Mizanur Rahman
- Biological Program, Department of Biological and Environmental Sciences, College of Arts and Sciences, Qatar University, Doha P.O. Box 2713, Qatar;
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Oczkowicz J, Piasna-Słupecka E, Drozdowska M, Koronowicz A, Kopeć A. The Combination of Resveratrol and Conjugated Linoleic Acid Dienes Enhances the Individual Effects of These Molecules on De Novo Fatty Acid Biosynthesis in 3T3-L1 Adipocytes. Int J Mol Sci 2024; 25:13429. [PMID: 39769194 PMCID: PMC11677705 DOI: 10.3390/ijms252413429] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2024] [Revised: 12/01/2024] [Accepted: 12/10/2024] [Indexed: 01/11/2025] Open
Abstract
Consuming food containing ingredients with a documented impact on lipid metabolism can help fight overweight and obesity. The simplest way to reduce the level of fatty acids is to block their synthesis or increase the rate of their degradation. This study aimed to determine the effect of resveratrol, cis-9, trans-11 conjugated linoleic acid (CLA), trans-10, cis-12 CLA, and various variants of their combinations on de novo fatty acid biosynthesis in 3T3-L1 adipocytes. The influence of the above-mentioned bioactive substances on cells grown under standard conditions and after induction of oxidative stress was measured. The effect of the tested compounds on the expression of selected genes related to the de novo fatty acid biosynthesis process (Fasn, Acc1, Acly, Prkaa1, Prkaa2, Prkaca, Srebp1) was evaluated. As part of the conducted experiments, how the level of the corresponding mRNA translates into the content of selected proteins (acetyl-CoA carboxylase 1 (ACC) and fatty acid synthase (FASN) was studied. It was found that the inhibition of fatty acid biosynthesis processes was stronger in the case of the combination of the tested CLA isomers (cis-9, trans-11 CLA, trans-10, cis-12 CLA) with resveratrol than in cases of their individual action.
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Affiliation(s)
| | | | | | | | - Aneta Kopeć
- Department of Human Nutrition and Dietetics, University of Agriculture, Balicka 122, 30-149 Kraków, Poland
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3
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Terzo M, Iantomasi M, Tsiani E. Effects of Resveratrol on Adipocytes: Evidence from In Vitro and In Vivo Studies. Molecules 2024; 29:5359. [PMID: 39598748 PMCID: PMC11596734 DOI: 10.3390/molecules29225359] [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: 09/15/2024] [Revised: 11/07/2024] [Accepted: 11/12/2024] [Indexed: 11/29/2024] Open
Abstract
Obesity, a prevalent global health issue, arises from an imbalance between caloric intake and energy expenditure, leading to the expansion of adipose tissue and metabolic dysfunction. White adipose tissue (WAT) stores energy as lipids, while brown adipose tissue (BAT) plays a pivotal role in energy dissipation through adaptive thermogenesis. Recent research initiatives have focused on finding strategies to decrease adipogenesis and fat mass accumulation and increase thermogenesis. Finding chemicals with anti-obesity properties would be beneficial. Resveratrol, a polyphenolic compound abundantly found in the skin of grapes and red wine, possesses anti-oxidant, anti-inflammatory, anti-cancer, and anti-obesity properties. This literature review examines the effects of resveratrol on adipocytes in culture and adipose tissue in animal models of obesity. The existing evidence indicates that resveratrol may exert its anti-obesity effects by inhibiting adipogenesis, promoting the apoptosis of mature adipocytes, reducing lipid accumulation, and increasing thermogenesis. Further research utilizing animal and clinical studies is required to understand in detail the anti-obesity potential of resveratrol.
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Affiliation(s)
- Matthew Terzo
- Department of Health Sciences, Brock University, St. Catharines, ON L2S 3A1, Canada
| | - Michael Iantomasi
- Department of Health Sciences, Brock University, St. Catharines, ON L2S 3A1, Canada
| | - Evangelia Tsiani
- Department of Health Sciences, Brock University, St. Catharines, ON L2S 3A1, Canada
- Centre for Bone and Muscle Health, Brock University, St. Catharines, ON L2S 3A1, Canada
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Omachi DO, Aryee ANA, Onuh JO. Functional Lipids and Cardiovascular Disease Reduction: A Concise Review. Nutrients 2024; 16:2453. [PMID: 39125334 PMCID: PMC11314407 DOI: 10.3390/nu16152453] [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: 06/12/2024] [Revised: 07/25/2024] [Accepted: 07/26/2024] [Indexed: 08/12/2024] Open
Abstract
Functional lipids are dietary substances that may have an impact on human health by lowering the risk of chronic illnesses and enhancing the quality of life. Numerous functional lipids have been reported to have potential health benefits in the prevention, management, and treatment of cardiovascular disease, the leading cause of death in the United States. However, there is still insufficient and contradictory information in the literature about their effectiveness and associated mechanisms of action. The objective of this review, therefore, is to evaluate available literature regarding these functional lipids and their health benefits. Various studies have been conducted to understand the links between functional lipids and the prevention and treatment of chronic diseases. Recent studies on phytosterols have reported that CLA, medium-chain triglycerides, and omega-3 and 6 fatty acids have positive effects on human health. Also, eicosanoids, which are the metabolites of these fatty acids, are produced in relation to the ratio of omega-3 to omega-6 polyunsaturated fatty acids and may modulate disease conditions. These functional lipids are available either in dietary or supplement forms and have been proven to be efficient, accessible, and inexpensive to be included in the diet. However, further research is required to properly elucidate the dosages, dietary intake, effectiveness, and their mechanisms of action in addition to the development of valid disease biomarkers and long-term effects in humans.
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Affiliation(s)
- Deborah O. Omachi
- Department of Food and Nutritional Sciences, Tuskegee University, 1200 W. Montgomery Rd, Tuskegee, AL 36088, USA;
| | - Alberta N. A. Aryee
- Food Science and Biotechnology Program, Department of Human Ecology, Delaware State University, 1200 Dupont Highway, Dover, DE 19901, USA;
| | - John O. Onuh
- Department of Food and Nutritional Sciences, Tuskegee University, 1200 W. Montgomery Rd, Tuskegee, AL 36088, USA;
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Ahmad K, Shaikh S, Lim JH, Ahmad SS, Chun HJ, Lee EJ, Choi I. Therapeutic application of natural compounds for skeletal muscle-associated metabolic disorders: A review on diabetes perspective. Biomed Pharmacother 2023; 168:115642. [PMID: 37812896 DOI: 10.1016/j.biopha.2023.115642] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2023] [Revised: 09/19/2023] [Accepted: 10/03/2023] [Indexed: 10/11/2023] Open
Abstract
Skeletal muscle (SM) plays a vital role in energy and glucose metabolism by regulating insulin sensitivity, glucose uptake, and blood glucose homeostasis. Impaired SM metabolism is strongly linked to several diseases, particularly type 2 diabetes (T2D). Insulin resistance in SM may result from the impaired activities of insulin receptor tyrosine kinase, insulin receptor substrate 1, phosphoinositide 3-kinase, and AKT pathways. This review briefly discusses SM myogenesis and the critical roles that SM plays in insulin resistance and T2D. The pharmacological targets of T2D which are associated with SM metabolism, such as DPP4, PTB1B, SGLT, PPARγ, and GLP-1R, and their potential modulators/inhibitors, especially natural compounds, are discussed in detail. This review highlights the significance of SM in metabolic disorders and the therapeutic potential of natural compounds in targeting SM-associated T2D targets. It may provide novel insights for the future development of anti-diabetic drug therapies. We believe that scientists working on T2D therapies will benefit from this review by enhancing their knowledge and updating their understanding of the subject.
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Affiliation(s)
- Khurshid Ahmad
- Department of Medical Biotechnology, Yeungnam University, Gyeongsan 38541, South Korea; Research Institute of Cell Culture, Yeungnam University, Gyeongsan 38541, South Korea
| | - Sibhghatulla Shaikh
- Department of Medical Biotechnology, Yeungnam University, Gyeongsan 38541, South Korea; Research Institute of Cell Culture, Yeungnam University, Gyeongsan 38541, South Korea
| | - Jeong Ho Lim
- Department of Medical Biotechnology, Yeungnam University, Gyeongsan 38541, South Korea; Research Institute of Cell Culture, Yeungnam University, Gyeongsan 38541, South Korea
| | - Syed Sayeed Ahmad
- Department of Medical Biotechnology, Yeungnam University, Gyeongsan 38541, South Korea; Research Institute of Cell Culture, Yeungnam University, Gyeongsan 38541, South Korea
| | - Hee Jin Chun
- Department of Medical Biotechnology, Yeungnam University, Gyeongsan 38541, South Korea
| | - Eun Ju Lee
- Department of Medical Biotechnology, Yeungnam University, Gyeongsan 38541, South Korea; Research Institute of Cell Culture, Yeungnam University, Gyeongsan 38541, South Korea
| | - Inho Choi
- Department of Medical Biotechnology, Yeungnam University, Gyeongsan 38541, South Korea; Research Institute of Cell Culture, Yeungnam University, Gyeongsan 38541, South Korea.
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Badawy S, Liu Y, Guo M, Liu Z, Xie C, Marawan MA, Ares I, Lopez-Torres B, Martínez M, Maximiliano JE, Martínez-Larrañaga MR, Wang X, Anadón A, Martínez MA. Conjugated linoleic acid (CLA) as a functional food: Is it beneficial or not? Food Res Int 2023; 172:113158. [PMID: 37689911 DOI: 10.1016/j.foodres.2023.113158] [Citation(s) in RCA: 37] [Impact Index Per Article: 18.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2022] [Revised: 06/15/2023] [Accepted: 06/16/2023] [Indexed: 09/11/2023]
Abstract
Conjugated linoleic acid (CLA) has attracted great attention in recent years as a popular class of functional food that is broadly used. It refers to a group of geometric and positional isomers of linoleic acid (LA) with a conjugated double bond. The main natural sources of CLA are dairy products, beef and lamb, whereas only trace amounts occur naturally in plant lipids. CLA has been shown to improve various health issues, having effects on obesity, inflammatory, anti-carcinogenicity, atherogenicity, immunomodulation, and osteosynthesis. Also, compared to studies on humans, many animal researches reveal more positive benefits on health. CLA represents a nutritional avenue to improve lifestyle diseases and metabolic syndrome. Most of these effects are attributed to the two major CLA isomers [conjugated linoleic acid cis-9,trans-11 isomer (c9,t11), and conjugated linoleic acid trans-10,cis-12 isomer (t10,c12)], and their mixture (CLA mix). In contrast, adverse effects of CLA have been also reported, such as glucose homeostasis, insulin resistance, hepatic steatosis and induction of colon carcinogenesis in humans, as well as milk fat inhibition in ruminants, lowering chicken productivity, influencing egg quality and altering growth performance in fish. This review article aims to discuss the health benefits of CLA as a nutraceutical supplement and highlight the possible mechanisms of action that may contribute to its outcome. It also outlines the feasible adverse effects of CLA besides summarizing the recent peer-reviewed publications on CLA to ensure its efficacy and safety for proper application in humans.
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Affiliation(s)
- Sara Badawy
- National Reference Laboratory of Veterinary Drug Residues (HZAU) and MAO Key Laboratory for Detection of Veterinary Drug Residues, Huazhong Agricultural University, Wuhan, Hubei 430070, China; Pathology Department of Animal Medicine, Faculty of Veterinary Medicine, Benha University, Egypt
| | - Yanan Liu
- MAO Laboratory for Risk Assessment of Quality and Safety of Livestock and Poultry Products, Huazhong Agricultural University, Wuhan, Hubei 430070, China
| | - Mingyue Guo
- MAO Laboratory for Risk Assessment of Quality and Safety of Livestock and Poultry Products, Huazhong Agricultural University, Wuhan, Hubei 430070, China
| | - Zhenli Liu
- MAO Laboratory for Risk Assessment of Quality and Safety of Livestock and Poultry Products, Huazhong Agricultural University, Wuhan, Hubei 430070, China
| | - Changqing Xie
- MAO Laboratory for Risk Assessment of Quality and Safety of Livestock and Poultry Products, Huazhong Agricultural University, Wuhan, Hubei 430070, China
| | - Marawan A Marawan
- The State Key Laboratory of Agricultural Microbiology, Huazhong Agricultural University, Wuhan, Hubei 430070, China; Infectious Diseases, Animal Medicine Department, Faculty of Veterinary Medicine, Benha University, Egypt
| | - Irma Ares
- Department of Pharmacology and Toxicology, Faculty of Veterinary Medicine, Universidad Complutense de Madrid (UCM), and Research Institute Hospital 12 de Octubre (i+12), 28040 Madrid, Spain
| | - Bernardo Lopez-Torres
- Department of Pharmacology and Toxicology, Faculty of Veterinary Medicine, Universidad Complutense de Madrid (UCM), and Research Institute Hospital 12 de Octubre (i+12), 28040 Madrid, Spain
| | - Marta Martínez
- Department of Pharmacology and Toxicology, Faculty of Veterinary Medicine, Universidad Complutense de Madrid (UCM), and Research Institute Hospital 12 de Octubre (i+12), 28040 Madrid, Spain
| | - Jorge-Enrique Maximiliano
- Department of Pharmacology and Toxicology, Faculty of Veterinary Medicine, Universidad Complutense de Madrid (UCM), and Research Institute Hospital 12 de Octubre (i+12), 28040 Madrid, Spain
| | - María-Rosa Martínez-Larrañaga
- Department of Pharmacology and Toxicology, Faculty of Veterinary Medicine, Universidad Complutense de Madrid (UCM), and Research Institute Hospital 12 de Octubre (i+12), 28040 Madrid, Spain
| | - Xu Wang
- National Reference Laboratory of Veterinary Drug Residues (HZAU) and MAO Key Laboratory for Detection of Veterinary Drug Residues, Huazhong Agricultural University, Wuhan, Hubei 430070, China; MAO Laboratory for Risk Assessment of Quality and Safety of Livestock and Poultry Products, Huazhong Agricultural University, Wuhan, Hubei 430070, China.
| | - Arturo Anadón
- Department of Pharmacology and Toxicology, Faculty of Veterinary Medicine, Universidad Complutense de Madrid (UCM), and Research Institute Hospital 12 de Octubre (i+12), 28040 Madrid, Spain.
| | - María-Aránzazu Martínez
- Department of Pharmacology and Toxicology, Faculty of Veterinary Medicine, Universidad Complutense de Madrid (UCM), and Research Institute Hospital 12 de Octubre (i+12), 28040 Madrid, Spain
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Nie T, Cooper GJS. Mechanisms Underlying the Antidiabetic Activities of Polyphenolic Compounds: A Review. Front Pharmacol 2021; 12:798329. [PMID: 34970150 PMCID: PMC8712966 DOI: 10.3389/fphar.2021.798329] [Citation(s) in RCA: 24] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/20/2021] [Accepted: 11/18/2021] [Indexed: 12/16/2022] Open
Abstract
Polyphenolic compounds are thought to show considerable promise for the treatment of various metabolic disorders, including type 2 diabetes mellitus (T2DM). This review addresses evidence from in vitro, in vivo, and clinical studies for the antidiabetic effects of certain polyphenolic compounds. We focus on the role of cytotoxic human amylin (hA) aggregates in the pathogenesis of T2DM, and how polyphenols can ameliorate this process by suppressing or modifying their formation. Small, soluble amylin oligomers elicit cytotoxicity in pancreatic islet β-cells and may thus cause β-cell disruption in T2DM. Amylin oligomers may also contribute to oxidative stress and inflammation that lead to the triggering of β-cell apoptosis. Polyphenols may exert antidiabetic effects via their ability to inhibit hA aggregation, and to modulate oxidative stress, inflammation, and other pathways that are β-cell-protective or insulin-sensitizing. There is evidence that their ability to inhibit and destabilize self-assembly by hA requires aromatic molecular structures that bind to misfolding monomers or oligomers, coupled with adjacent hydroxyl groups present on single phenyl rings. Thus, these multifunctional compounds have the potential to be effective against the pleiotropic mechanisms of T2DM. However, substantial further research will be required before it can be determined whether a polyphenol-based molecular entity can be used as a therapeutic for type 2 diabetes.
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Affiliation(s)
- Tina Nie
- School of Biological Sciences, Faculty of Science, the University of Auckland, Auckland, New Zealand
| | - Garth J. S. Cooper
- School of Biological Sciences, Faculty of Science, the University of Auckland, Auckland, New Zealand
- The Maurice Wilkins Centre for Molecular Biodiscovery, Faculty of Science, the University of Auckland, Auckland, New Zealand
- Centre for Advanced Discovery and Experimental Therapeutics, Division of Cardiovascular Sciences, Faculty of Biology Medicine & Health, School of Medical Sciences, The University of Manchester, Manchester, United Kingdom
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Mohammadi I, Mahdavi AH, Rabiee F, Nasr Esfahani MH, Ghaedi K. Positive effects of conjugated linoleic acid (CLA) on the PGC1-α expression under the inflammatory conditions induced by TNF-α in the C2C12 cell line. Gene 2020; 735:144394. [DOI: 10.1016/j.gene.2020.144394] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2019] [Revised: 01/22/2020] [Accepted: 01/23/2020] [Indexed: 12/17/2022]
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9
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Lee D, Kim YR, Kim JS, Kim D, Kim S, Kim SY, Jang K, Lee JD, Yang CS. Dietary schizophyllan reduces mitochondrial damage by activating SIRT3 in mice. Arch Pharm Res 2020; 43:449-461. [PMID: 32236798 DOI: 10.1007/s12272-020-01231-4] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2019] [Accepted: 03/23/2020] [Indexed: 12/11/2022]
Abstract
Schizophyllan (SPG), produced by Schizophyllum commune, is an exopolysaccharide with multiple academic and commercial uses, including in the food industry and for various medical functions. We previously demonstrated that SPG conjugated with c-Src peptide exerted a significant therapeutic effect on mouse models of the acute inflammatory diseases polymicrobial sepsis and ulcerative colitis. Here we extended these results by investigating whether SPG exerted a protective effect against mitochondrial damage in the liver via sirtuin 3 (SIRT3) induction, focusing on the deacetylation of succinate dehydrogenase A (SDHA) and superoxide dismutase 2 (SOD2). Liver damage models induced by alcohol or conjugated linoleic acid (CLA, which simulates lipodystrophy) in SIRT3-/-, SOD2-/-, and SDHA-/- mice were used. Results showed that dietary supplementation with SPG induced SIRT3 activation; this was involved in mitochondrial metabolic resuscitation that countered the adverse effects of alcoholic liver disease and CLA-induced damage. The mitochondrial SIRT3 mediated the deacetylation and activation of SOD2 in the liver and SDHA in adipose tissues, suggesting that SPG supplementation reduced ethanol-induced liver damage and CLA-induced adverse dietary effects via SIRT3-SOD2 and SIRT3-SDHA signaling, respectively. Together, these results suggest that dietary SPG has a previously unrecognized role in SIRT3-mediated mitochondrial metabolic resuscitation during mitochondria-related diseases.
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Affiliation(s)
- Daeun Lee
- Department of Molecular and Life Science, Hanyang University, 55 Hanyangdaehak-ro, Sangnok-gu, Ansan-si, Gyeonggi-do, 15588, South Korea
| | - Ye-Ram Kim
- Department of Molecular and Life Science, Hanyang University, 55 Hanyangdaehak-ro, Sangnok-gu, Ansan-si, Gyeonggi-do, 15588, South Korea.,Department of Bionano Technology, Hanyang University, Seoul, 04673, South Korea
| | - Jae-Sung Kim
- Department of Molecular and Life Science, Hanyang University, 55 Hanyangdaehak-ro, Sangnok-gu, Ansan-si, Gyeonggi-do, 15588, South Korea.,Department of Bionano Technology, Hanyang University, Seoul, 04673, South Korea
| | - Donggyu Kim
- Department of Molecular and Life Science, Hanyang University, 55 Hanyangdaehak-ro, Sangnok-gu, Ansan-si, Gyeonggi-do, 15588, South Korea
| | - Sojin Kim
- Department of Molecular and Life Science, Hanyang University, 55 Hanyangdaehak-ro, Sangnok-gu, Ansan-si, Gyeonggi-do, 15588, South Korea
| | - Sun Young Kim
- Department of Molecular and Life Science, Hanyang University, 55 Hanyangdaehak-ro, Sangnok-gu, Ansan-si, Gyeonggi-do, 15588, South Korea.,Department of Bionano Technology, Hanyang University, Seoul, 04673, South Korea
| | - Kiseok Jang
- Department of Pathology, Hanyang University College of Medicine, Seoul, 04673, South Korea
| | | | - Chul-Su Yang
- Department of Molecular and Life Science, Hanyang University, 55 Hanyangdaehak-ro, Sangnok-gu, Ansan-si, Gyeonggi-do, 15588, South Korea. .,Department of Bionano Technology, Hanyang University, Seoul, 04673, South Korea.
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Qin N, Bayat AR, Trevisi E, Minuti A, Kairenius P, Viitala S, Mutikainen M, Leskinen H, Elo K, Kokkonen T, Vilkki J. Dietary supplement of conjugated linoleic acids or polyunsaturated fatty acids suppressed the mobilization of body fat reserves in dairy cows at early lactation through different pathways. J Dairy Sci 2018; 101:7954-7970. [PMID: 29960784 DOI: 10.3168/jds.2017-14298] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2017] [Accepted: 05/08/2018] [Indexed: 01/25/2023]
Abstract
To investigate the metabolic changes in the adipose tissue (AT) of dairy cows under milk fat depression (MFD), 30 cows were randomly allocated to a control diet, a conjugated linoleic acid (CLA)-supplemented diet, or a high-starch diet supplemented with a mixture of sunflower and fish oil (2:1; as HSO diet) from 1 to 112 d in milk. Performance of animals, milk yield, milk composition, energy balance, and blood metabolites were measured during lactation. Quantitative PCR analyses were conducted on the AT samples collected at wk 3 and 15 of lactation. The CLA and HSO diets considerably depressed milk fat yield and milk fat content at both wk 3 and 15 in the absence of significant changes in milk protein and lactose contents. In addition, the HSO diet lowered milk yield at wk 15 and decreased dry matter intake of cows from wk 3 to 15. Compared with the control, both CLA and HSO groups showed reduced body weight loss, improved energy balance, and decreased plasma concentrations of nonesterified fatty acids and β-hydroxybutyrate at early lactation. The gene expression analyses reflected suppressed lipolysis in AT of the CLA and HSO groups compared with the control at wk 3, as suggested by the downregulation of hormone-sensitive lipase and fatty acid binding protein 4 and the upregulation of perilipin 2. In addition, the HSO diet promoted lipogenesis in AT at wk 15 through the upregulation of 1-acylglycerol-3-phosphate O-acyltransferase 2, mitochondrial glycerol-3-phosphate acyltransferase, perilipin 2, and peroxisome proliferator-activated receptor γ. The CLA diet likely regulated insulin sensitivity in AT as it upregulated the transcription of various genes involved in insulin signaling, inflammatory responses, and ceramide metabolism, including protein kinase B2, nuclear factor κ B1, toll-like receptor 4, caveolin 1, serine palmitoyltransferase long chain base subunit 1, and N-acylsphingosine amidohydrolase 1. In contrast, the HSO diet resulted in little or no change in the pathways relevant to insulin sensitivity. In conclusion, the CLA and HSO diets induced a shift in energy partitioning toward AT instead of mammary gland during lactation through the regulation of different pathways.
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Affiliation(s)
- Nanbing Qin
- Department of Agricultural Sciences, PO Box 28, FI-00014 University of Helsinki, Finland
| | - Ali-Reza Bayat
- Production Systems, Natural Resources Institute Finland (Luke), 31600 Jokioinen, Finland
| | - Erminio Trevisi
- Department of Animal Sciences, Food and Nutrition, Faculty of Agriculture, Food and Environmental Science, Università Cattolica del Sacro Cuore, 20123 Milan, Italy
| | - Andrea Minuti
- Department of Animal Sciences, Food and Nutrition, Faculty of Agriculture, Food and Environmental Science, Università Cattolica del Sacro Cuore, 20123 Milan, Italy
| | - Piia Kairenius
- Production Systems, Natural Resources Institute Finland (Luke), 31600 Jokioinen, Finland
| | - Sirja Viitala
- Production Systems, Natural Resources Institute Finland (Luke), 31600 Jokioinen, Finland
| | - Mervi Mutikainen
- Production Systems, Natural Resources Institute Finland (Luke), 31600 Jokioinen, Finland
| | - Heidi Leskinen
- Production Systems, Natural Resources Institute Finland (Luke), 31600 Jokioinen, Finland
| | - Kari Elo
- Department of Agricultural Sciences, PO Box 28, FI-00014 University of Helsinki, Finland
| | - Tuomo Kokkonen
- Department of Agricultural Sciences, PO Box 28, FI-00014 University of Helsinki, Finland
| | - Johanna Vilkki
- Production Systems, Natural Resources Institute Finland (Luke), 31600 Jokioinen, Finland.
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Bernard L, Bonnet M, Delavaud C, Delosière M, Ferlay A, Fougère H, Graulet B. Milk Fat Globule in Ruminant: Major and Minor Compounds, Nutritional Regulation and Differences Among Species. EUR J LIPID SCI TECH 2018. [DOI: 10.1002/ejlt.201700039] [Citation(s) in RCA: 46] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Affiliation(s)
- Laurence Bernard
- Université Clermont Auvergne, INRA, VetAgro Sup, UMR Herbivores; F-63122 Saint-Genès-Champanelle France
| | - Muriel Bonnet
- Université Clermont Auvergne, INRA, VetAgro Sup, UMR Herbivores; F-63122 Saint-Genès-Champanelle France
| | - Carole Delavaud
- Université Clermont Auvergne, INRA, VetAgro Sup, UMR Herbivores; F-63122 Saint-Genès-Champanelle France
| | - Mylène Delosière
- Université Clermont Auvergne, INRA, VetAgro Sup, UMR Herbivores; F-63122 Saint-Genès-Champanelle France
| | - Anne Ferlay
- Université Clermont Auvergne, INRA, VetAgro Sup, UMR Herbivores; F-63122 Saint-Genès-Champanelle France
| | - Hélène Fougère
- Université Clermont Auvergne, INRA, VetAgro Sup, UMR Herbivores; F-63122 Saint-Genès-Champanelle France
| | - Benoît Graulet
- Université Clermont Auvergne, INRA, VetAgro Sup, UMR Herbivores; F-63122 Saint-Genès-Champanelle France
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12
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Shen W, McIntosh MK. Nutrient Regulation: Conjugated Linoleic Acid's Inflammatory and Browning Properties in Adipose Tissue. Annu Rev Nutr 2017; 36:183-210. [PMID: 27431366 DOI: 10.1146/annurev-nutr-071715-050924] [Citation(s) in RCA: 33] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
Abstract
Obesity is the most widespread nutritional disease in the United States. Developing effective and safe strategies to manage excess body weight is therefore of paramount importance. One potential strategy to reduce obesity is to consume conjugated linoleic acid (CLA) supplements containing isomers cis-9, trans-11 and trans-10, cis-12, or trans-10, cis-12 alone. Proposed antiobesity mechanisms of CLA include regulation of (a) adipogenesis, (b) lipid metabolism, (c) inflammation, (d) adipocyte apoptosis, (e) browning or beiging of adipose tissue, and (f) energy metabolism. However, causality of CLA-mediated responses to body fat loss, particularly the linkage between inflammation, thermogenesis, and energy metabolism, is unclear. This review examines whether CLA's antiobesity properties are due to inflammatory signaling and considers CLA's linkage with lipogenesis, lipolysis, thermogenesis, and browning of white and brown adipose tissue. We propose a series of questions and studies to interrogate the role of the sympathetic nervous system in mediating CLA's antiobesity properties.
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Affiliation(s)
- Wan Shen
- Department of Nutrition, The University of North Carolina at Greensboro, Greensboro, North Carolina 27402; ,
| | - Michael K McIntosh
- Department of Nutrition, The University of North Carolina at Greensboro, Greensboro, North Carolina 27402; ,
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Abbasi Oshaghi E, Goodarzi MT, Higgins V, Adeli K. Role of resveratrol in the management of insulin resistance and related conditions: Mechanism of action. Crit Rev Clin Lab Sci 2017; 54:267-293. [DOI: 10.1080/10408363.2017.1343274] [Citation(s) in RCA: 34] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Affiliation(s)
- Ebrahim Abbasi Oshaghi
- Department of Clinical Biochemistry, School of Medicine, Hamadan University of Medical Sciences, Hamadan, Iran
- Neurophysiology Research Center, Hamadan University of Medical Sciences, Hamadan, Iran
| | - Mohammad Taghi Goodarzi
- Department of Clinical Biochemistry, School of Medicine, Hamadan University of Medical Sciences, Hamadan, Iran
| | - Victoria Higgins
- Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada
| | - Khosrow Adeli
- Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada
- Department of Biochemistry, University of Toronto, Toronto, ON, Canada
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Vahmani P, Meadus WJ, Rolland DC, Duff P, Dugan MER. Trans10,cis15 18:2 Isolated from Beef Fat Does Not Have the Same Anti-Adipogenic Properties as Trans10,cis12–18:2 in 3T3-L1 Adipocytes. Lipids 2016; 51:1231-1239. [DOI: 10.1007/s11745-016-4192-3] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2016] [Accepted: 08/22/2016] [Indexed: 10/21/2022]
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15
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Chen WM, Shaw LH, Chang PJ, Tung SY, Chang TS, Shen CH, Hsieh YY, Wei KL. Hepatoprotective effect of resveratrol against ethanol-induced oxidative stress through induction of superoxide dismutase in vivo and in vitro. Exp Ther Med 2016; 11:1231-1238. [PMID: 27073428 PMCID: PMC4812565 DOI: 10.3892/etm.2016.3077] [Citation(s) in RCA: 46] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2015] [Accepted: 12/01/2015] [Indexed: 12/14/2022] Open
Abstract
The present study aimed to investigate the hepatoprotective effect of resveratrol (RSV) against ethanol-induced oxidative stress in vivo, and investigate the underlying mechanisms by which RSV exerts its anti-oxidative effects on hepatic cells. C57BL/6J mice were divided into four groups: Untreated control, ethanol-treated, RSV-treated, and ethanol + RSV-treated. The plasma lipid profile, hepatic lipid accumulation and antioxidative enzyme activities were analyzed. HepG2 cells were used as a cellular model to analyze the effects of superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx) and peroxisome proliferator-activated receptors (PPARs) in the RSV-mediated protection of ethanol-induced oxidative stress. In C57BL/6J mice, ethanol caused a significant increase in plasma triglyceride levels and hepatic lipid accumulation (P<0.05), whereas RSV notably increased SOD activity. In HepG2 cells, SOD activity was enhanced in the RSV-treated HepG2 cells, whereas the activity of CAT and GPx was not affected. Western blot and quantitative polymerase chain reaction analyses demonstrated that RSV significantly increased SOD protein and mRNA expression levels (P<0.05). Using a transient transfection assay, PPARγ was observed to participate in the regulation of SOD gene expression in RSV-administered HepG2 cells. To conclude, the results from the present study suggest that RSV may contribute towards the protection of hepatic cells from ethanol-induced oxidative stress via the induction of SOD activity and gene expression.
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Affiliation(s)
- Wei-Ming Chen
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Chang Gung Memorial Hospital, Puzi, Chiayi 61363, Taiwan, R.O.C.; Graduate Institute of Clinical Medical Sciences, College of Medicine, Chang Gung University, Taoyuan 333, Taiwan, R.O.C.; College of Medicine, Chang Gung University, Taoyuan 333, Taiwan, R.O.C
| | - Lee-Hsin Shaw
- Institute of Traditional Medicine, National Yang-Ming University, Taipei 11221, Taiwan, R.O.C
| | - Pey-Jium Chang
- Graduate Institute of Clinical Medical Sciences, College of Medicine, Chang Gung University, Taoyuan 333, Taiwan, R.O.C
| | - Shui-Yi Tung
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Chang Gung Memorial Hospital, Puzi, Chiayi 61363, Taiwan, R.O.C.; College of Medicine, Chang Gung University, Taoyuan 333, Taiwan, R.O.C
| | - Te-Sheng Chang
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Chang Gung Memorial Hospital, Puzi, Chiayi 61363, Taiwan, R.O.C.; Graduate Institute of Clinical Medical Sciences, College of Medicine, Chang Gung University, Taoyuan 333, Taiwan, R.O.C
| | - Chein-Heng Shen
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Chang Gung Memorial Hospital, Puzi, Chiayi 61363, Taiwan, R.O.C.; Graduate Institute of Clinical Medical Sciences, College of Medicine, Chang Gung University, Taoyuan 333, Taiwan, R.O.C
| | - Yung-Yu Hsieh
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Chang Gung Memorial Hospital, Puzi, Chiayi 61363, Taiwan, R.O.C.; College of Medicine, Chang Gung University, Taoyuan 333, Taiwan, R.O.C
| | - Kuo-Liang Wei
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Chang Gung Memorial Hospital, Puzi, Chiayi 61363, Taiwan, R.O.C.; College of Medicine, Chang Gung University, Taoyuan 333, Taiwan, R.O.C
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Lehnen TE, da Silva MR, Camacho A, Marcadenti A, Lehnen AM. A review on effects of conjugated linoleic fatty acid (CLA) upon body composition and energetic metabolism. J Int Soc Sports Nutr 2015; 12:36. [PMID: 26388708 PMCID: PMC4574006 DOI: 10.1186/s12970-015-0097-4] [Citation(s) in RCA: 95] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/20/2015] [Accepted: 09/04/2015] [Indexed: 01/01/2023] Open
Abstract
Conjugated linoleic acid (CLA) is highly found in fats from ruminants and it appears to favorably modify the body composition and cardiometabolic risk factors. The capacity of CLA to reduce the body fat levels as well as its benefic actions on glycemic profile, atherosclerosis and cancer has already been proved in experimental models. Furthermore, CLA supplementation may modulate the immune function, help re-synthetize of glycogen and potentiate the bone mineralization. CLA supplementation also could increase the lipolysis and reduce the accumulation of fatty acids on the adipose tissue; the putative mechanisms involved may be its action in reducing the lipase lipoprotein activity and to increase the carnitine-palmitoil-transferase-1 (CAT-1) activity, its interaction with PPARγ, and to raise the expression of UCP-1. Although studies made in human have shown some benefits of CLA supplementation as the weight loss, the results are still discordant. Moreover, some have shown adverse effects, such as negative effects on glucose metabolism and lipid profile. The purpose of this article is to review the available data regarding the benefits of CLA on the energetic metabolism and body composition, emphasizing action mechanisms.
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Affiliation(s)
- Tatiana Ederich Lehnen
- Faculdade Sogipa de Educação Física, Porto Alegre, Brazil ; Instituto de Cardiologia do Rio Grande do Sul, Av. Princesa Isabel, 395 Santana, 90620-001 Porto Alegre, RS Brazil
| | | | - Augusto Camacho
- Faculdade Sogipa de Educação Física, Porto Alegre, Brazil ; Instituto de Cardiologia/Fundação Universitária de Cardiologia (IC/FUC), Porto Alegre, Brazil
| | - Aline Marcadenti
- Instituto de Cardiologia/Fundação Universitária de Cardiologia (IC/FUC), Porto Alegre, Brazil ; Universidade Federal de Ciências da Saúde de Porto Alegre (UFCSPA), Porto Alegre, Brazil
| | - Alexandre Machado Lehnen
- Faculdade Sogipa de Educação Física, Porto Alegre, Brazil ; Instituto de Cardiologia/Fundação Universitária de Cardiologia (IC/FUC), Porto Alegre, Brazil
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Sottero B, Gargiulo S, Russo I, Barale C, Poli G, Cavalot F. Postprandial Dysmetabolism and Oxidative Stress in Type 2 Diabetes: Pathogenetic Mechanisms and Therapeutic Strategies. Med Res Rev 2015; 35:968-1031. [PMID: 25943420 DOI: 10.1002/med.21349] [Citation(s) in RCA: 39] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/17/2023]
Abstract
Postprandial dysmetabolism in type 2 diabetes (T2D) is known to impact the progression and evolution of this complex disease process. However, the underlying pathogenetic mechanisms still require full elucidation to provide guidance for disease prevention and treatment. This review focuses on the marked redox changes and inflammatory stimuli provoked by the spike in blood glucose and lipids in T2D individuals after meals. All the causes of exacerbated postprandial oxidative stress in T2D were analyzed, also considering the consequence of enhanced inflammation on vascular damage. Based on this in-depth analysis, current strategies of prevention and pharmacologic management of T2D were critically reexamined with particular emphasis on their potential redox-related rationale.
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Affiliation(s)
- Barbara Sottero
- Department of Clinical and Biological Sciences, University of Turin, San Luigi Gonzaga Hospital, Orbassano, Turin, 10043, Italy
| | - Simona Gargiulo
- Department of Clinical and Biological Sciences, University of Turin, San Luigi Gonzaga Hospital, Orbassano, Turin, 10043, Italy
| | - Isabella Russo
- Internal Medicine and Metabolic Disease Unit, Department of Clinical and Biological Sciences, University of Turin, San Luigi Gonzaga Hospital, Orbassano, Turin, 10043, Italy
| | - Cristina Barale
- Internal Medicine and Metabolic Disease Unit, Department of Clinical and Biological Sciences, University of Turin, San Luigi Gonzaga Hospital, Orbassano, Turin, 10043, Italy
| | - Giuseppe Poli
- Department of Clinical and Biological Sciences, University of Turin, San Luigi Gonzaga Hospital, Orbassano, Turin, 10043, Italy
| | - Franco Cavalot
- Internal Medicine and Metabolic Disease Unit, Department of Clinical and Biological Sciences, University of Turin, San Luigi Gonzaga Hospital, Orbassano, Turin, 10043, Italy
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Wang W, Fromm M. Sphingolipids are required for efficient triacylglycerol loss in conjugated linoleic Acid treated adipocytes. PLoS One 2015; 10:e0119005. [PMID: 25906159 PMCID: PMC4407960 DOI: 10.1371/journal.pone.0119005] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2014] [Accepted: 01/13/2015] [Indexed: 11/19/2022] Open
Abstract
Conjugated linoleic acid (CLA) reduces adiposity in human and mouse adipocytes. This outcome is achieved through a variety of biological responses including increased energy expenditure and fatty acid oxidation, increased inflammation, repression of fatty acid biosynthesis, attenuated glucose transport, and apoptosis. In the current study, profiling of 261 metabolites was conducted to gain new insights into the biological pathways responding to CLA in 3T3-L1 adipocytes. Sphinganine and sphingosine levels were observed to be highly elevated in CLA treated adipocytes. Exogenous chemicals that increased endogenous ceramide levels decreased lipid levels in adipocytes, and activated AMP-activated protein kinase (AMPK) as well as NF-κB, both of which are typically activated in CLA treated adipocytes. Concurrent inhibition of ceramide de novo biosynthesis and recycling from existing sphingolipid pools attenuated the lipid lowering effect normally associated with responses to CLA, implicating ceramides as an important component of the lipid lowering response in CLA treated adipocytes.
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Affiliation(s)
- Wei Wang
- Department of Animal Science, University of Nebraska, Lincoln, Nebraska, United States of America
| | - Michael Fromm
- Center for Biotechnology, University of Nebraska, Lincoln, Nebraska, United States of America
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19
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Yuan G, Chen X, Li D. Modulation of peroxisome proliferator-activated receptor gamma (PPAR γ) by conjugated fatty acid in obesity and inflammatory bowel disease. JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY 2015; 63:1883-1895. [PMID: 25634802 DOI: 10.1021/jf505050c] [Citation(s) in RCA: 53] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/04/2023]
Abstract
Conjugated fatty acids including conjugated linoleic acid (CLA) and conjugated linolenic acid (CLNA) have drawn significant attention for their variety of biologically beneficial effects. Evidence suggested that CLA and CLNA could play physiological roles by regulating the expression and activity of PPAR γ. This review summarizes the current understanding of evidence of the role of CLA (cis-9,trans-11 CLA and trans-10,cis-12 CLA) and CLNA (punicic acid and α-eleostearic acid) in modulating the expression or activity of PPAR γ that could in turn be employed as complementary treatment for obesity and inflammatory bowel disease.
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Affiliation(s)
- Gaofeng Yuan
- Zhejiang Provincial Key Laboratory of Health Risk Factors for Seafood, Zhejiang Ocean University , Zhoushan 316022, China
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20
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Wang L, Waltenberger B, Pferschy-Wenzig EM, Blunder M, Liu X, Malainer C, Blazevic T, Schwaiger S, Rollinger JM, Heiss EH, Schuster D, Kopp B, Bauer R, Stuppner H, Dirsch VM, Atanasov AG. Natural product agonists of peroxisome proliferator-activated receptor gamma (PPARγ): a review. Biochem Pharmacol 2014; 92:73-89. [PMID: 25083916 PMCID: PMC4212005 DOI: 10.1016/j.bcp.2014.07.018] [Citation(s) in RCA: 436] [Impact Index Per Article: 39.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2014] [Revised: 07/18/2014] [Accepted: 07/21/2014] [Indexed: 12/13/2022]
Abstract
Agonists of the nuclear receptor PPARγ are therapeutically used to combat hyperglycaemia associated with the metabolic syndrome and type 2 diabetes. In spite of being effective in normalization of blood glucose levels, the currently used PPARγ agonists from the thiazolidinedione type have serious side effects, making the discovery of novel ligands highly relevant. Natural products have proven historically to be a promising pool of structures for drug discovery, and a significant research effort has recently been undertaken to explore the PPARγ-activating potential of a wide range of natural products originating from traditionally used medicinal plants or dietary sources. The majority of identified compounds are selective PPARγ modulators (SPPARMs), transactivating the expression of PPARγ-dependent reporter genes as partial agonists. Those natural PPARγ ligands have different binding modes to the receptor in comparison to the full thiazolidinedione agonists, and on some occasions activate in addition PPARα (e.g. genistein, biochanin A, sargaquinoic acid, sargahydroquinoic acid, resveratrol, amorphastilbol) or the PPARγ-dimer partner retinoid X receptor (RXR; e.g. the neolignans magnolol and honokiol). A number of in vivo studies suggest that some of the natural product activators of PPARγ (e.g. honokiol, amorfrutin 1, amorfrutin B, amorphastilbol) improve metabolic parameters in diabetic animal models, partly with reduced side effects in comparison to full thiazolidinedione agonists. The bioactivity pattern as well as the dietary use of several of the identified active compounds and plant extracts warrants future research regarding their therapeutic potential and the possibility to modulate PPARγ activation by dietary interventions or food supplements.
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Affiliation(s)
- Limei Wang
- Department of Pharmacognosy, University of Vienna, Austria
| | - Birgit Waltenberger
- Institute of Pharmacy/Pharmacognosy and Center for Molecular Biosciences Innsbruck (CMBI), University of Innsbruck, Austria
| | | | - Martina Blunder
- Institute of Pharmaceutical Sciences, Department of Pharmacognosy, University of Graz, Austria
| | - Xin Liu
- Institute of Pharmaceutical Sciences, Department of Pharmacognosy, University of Graz, Austria
| | | | - Tina Blazevic
- Department of Pharmacognosy, University of Vienna, Austria
| | - Stefan Schwaiger
- Institute of Pharmacy/Pharmacognosy and Center for Molecular Biosciences Innsbruck (CMBI), University of Innsbruck, Austria
| | - Judith M Rollinger
- Institute of Pharmacy/Pharmacognosy and Center for Molecular Biosciences Innsbruck (CMBI), University of Innsbruck, Austria
| | - Elke H Heiss
- Department of Pharmacognosy, University of Vienna, Austria
| | - Daniela Schuster
- Institute of Pharmacy/Pharmaceutical Chemistry and Center for Molecular Biosciences Innsbruck (CMBI), University of Innsbruck, Austria
| | - Brigitte Kopp
- Department of Pharmacognosy, University of Vienna, Austria
| | - Rudolf Bauer
- Institute of Pharmaceutical Sciences, Department of Pharmacognosy, University of Graz, Austria
| | - Hermann Stuppner
- Institute of Pharmacy/Pharmacognosy and Center for Molecular Biosciences Innsbruck (CMBI), University of Innsbruck, Austria
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Liu K, Zhou R, Wang B, Mi MT. Effect of resveratrol on glucose control and insulin sensitivity: a meta-analysis of 11 randomized controlled trials. Am J Clin Nutr 2014; 99:1510-9. [PMID: 24695890 DOI: 10.3945/ajcn.113.082024] [Citation(s) in RCA: 175] [Impact Index Per Article: 15.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022] Open
Abstract
BACKGROUND The results of human clinical trials investigating the effects of resveratrol on glucose control and insulin sensitivity are inconsistent. OBJECTIVE We aimed to quantitatively evaluate the effects of resveratrol on glucose control and insulin sensitivity. DESIGN We performed a strategic literature search of PubMed, Embase, MEDLINE, and the Cochrane Library (updated to March 2014) for randomized controlled trials that estimated the effects of resveratrol on glucose control and insulin sensitivity. Study quality was assessed by using the Jadad scale. Weighted mean differences were calculated for net changes in glycemic measures by using fixed-effects or random-effects models. We performed prespecified subgroup and sensitivity analyses to evaluate potential heterogeneity. Meta-regression analyses were conducted to investigate dose effects of resveratrol on fasting glucose and insulin concentrations in nondiabetic subjects. RESULTS Eleven studies comprising a total of 388 subjects were included in this meta-analysis. Resveratrol consumption significantly reduced fasting glucose, insulin, glycated hemoglobin, and insulin resistance (measured by using the homeostatic model assessment) levels in participants with diabetes. No significant effect of resveratrol on glycemic measures of nondiabetic participants was found in the meta-analysis. Subgroup and sensitivity analyses indicated that the pooled effects of resveratrol on fasting glucose and insulin concentrations in nondiabetic participants were not affected by body mass index, study design, resveratrol dose, study duration, or Jadad score. CONCLUSIONS Resveratrol significantly improves glucose control and insulin sensitivity in persons with diabetes but does not affect glycemic measures in nondiabetic persons. Additional high-quality studies are needed to further evaluate the potential benefits of resveratrol in humans.
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Affiliation(s)
- Kai Liu
- From the Research Center for Nutrition and Food Safety, Institute of Military Preventive Medicine, Third Military Medical University, Chongqing Key Laboratory of Nutrition and Food Safety, Chongqing Medical Nutrition Research Center, Chongqing, PR China
| | - Rui Zhou
- From the Research Center for Nutrition and Food Safety, Institute of Military Preventive Medicine, Third Military Medical University, Chongqing Key Laboratory of Nutrition and Food Safety, Chongqing Medical Nutrition Research Center, Chongqing, PR China
| | - Bin Wang
- From the Research Center for Nutrition and Food Safety, Institute of Military Preventive Medicine, Third Military Medical University, Chongqing Key Laboratory of Nutrition and Food Safety, Chongqing Medical Nutrition Research Center, Chongqing, PR China
| | - Man-Tian Mi
- From the Research Center for Nutrition and Food Safety, Institute of Military Preventive Medicine, Third Military Medical University, Chongqing Key Laboratory of Nutrition and Food Safety, Chongqing Medical Nutrition Research Center, Chongqing, PR China
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Inhibitory effects of resveratrol on hypoxia-induced inflammation in 3T3-L1 adipocytes and macrophages. J Funct Foods 2014. [DOI: 10.1016/j.jff.2014.02.015] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/10/2023] Open
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Abstract
Resveratrol is a stilbene compound, and a phytoalexin, synthesized by plants in response to stressful stimuli, usually caused by infection. It is abundantly present in red wine, ports and sherries, red grapes, blueberries, peanuts, itadori tea, as well as hops, pistachios, and in grape and cranberry juices. The anti-hyperglycemic effects of resveratrol seem to be the result of an increased action of the glucose transporter in the cytoplasmic membrane. Studies on rats with streptozotocin-induced diabetes have demonstrated that the expression of the insulin-dependent glucose transporter, GLUT4, is increased after resveratrol ingestion. Also, resveratrol enhances adiponectin levels, which could be one of the potential mechanisms by which it improves insulin sensitivity. Another important observation is that resveratrol induces the secretion of the gut incretin hormone, glucagon-like peptide-1. Resveratrol is also reported to activate Sir2 (silent information regulatory 2), a SIRT1 homolog, thus mimicking the benefits of calorie restriction. It produces a wide variety of effects in mammalian cells, including activation of AMP-activated protein kinase, which is involved in some of the same metabolic pathways as SIRT1, which may influence other mechanisms via the involvement of nuclear factor kappa B (NF-κB). In the near future, resveratrol-based therapies with either resveratrol or its analogs that have better bioavailability could be useful in the treatment of diabetes and its complications, either alone or in combination with other anti-diabetic drugs.
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Affiliation(s)
- Natalia G Vallianou
- First Department of Internal Medicine, Evangelismos General Hospital, 10676 Athens, Greece
| | | | - Christos Kazazis
- Honorary Lecturer, School of Medicine, University of Leicester, University Rd, Leicester, LE1 9HN, UK
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Jimenez-Gomez Y, Mattison JA, Pearson KJ, Martin-Montalvo A, Palacios HH, Sossong AM, Ward TM, Younts CM, Lewis K, Allard JS, Longo DL, Belman JP, Malagon MM, Navas P, Sanghvi M, Moaddel R, Tilmont EM, Herbert RL, Morrell CH, Egan JM, Baur JA, Ferrucci L, Bogan JS, Bernier M, de Cabo R. Resveratrol improves adipose insulin signaling and reduces the inflammatory response in adipose tissue of rhesus monkeys on high-fat, high-sugar diet. Cell Metab 2013; 18:533-45. [PMID: 24093677 PMCID: PMC3832130 DOI: 10.1016/j.cmet.2013.09.004] [Citation(s) in RCA: 192] [Impact Index Per Article: 16.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/07/2012] [Revised: 09/15/2012] [Accepted: 08/28/2013] [Indexed: 02/06/2023]
Abstract
Obesity is associated with a chronic, low-grade, systemic inflammation that may contribute to the development of insulin resistance and type 2 diabetes. Resveratrol, a natural compound with anti-inflammatory properties, is shown to improve glucose tolerance and insulin sensitivity in obese mice and humans. Here, we tested the effect of a 2-year resveratrol administration on proinflammatory profile and insulin resistance caused by a high-fat, high-sugar (HFS) diet in white adipose tissue (WAT) from rhesus monkeys. Resveratrol supplementation (80 and 480 mg/day for the first and second year, respectively) decreased adipocyte size, increased sirtuin 1 expression, decreased NF-κB activation, and improved insulin sensitivity in visceral, but not subcutaneous, WAT from HFS-fed animals. These effects were reproduced in 3T3-L1 adipocytes cultured in media supplemented with serum from monkeys fed HFS ± resveratrol diets. In conclusion, chronic administration of resveratrol exerts beneficial metabolic and inflammatory adaptations in visceral WAT from diet-induced obese monkeys.
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Affiliation(s)
- Yolanda Jimenez-Gomez
- Translational Gerontology Branch, Intramural Research Program, National Institute on Aging (NIA), National Institutes of Health (NIH), Baltimore, MD 21224, USA
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Arias N, Miranda J, Macarulla MT, Aguirre L, Fernández-Quintela A, Andres-Lacueva C, Urpi-Sarda M, Portillo MP. The combination of resveratrol and conjugated linoleic acid attenuates the individual effects of these molecules on triacylglycerol metabolism in adipose tissue. Eur J Nutr 2013; 53:575-82. [PMID: 23896999 DOI: 10.1007/s00394-013-0566-y] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2013] [Accepted: 07/17/2013] [Indexed: 02/07/2023]
Abstract
PURPOSE The combination of resveratrol + conjugated linoleic acid (RSV + CLA) did not show the body fat-lowering effect exhibited by these molecules when administered separately. This study aimed to find metabolic explanations for this situation in an experimental model of diet-induced obesity. METHODS Thirty-six male Wistar rats were divided into four groups: rats treated with saline (control), resveratrol (RSV), conjugated linoleic acid (CLA) and a combination of these molecules (RSV + CLA). RESULTS Rats treated with RSV + CLA did not show the reduction in heparin-releasable lipoprotein lipase (HR-LPL) and fatty acid synthase activities observed in RSV group or the increased HSL expression found in RSV and CLA groups. These animals showed reduced sirtuin 1 expression and CLA isomer amounts in adipose tissue. Finally, intracellular Ca(2+) concentration was increased. CONCLUSION The attenuation of the effects induced in adipose tissue triacylglycerol metabolism by RSV and CLA separately, such as the decrease in lipogenesis and fatty acid uptake and the increase in lipolysis, contributes to explain the lack of body fat-lowering effect of the combination RSV + CLA.
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Affiliation(s)
- N Arias
- Nutrition and Obesity Group, Department of Nutrition and Food Sciences, Faculty of Pharmacy, University of the Basque Country (UPV/EHU), Paseo de la Universidad, 7, 01006, Vitoria-Gasteiz, Spain
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Shen W, Martinez K, Chuang CC, McIntosh M. The phospholipase C inhibitor U73122 attenuates trans-10, cis-12 conjugated linoleic acid-mediated inflammatory signaling and insulin resistance in human adipocytes. J Nutr 2013; 143:584-90. [PMID: 23468551 PMCID: PMC3738231 DOI: 10.3945/jn.112.173161] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/08/2023] Open
Abstract
We have demonstrated that trans-10, cis-12 conjugated linoleic acid (18:2t10,c12)-mediated delipidation of human adipocytes was dependent on increased intracellular calcium and activation of inflammatory signaling in human primary adipocytes. These data are consistent with the actions of diacylglycerol and inositol triphosphate derived from phospholipase C (PLC)-dependent cell signaling. To test the hypothesis that PLC was an upstream activator of these cellular responses to 18:2t10,c12, primary cultures of human adipocytes were pretreated with 1-[6-((17β-3-methoxyestra-1,3,5 (10)-trien-17-yl)amino)hexyl]-1H-pyrrole-2,5-dione (U73122), a universal PLC inhibitor, followed by 18:2t10,c12 treatment. U73122 attenuated 18:2t10,c12-mediated insulin resistance within 48 h and suppression of the mRNA levels of peroxisome proliferator-activated receptor (PPAR)γ, insulin-stimulated glucose transporter-4, acetyl-CoA carboxylase-1, and stearoyl-CoA desaturase-1, and the protein levels of PPARγ within 18-24 h. U73122 inhibited 18:2t10,c12-mediated induction of the inflammatory-related genes calcium/calmodulin-dependent protein kinase-β, cyclooxygenase-2, monocyte chemoattractant protein-1, interleukin (IL)-6, and IL-8, secretion of IL-6 and IL-8, and the activation of extracellular signal-related kinase, c-Jun N-terminal kinase, and c-Jun within 18-24 h. Moreover, 18:2t10,c12 increased the mRNA levels of heat shock proteins within 6-24 h and intracellular calcium concentrations within 3 min, which were inhibited by U73122. Lastly, 18:2t10,c12 increased the abundance of PLCγ1 in the plasma membrane within 3 min. Taken together, these data suggest that PLC plays an important role in 18:2t10,c12-mediated activation of intracellular calcium accumulation, inflammatory signaling, delipidation, and insulin resistance in human primary adipocytes.
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Martinez K, Shyamasundar S, Kennedy A, Chuang CC, Marsh A, Kincaid J, Reid T, McIntosh M. Diacylglycerol kinase inhibitor R59022 attenuates conjugated linoleic acid-mediated inflammation in human adipocytes. J Lipid Res 2013; 54:662-670. [PMID: 23264678 PMCID: PMC3617941 DOI: 10.1194/jlr.m031211] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/14/2012] [Revised: 12/17/2012] [Indexed: 11/20/2022] Open
Abstract
Diacylglycerol kinases (DGK) convert diacylglycerol to phosphatidic acid, which has been reported to stimulate calcium release from the endoplasmic reticulum. Based on our published data showing that trans-10, cis-12 conjugated linoleic acid (t10,c12 CLA)-mediated intracellular calcium accumulation is linked to inflammation and insulin resistance, we hypothesized that inhibiting DGKs with R59022 would prevent t10,c12 CLA-mediated inflammatory signaling and insulin resistance in human adipocytes. Consistent with our hypothesis, R59022 attenuated t10,c12 CLA-mediated i) increased gene expression and protein secretion of interleukin (IL)-8, IL-6, and monocyte chemoattractant protein-1 (MCP-1); ii) increased activation of extracellular signal-related kinase (ERK), cJun-NH2-terminal kinase (JNK), and cJun; iii) increased intracellular calcium levels; iv) suppressed mRNA or protein levels of peroxisome proliferator activated receptor γ, adiponectin, and insulin-dependent glucose transporter 4; and v) decreased fatty acid and glucose uptake and triglyceride content. DGKη was targeted for investigation based on our findings that i) DGKη was highly expressed in primary human adipocytes and time-dependently induced by t10,c12 CLA and that ii) t10,c12 CLA-induced DGKη expression was dose-dependently decreased with R59022. Small interfering RNA (siRNA) targeting DGKη decreased t10,c12 CLA-induced DGKη, IL-8, and MCP-1 gene expression, as well as activation of JNK and cJun. Taken together, these data suggest that DGKs mediate, in part, t10,c12 CLA-induced inflammatory signaling in primary human adipocytes.
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Affiliation(s)
- Kristina Martinez
- Department of Nutrition, University of North Carolina at Greensboro, Greensboro, NC
| | - Shruthi Shyamasundar
- Department of Nutrition, University of North Carolina at Greensboro, Greensboro, NC
| | - Arion Kennedy
- Department of Molecular Physiology, Vanderbilt University Medical Center, Nashville, TN
| | - Chia Chi Chuang
- Department of Nutrition, University of North Carolina at Greensboro, Greensboro, NC
| | - Angel Marsh
- Department of Nutrition, University of North Carolina at Greensboro, Greensboro, NC
| | - Jennifer Kincaid
- Department of Nutrition, University of North Carolina at Greensboro, Greensboro, NC
| | - Tanya Reid
- Department of Nutrition, University of North Carolina at Greensboro, Greensboro, NC
| | - Michael McIntosh
- Department of Nutrition, University of North Carolina at Greensboro, Greensboro, NC
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Cullberg KB, Olholm J, Paulsen SK, Foldager CB, Lind M, Richelsen B, Pedersen SB. Resveratrol has inhibitory effects on the hypoxia-induced inflammation and angiogenesis in human adipose tissue in vitro. Eur J Pharm Sci 2013; 49:251-7. [PMID: 23466666 DOI: 10.1016/j.ejps.2013.02.014] [Citation(s) in RCA: 36] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2012] [Revised: 01/21/2013] [Accepted: 02/03/2013] [Indexed: 12/13/2022]
Abstract
Hypoxia modulates the production of proteins involved in e.g. inflammation, angiogenesis and glucose utilization and hypoxia may therefore be an important factor underlying adipose tissue dysfunction in obesity. Resveratrol (RSV) is a natural polyphenolic compound and has been shown to have powerful anti-inflammatory effects and beneficial effects on several obesity-related complications. Thus, in the present study we investigated whether RSV has effects on hypoxic markers (GLUT-1, VEGF), hypoxia-induced key markers of inflammation (IL8, IL6), and leptin in human adipose tissue in vitro. Hypoxia was induced by incubating human adipose tissue fragments with 1% O2 for 24h as compared to 21% O2 The gene expressions were investigated by RT-PCR and protein release by Elisa. Hypoxia increases the expression of glucose transporter-1 (GLUT-1) (19-fold, p<0.001), vascular endothelial growth factor (VEGF) (10-fold, p<0.05), interleukin-8 (IL8) (8-fold, p<0.05), interleukin-6 (IL6) (5-fold, p<0.05) and leptin (9-fold). The protein levels of VEGF released to the medium was increased (8-fold, p<0.01) by hypoxia. RSV dose-dependently inhibited several of these hypoxia-induced expressions and at a concentration of 50 μM RSV almost completely inhibited the hypoxic responses at the above mentioned gene expression levels (p<0.05-p<0.001) and significantly attenuated the hypoxia-induced protein releases by 50-60%. These results demonstrate that hypoxia induces extensive changes in human adipose tissue in the expression and release of inflammation and angiogenesis-related adipokines. In addition the inhibition of hypoxia-mediated inflammation and angiogenesis might represent a novel mechanism of RSV in preventing obesity-related pathologies.
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Affiliation(s)
- Karina B Cullberg
- Department of Endocrinology and Internal Medicine, MEA, THG, Aarhus University Hospital, 8000 Aarhus C, Denmark.
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Gomez-Zorita S, Tréguer K, Mercader J, Carpéné C. Resveratrol directly affects in vitro lipolysis and glucose transport in human fat cells. J Physiol Biochem 2013; 69:585-93. [PMID: 23315205 DOI: 10.1007/s13105-012-0229-0] [Citation(s) in RCA: 59] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2012] [Accepted: 12/21/2012] [Indexed: 02/07/2023]
Abstract
Resveratrol is a naturally occurring polyphenol found in many dietary sources and red wine. Recognized as a cancer chemoprevention agent, an anti-inflammatory factor and an antioxidant molecule, resveratrol has been proposed as a potential anti-obesity compound and to be beneficial in diabetes. Most of the studies demonstrating the anti-adipogenic action of resveratrol were performed as long-term treatments on cultured preadipocytes. The aim of this study was to analyse the acute effects of resveratrol on glucose uptake and lipolysis in human mature adipocytes. Samples of subcutaneous abdominal adipose tissue were obtained from overweight humans and immediately digested by liberase. Fat cells were incubated (from 45 min to 4 h) with resveratrol 1 μM-1 mM. Then, glycerol release or hexose uptake was determined. Regarding lipolysis, the significant effects of resveratrol were found at 100 μM, consisting in a facilitation of isoprenaline stimulation and an impairment of insulin antilipolytic action. At 1 and 10 μM, resveratrol only tended to limit glucose uptake. Resveratrol 100 μM did not change basal glucose uptake but impaired its activation by insulin or by benzylamine. This inhibition was not found with other antioxidants. Such impairment of glucose uptake activation in fat cells may led to a reduced availability of glycerol phosphate and then to a decreased triacylglycerol assembly. Therefore, resveratrol increased triacylglycerol breakdown triggered by β-adrenergic activation and impaired lipogenesis. Consequently, our data indicate that resveratrol can be considered as limiting fat accumulation in human fat cells and further support its use for the mitigation of obesity.
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Jiang S, Wang W, Miner J, Fromm M. Cross regulation of sirtuin 1, AMPK, and PPARγ in conjugated linoleic acid treated adipocytes. PLoS One 2012; 7:e48874. [PMID: 23155420 PMCID: PMC3498327 DOI: 10.1371/journal.pone.0048874] [Citation(s) in RCA: 32] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2012] [Accepted: 10/02/2012] [Indexed: 02/04/2023] Open
Abstract
Trans-10, cis-12 conjugated linoleic acid (t10c12 CLA) reduces triglyceride (TG) levels in adipocytes through multiple pathways, with AMP-activated protein kinase (AMPK) generally facilitating, and peroxisome proliferator-activated receptor γ (PPARγ) generally opposing these reductions. Sirtuin 1 (SIRT1), a histone/protein deacetylase that affects energy homeostasis, often functions coordinately with AMPK, and is capable of binding to PPARγ, thereby inhibiting its activity. This study investigated the role of SIRT1 in the response of 3T3-L1 adipocytes to t10c12 CLA by testing the following hypotheses: 1) SIRT1 is functionally required for robust TG reduction; and 2) SIRT1, AMPK, and PPARγ cross regulate each other. These experiments were performed by using activators, inhibitors, or siRNA knockdowns that affected these pathways in t10c12 CLA-treated 3T3-L1 adipocytes. Inhibition of SIRT1 amounts or activity using siRNA, sirtinol, nicotinamide, or etomoxir attenuated the amount of TG loss, while SIRT1 activator SRT1720 increased the TG loss. SRT1720 increased AMPK activity while sirtuin-specific inhibitors decreased AMPK activity. Reciprocally, an AMPK inhibitor reduced SIRT1 activity. Treatment with t10c12 CLA increased PPARγ phosphorylation in an AMPK-dependent manner and increased the amount of PPARγ bound to SIRT1. Reciprocally, a PPARγ agonist attenuated AMPK and SIRT1 activity levels. These results indicated SIRT1 increased TG loss and that cross regulation between SIRT1, AMPK, and PPARγ occurred in 3T3-L1 adipocytes treated with t10c12 CLA.
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Affiliation(s)
- Shan Jiang
- Department of Molecular Genetics, University of Texas Southwestern Medical Center, Dallas, Texas, United States of America
| | - Wei Wang
- Department of Animal Science, University of Nebraska, Lincoln, Nebraska, United States of America
| | - Jess Miner
- Department of Animal Science, University of Nebraska, Lincoln, Nebraska, United States of America
| | - Michael Fromm
- Center for Biotechnology, University of Nebraska, Lincoln, Nebraska, United States of America
- * E-mail:
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Cheng AS, Cheng YH, Chiou CH, Chang TL. Resveratrol upregulates Nrf2 expression to attenuate methylglyoxal-induced insulin resistance in Hep G2 cells. JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY 2012; 60:9180-7. [PMID: 22917016 DOI: 10.1021/jf302831d] [Citation(s) in RCA: 120] [Impact Index Per Article: 9.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/08/2023]
Abstract
Oxidative stress can result in insulin resistance, a primary cause of type-2 diabetes. Methylglyoxal (MG), a highly reactive dicarbonyl metabolite generated during glucose metabolism, has also been confirmed to cause pancreatic injury and induce inflammation, thereby resulting in insulin resistance. Recently, resveratrol has been reported to exert antioxidant properties, protecting cells from the generation of reactive oxygen species (ROS). The aim of this study was to evaluate resveratrol activation of nuclear factor erythroid 2-related factor 2 (Nrf2) to attenuate MG-induced insulin resistance in Hep G2 cells. Therefore, the molecular signaling events affecting resveratrol-mediated heme oxygenase-1 (HO-1) and glyoxalase expression levels were further investigated in this study. Our findings indicated that resveratrol activated the extracellular signal-regulated kinase (ERK) pathway but not the p38 or c-Jun N-terminal kinase (JNK) pathways, subsequently leading to Nrf2 nuclear translocation and elevation of HO-1 and glyoxalase expression levels. Moreover, resveratrol significantly elevated glucose uptake and protected against MG-induced insulin resistance in Hep G2 cells. In contrast, depletion of Nrf2 by small interfering RNA (si-RNA) resulted in the abrogation of HO-1 and glyoxalase expression in the MG-treated resveratrol group in Hep G2 cells. Administration of an appropriate chemopreventive agent, such as resveratrol, may be an alternative strategy for protecting against MG-induced diabetes.
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Affiliation(s)
- An-Sheng Cheng
- Department of Horticulture and Landscape Architecture, National Taiwan University, Taipei 10617, Taiwan, Republic of China
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Leiherer A, Mündlein A, Drexel H. Phytochemicals and their impact on adipose tissue inflammation and diabetes. Vascul Pharmacol 2012; 58:3-20. [PMID: 22982056 DOI: 10.1016/j.vph.2012.09.002] [Citation(s) in RCA: 106] [Impact Index Per Article: 8.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2012] [Revised: 09/03/2012] [Accepted: 09/04/2012] [Indexed: 01/17/2023]
Abstract
Type 2 diabetes mellitus is an inflammatory disease and the mechanisms that underlie this disease, although still incompletely understood, take place in the adipose tissue of obese subjects. Concurrently, the prevalence of obesity caused by Western diet's excessive energy intake and the lack of exercise escalates, and is believed to be causative for the chronic inflammatory state in adipose tissue. Overnutrition itself as an overload of energy may induce the adipocytes to secrete chemokines activating and attracting immune cells to adipose tissue. But also inflammation-mediating food ingredients like saturated fatty acids are believed to directly initiate the inflammatory cascade. In addition, hypoxia in adipose tissue as a direct consequence of obesity, and its effect on gene expression in adipocytes and surrounding cells in fat tissue of obese subjects appears to play a central role in this inflammatory response too. In contrast, revisiting diet all over the world, there are also some natural food products and beverages which are associated with curative effects on human health. Several natural compounds known as spices such as curcumin, capsaicin, and gingerol, or secondary plant metabolites catechin, resveratrol, genistein, and quercetin have been reported to provide an improved health status to their consumers, especially with regard to diabetes, and therefore have been investigated for their anti-inflammatory effect. In this review, we will give an overview about these phytochemicals and their role to interfere with inflammatory cascades in adipose tissue and their potential for fighting against inflammatory diseases like diabetes as investigated in vivo.
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Affiliation(s)
- Andreas Leiherer
- Vorarlberg Institute for Vascular Investigation and Treatment, Feldkirch, Austria
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34
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Resveratrol role in cardiovascular and metabolic health and potential mechanisms of action. Nutr Res 2012; 32:648-58. [DOI: 10.1016/j.nutres.2012.07.002] [Citation(s) in RCA: 46] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2012] [Revised: 07/03/2012] [Accepted: 07/05/2012] [Indexed: 12/18/2022]
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Mohankumar SK, Taylor CG, Siemens L, Zahradka P. Activation of phosphatidylinositol-3 kinase, AMP-activated kinase and Akt substrate-160 kDa by trans-10, cis-12 conjugated linoleic acid mediates skeletal muscle glucose uptake. J Nutr Biochem 2012; 24:445-56. [PMID: 22704782 DOI: 10.1016/j.jnutbio.2012.01.006] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2011] [Revised: 11/09/2011] [Accepted: 01/06/2012] [Indexed: 10/28/2022]
Abstract
Conjugated linoleic acid (CLA), a dietary lipid, has been proposed as an antidiabetic agent. However, studies specifically addressing the molecular dynamics of CLA on skeletal muscle glucose transport and differences between the key isomers are limited. We demonstrate that acute exposure of L6 myotubes to cis-9, trans-11 (c9,t11) and trans-10, cis-12 (t10,c12) CLA isomers mimics insulin action by stimulating glucose uptake and glucose transporter-4 (GLUT4) trafficking. Both c9,t10-CLA and t10,c12-CLA stimulate the phosphorylation of phosphatidylinositol 3-kinase (PI3-kinase) p85 subunit and Akt substrate-160 kDa (AS160), while showing isomer-specific effects on AMP-activated protein kinase (AMPK). CLA isomers showed synergistic effects with the AMPK activator, 5-aminoimidazole-4-carboxamide-1-β-d-ribonucleoside (AICAR). Blocking PI3-kinase and AMPK prevented the stimulatory effects of t10,c12-CLA on AS160 phosphorylation and glucose uptake, indicating that this isomer acts via a PI3-kinase and AMPK-dependent mechanism, whereas the mechanism of c9,t11-CLA remains unclear. Intriguingly, CLA isomers sensitized insulin-Akt-responsive glucose uptake and prevented high insulin-induced Akt desensitisation. Together, these results establish that CLA exhibits isomer-specific effects on GLUT4 trafficking and the increase in glucose uptake induced by CLA treatment of L6 myotubes occurs via pathways that are distinctive from those utilised by insulin.
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Escoté X, Miranda M, Menoyo S, Rodríguez-Porrata B, Carmona-Gutiérrez D, Jungwirth H, Madeo F, Cordero RR, Mas A, Tinahones F, Clotet J, Vendrell J. Resveratrol induces antioxidant defence via transcription factor Yap1p. Yeast 2012; 29:251-63. [DOI: 10.1002/yea.2903] [Citation(s) in RCA: 31] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2011] [Revised: 03/27/2012] [Accepted: 04/17/2012] [Indexed: 12/18/2022] Open
Affiliation(s)
- Xavier Escoté
- Hospital Universitari de Tarragona Joan XXIII. IISPV; Universitat Rovira i Virgili, CIBERDEM; Spain
| | - Merce Miranda
- Hospital Universitari de Tarragona Joan XXIII. IISPV; Universitat Rovira i Virgili, CIBERDEM; Spain
| | - Sandra Menoyo
- Department of Molecular and Cellular Biology; Universitat Internacional de Catalunya; Sant Cugat del Vallès; Spain
| | | | | | - Helmut Jungwirth
- Institute of Molecular Biosciences; University of Graz; Graz; Austria
| | - Frank Madeo
- Institute of Molecular Biosciences; University of Graz; Graz; Austria
| | | | - Albert Mas
- Facultat d'Enologia; Universitat Rovira i Virgili; Tarragona; Spain
| | - Francisco Tinahones
- Servicio de Endocrinología y Nutrición; Hospital Clínico Virgen de la Victoria, Málaga. CIBER de Fisiopatología Obesidad y Nutrición (CIBEROBN)
| | - Josep Clotet
- Department of Molecular and Cellular Biology; Universitat Internacional de Catalunya; Sant Cugat del Vallès; Spain
| | - Joan Vendrell
- Hospital Universitari de Tarragona Joan XXIII. IISPV; Universitat Rovira i Virgili, CIBERDEM; Spain
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Belda BJ, Thompson JT, Sinha R, Prabhu KS, Vanden Heuvel JP. The dietary fatty acid 10E12Z-CLA induces epiregulin expression through COX-2 dependent PGF(2α) synthesis in adipocytes. Prostaglandins Other Lipid Mediat 2012; 99:30-7. [PMID: 22583689 DOI: 10.1016/j.prostaglandins.2012.05.001] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2012] [Revised: 05/01/2012] [Accepted: 05/02/2012] [Indexed: 02/06/2023]
Abstract
Conjugated linoleic acids (CLAs) are a group of dietary fatty acids that are widely marketed as weight loss supplements. The isomer responsible for this effect is the trans-10, cis-12 CLA (10E12Z-CLA) isomer. 10E12Z-CLA treatment during differentiation of 3T3-L1 adipocytes induces expression of prostaglandin-endoperoxide synthase-2 (Cyclooxygenase-2; COX-2). This work demonstrates that COX-2 is also induced in fully differentiated 3T3-L1 adipocytes after a single treatment of 10E12Z-CLA at both the mRNA (20-40 fold) and protein level (7 fold). Furthermore, prostaglandin (PG)F(2α), but not PGE(2), is significantly increased 10 fold. In female BALB/c mice fed 0.5% 10E12Z-CLA for 10 days, COX-2 was induced in uterine adipose (2 fold). In vitro, pharmacological COX-2 inhibition did not block the effect of 10E12Z-CLA on adipocyte-specific gene expression although PGF(2α) was dose-dependently decreased. These studies demonstrate that PGF(2α) was not by itself responsible for the reduction in adipocyte character due to 10E12Z-CLA treatment. However, PGF(2α), either exogenously or endogenously in response to 10E12Z-CLA, increased the expression of the potent mitogen and epidermal growth factor (EGF) receptor (EGFR) ligand epiregulin in 3T3-L1 adipocytes. Blocking PGF(2α) signaling with the PGF(2α) receptor (FP) antagonist AL-8810 returned epiregulin mRNA levels back to baseline. Although this pathway is not directly responsible for adipocyte dependent gene expression, these results suggest that this signaling pathway may still have broad effect on the adipocyte and surrounding cells.
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Affiliation(s)
- Benjamin J Belda
- The Center for Molecular Toxicology and Carcinogenesis and The Department of Veterinary and Biomedical Sciences, The Pennsylvania State University, University Park, PA 16802, United States
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Statement on the safety of the “conjugated linoleic acid (CLA) rich oils” Clarinol® and Tonalin® TG 80 as Novel Food ingredients. EFSA J 2012. [DOI: 10.2903/j.efsa.2012.2700] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/11/2022] Open
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10E12Z CLA alters adipocyte differentiation and adipocyte cytokine expression and induces macrophage proliferation. J Nutr Biochem 2012; 23:510-8. [DOI: 10.1016/j.jnutbio.2011.02.009] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2010] [Revised: 02/16/2011] [Accepted: 02/17/2011] [Indexed: 12/26/2022]
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Nakamura YK, Dubick MA, Omaye ST. Modulation of oxidative stress by γ-glutamylcysteine (GGC) and conjugated linoleic acid (CLA) isomer mixture in human umbilical vein endothelial cells. Food Chem Toxicol 2012; 50:1854-9. [PMID: 22490668 DOI: 10.1016/j.fct.2012.03.066] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2011] [Revised: 03/20/2012] [Accepted: 03/22/2012] [Indexed: 12/24/2022]
Abstract
Individually, γ-glutamylcysteine (GGC), a dipeptide and precursor of glutathione (GSH), and conjugated linoleic acid (CLA), a trans-fatty acid, exhibit antioxidant properties. The objective of this study was to compare effects of co-administration of GGC and CLA to treatment with GGC alone on oxidative stress and GSH synthesis in human endothelial cells. Changes in levels of 8-epi-PGF2α, thiobarbituric acid reactive substances (TBARS), GSH, total antioxidants, GSH synthetase (GSS) expression, and transcription factor DNA binding were assessed in human umbilical vein endothelial cells (HUVEC) treated with GGC alone (100 μmol/L) or combined with CLA isomer mixture (10, 50, 100 μmol/L) for 24h. Significantly higher levels of TBARS, 8-epi-PGF2α, GSH, and GSS protein were found in cells treated with GGC and 10 μmol/L CLA, compared to cells treated with GGC alone, indicative of prooxidant effects of CLA. Approximately 40% cell death was microscopically observed in cells incubated with GGC and 100 μmol/L CLA. Despite lower levels of GSH, treatment with GGC and 50 μmol/L CLA appeared to be protective from oxidative stress similar to treatment with GGC alone, as indicated by lower levels of TBARS, compared to control cells not treated with GGC and CLA.
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Affiliation(s)
- Yukiko K Nakamura
- Department of Nutrition, University of Nevada Reno, Reno, NV 89557, USA
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Lappas M, Andrikopoulos S, Permezel M. Hypoxanthine-xanthine oxidase down-regulates GLUT1 transcription via SIRT1 resulting in decreased glucose uptake in human placenta. J Endocrinol 2012; 213:49-57. [PMID: 22266962 DOI: 10.1530/joe-11-0355] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
Appropriate foetal growth and development is dependent on adequate placental glucose uptake. Oxidative stress regulates glucose uptake in various tissues. The effect of oxidative stress on placental glucose transport is not known. Thus, the aim of this study was to determine the effect of oxidative stress on glucose uptake and glucose transporters (GLUTs) in human placenta. Human placenta was incubated in the absence or presence of 0.5 mM hypoxanthine+15 mU/ml xanthine oxidase (HX/XO) for 24 h. Gene and protein expressions of the GLUTs were analysed by quantitative RT-PCR and western blotting respectively. Glucose uptake was measured using radiolabelled ((14)C) glucose. HX/XO significantly decreased GLUT1 gene and protein expression and resultant glucose uptake. There was no effect of the antioxidants N-acetylcysteine, catalase and superoxide dismutase or the NF-κB inhibitor BAY 11-0782 on HX/XO-induced decrease in glucose uptake. However, HX/XO treatment significantly decreased both gene and protein expression of SIRT1. In the presence of the SIRT1 activator resveratrol, the decrease in GLUT1 expression and glucose uptake mediated by HX/XO was abolished. Collectively, the data presented here demonstrate that oxidative stress reduces placental glucose uptake and GLUT1 expression by a SIRT1-dependent mechanism.
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Affiliation(s)
- Martha Lappas
- Department of Obstetrics and Gynaecology, Mercy Hospital for Women, University of Melbourne, Level 4/163 Studley Road, Heidelberg, Victoria, Australia.
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Influence of different CLA isomers on insulin resistance and adipocytokines in pre-diabetic, middle-aged men with PPARγ2 Pro12Ala polymorphism. GENES AND NUTRITION 2012; 7:499-509. [PMID: 22399314 DOI: 10.1007/s12263-012-0289-3] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/16/2011] [Accepted: 02/17/2012] [Indexed: 12/13/2022]
Abstract
Conjugated linoleic acids (CLAs) are natural PPARγ ligands, which showed conflicting effects on metabolism in humans. We examined metabolic effects of different isomers of CLA in subjects with PPARγ2 Pro12Ala polymorphisms. A total of 35 men underwent four intervention periods in a crossover study design: subjects with either genotypes received c9, t11 CLA or t10, c12 CLA, a commercially available 1:1 mix of both isomers or reference oil (linoleic acid (LA)). Adipocytokines, insulin, glucose and triglycerides were assessed in the fasting state and after a standardized mixed meal. Across all genotypes, there was a significant (p = 0.025) CLA treatment effect upon postprandial (pp) HOMA-IR values, with c9, t11 CLA and CLA isomer mix improving, but t10, c12 CLA isomer worsening. In Ala12Ala subjects, the t10, c12 isomer caused weight gain (p = 0.03) and tended to increase postprandial insulin levels (p = 0.05). In Pro12Pro subjects, t10, c12 resulted in reduction in waist circumference (p = 0.03). The comparison of the different genotype groups revealed statistically different changes in fasting and postprandial insulin, HOMA-IR and leptin after intervention. c9, t11 CLA and the commercial CLA mix showed beneficial effects on insulin sensitivity compared with LA, while t10, c12 CLA adversely affects body weight and insulin sensitivity in different PPAR genotypes. CLA isomers have different effects on metabolism in Ala and Pro carriers.
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Luo B, Zou T, Lu N, Chai F, Ye X, Wang Y, Qi Y. Role of suppressor of cytokine signaling 3 in lipid metabolism: analysis based on a phage-display human liver cDNA library. Biochem Biophys Res Commun 2011; 416:39-44. [PMID: 22093833 DOI: 10.1016/j.bbrc.2011.10.129] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2011] [Accepted: 10/28/2011] [Indexed: 01/01/2023]
Abstract
Suppressor of cytokine signaling 3 (SOCS3) is a likely mediator of feedback inhibition on the leptin receptor and may cause physiological leptin-resistance, leading to the development of obesity. The aim of this study was to identify potential peptides interacting with purified SOCS3 by using a phage-display human liver cDNA library. We developed a T7 select phage-display system with purified SOCS3 as bait to screen a human liver cDNA library. After 4 rounds of screening and sequencing analysis, we found that phage-presenting peptide RGGVVTSNPLGF show significant binding to SOCS3. The peptide sequence was similar to the sequence of amino acids 644-655 of C-terminal extra-polypeptide of very-long-chain acyl-CoA dehydrogenase (VLCAD), which is 1 of 4 flavoproteins that catalyzing the initial step of the mitochondrial fatty acid β-oxidation, implying a close relationship between SOCS3 and VLCAD. We identified VLCAD as a novel SOCS3 interacting protein both in vitro and vivo, and found that SOCS3 mediates the ubiquitination pathway for proteasomal degradation of VLCAD C-terminal extra-polypeptide via its SOCS-box. Animal experimentation demonstrated that VLCAD is functionally involved in SOCS3 binding and thus, SOCS3 play an important role in the regulation of fatty acid β-oxidation. In conclusion, SOCS3 is an important factor for lipid metabolism and a potential drug-target for treatment of widespread obesity.
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Affiliation(s)
- Bin Luo
- State Key Laboratory of Virology, College of Life Sciences, Wuhan University, Wuhan 430072, People's Republic of China
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Martinez K, Kennedy A, McIntosh M. JNK inhibition by SP600125 attenuates trans-10, cis-12 conjugated linoleic acid-mediated regulation of inflammatory and lipogenic gene expression. Lipids 2011; 46:885-92. [PMID: 21744278 PMCID: PMC3167035 DOI: 10.1007/s11745-011-3587-4] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2011] [Accepted: 06/20/2011] [Indexed: 10/18/2022]
Abstract
Supplementation with a mixture of trans-10, cis-12 (t10,c12) and cis-9, trans-11 (c9,t11) isomers of conjugated linoleic acid (CLA), or t10,c12 CLA alone, reduces body weight and fat deposition in animals and some humans. However, these anti-obesity actions of t10,c12 CLA are routinely accompanied by increased markers of inflammation and insulin resistance. Thus, we examined the extent to which blocking c-Jun NH2-terminal kinase (JNK) signaling using the JNK inhibitor SP600125 attenuated markers of inflammation and insulin resistance in primary human adipocytes treated with t10,c12 CLA. SP600125 attenuated t10,c12 CLA-mediated phosphorylation of cJun and increased protein levels of activating transcription factor (ATF) 3, two downstream targets of JNK. SP600125 attenuated t10,c12 CLA-mediated induction of inflammatory genes, including interleukin (IL)-6, IL-8, IL-1β, ATF3, monocyte chemoattractant protein (MCP)-1, and cyclooxygenase-2. Consistent with these data, SP600125 prevented t10,c12 CLA-mediated secretion of IL-8, IL-6, and MCP-1. SP600125 prevented t10,c12 CLA suppression of lipogenic genes including peroxisome proliferator activated receptor gamma, liver X receptor, sterol regulatory element binding protein, acetyl-CoA carboxylase, and stearoyl-CoA desaturase. Additionally, SP600125 blocked t10,c12 CLA-mediated induction of suppressor of cytokine synthesis-3 and suppression of adiponectin and insulin-dependent glucose transporter 4 mRNA levels. Collectively, these data suggest that JNK signaling plays an important role in t10,c12 CLA-mediated regulation of inflammatory and lipogenic gene expression in primary cultures of human adipocytes.
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Affiliation(s)
- Kristina Martinez
- Department of Nutrition, University of North Carolina at Greensboro, Greensboro, NC 27402, USA, ,
| | - Arion Kennedy
- Department of Molecular Physiology, Vanderbilt U. Medical Ctr, Nashville, TN 37232, USA, (Version 6-20-11)
| | - Michael McIntosh
- Department of Nutrition, University of North Carolina at Greensboro, Greensboro, NC 27402, USA, ,
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Mercader J, Palou A, Bonet ML. Resveratrol enhances fatty acid oxidation capacity and reduces resistin and Retinol-Binding Protein 4 expression in white adipocytes. J Nutr Biochem 2011; 22:828-34. [DOI: 10.1016/j.jnutbio.2010.07.007] [Citation(s) in RCA: 73] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2009] [Revised: 06/08/2010] [Accepted: 07/01/2010] [Indexed: 12/25/2022]
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Obsen T, Faergeman NJ, Chung S, Martinez K, Gobern S, Loreau O, Wabitsch M, Mandrup S, McIntosh M. Trans-10, cis-12 conjugated linoleic acid decreases de novo lipid synthesis in human adipocytes. J Nutr Biochem 2011; 23:580-90. [PMID: 21775116 DOI: 10.1016/j.jnutbio.2011.02.014] [Citation(s) in RCA: 27] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2010] [Revised: 02/16/2011] [Accepted: 02/28/2011] [Indexed: 11/25/2022]
Abstract
Conjugated linoleic acid (CLA) reduces adiposity in vivo. However, mechanisms mediating these changes are unclear. Therefore, we treated cultures of human adipocytes with trans-10, cis-12 (10,12) CLA, cis-9, trans-11 (9,11) CLA or other trans fatty acids (FA), and measured indices of lipid metabolism. The lipid-lowering effects of 10,12 CLA were unique, as other trans FA did not reduce TG content to the same extent. Using low levels of [(14)C]-CLA isomers, it was shown that both isomers were readily incorporated into acylglycerols and phospholipids, albeit at lower levels than [(14)C]-oleic or [(14)C]-linoleic acids. When using [(14)C]-acetic acid and [(14)C]-pyruvic acid as substrates, 30 μM 10,12 CLA, but not 9,11 CLA, decreased de novo synthesis of triglyceride, free FA, diacylglycerol, cholesterol esters, cardiolipin, phospholipids and ceramides within 3-24 h. Treatment with 30 μM 10,12 CLA, but not 9,11 CLA, decreased total cellular lipids within 3 days and the ratio of monounsaturated FA (MUFA) to saturated FA, and increased C18:0 acyl-CoA levels within 24 h. Consistent with these data, stearoyl-CoA desaturase (SCD)-1 mRNA and protein levels were down-regulated by 10,12 CLA within 7-12 h, respectively. The mRNA levels of liver X receptor (LXR)α and sterol regulatory element binding protein (SREBP)-1c, transcription factors that regulate SCD-1, were decreased by 10,12 CLA within 5 h. These data suggest that the isomer-specific decrease in de novo lipid synthesis by 10,12 CLA is due, in part, to the rapid repression of lipogenic transcription factors that regulate MUFA synthesis, suggesting an anti-obesity mechanism unique to this trans FA.
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Affiliation(s)
- Thomas Obsen
- Department of Biochemistry and Molecular Biology, University of Southern Denmark, Odense, Denmark
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González R, Ballester I, López-Posadas R, Suárez MD, Zarzuelo A, Martínez-Augustin O, Sánchez de Medina F. Effects of flavonoids and other polyphenols on inflammation. Crit Rev Food Sci Nutr 2011; 51:331-62. [PMID: 21432698 DOI: 10.1080/10408390903584094] [Citation(s) in RCA: 366] [Impact Index Per Article: 26.1] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Flavonoids are a family of polyphenolic compounds which are widespread in nature (vegetables) and are consumed as part of the human diet in significant amounts. There are other types of polyphenols, including, for example, tannins and resveratrol. Flavonoids and related polyphenolic compounds have significant antiinflammatory activity, among others. This short review summarizes the current knowledge on the effects of flavonoids and related polyphenolic compounds on inflammation, with a focus on structural requirements, the mechanisms involved, and pharmacokinetic considerations. Different molecular (cyclooxygenase, lipoxygenase) and cellular targets (macrophages, lymphocytes, epithelial cells, endothelium) have been identified. In addition, many flavonoids display significant antioxidant/radical scavenging properties. There is substantial structural variation in these compounds, which is bound to have an impact on their biological profile, and specifically on their effects on inflammatory conditions. However, in general terms there is substantial consistency in the effects of these compounds despite considerable structural variations. The mechanisms have been studied mainly in myeloid cells, where the predominant effect is an inhibition of NF-κB signaling and the downregulation of the expression of proinflammatory markers. At present there is a gap in knowledge of in vitro and in vivo effects, although the pharmacokinetics of flavonoids has advanced considerably in the last decade. Many flavonoids have been studied for their intestinal antiinflammatory activity which is only logical, since the gastrointestinal tract is naturally exposed to them. However, their potential therapeutic application in inflammation is not restricted to this organ and extends to other sites and conditions, including arthritis, asthma, encephalomyelitis, and atherosclerosis, among others.
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Affiliation(s)
- R González
- Department of Pharmacology, CIBERehd, School of Pharmacy, University of Granada, Granada, Spain
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Choi HJ, Kim ES. Conjugated Linoleic Acid Negatively Regulates TR4 Activity in 3T3-L1 Adipocytes. Korean J Food Sci Anim Resour 2011. [DOI: 10.5851/kosfa.2011.31.3.381] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/06/2022] Open
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Lan D, Lu M, Sharma S, Mellon PL, Olefsky JM, Webster NJG. Trans-resveratrol inhibits phosphorylation of Smad2/3 and represses FSHβ gene expression by a SirT1-independent pathway in LβT2 gonadotrope cells. Reprod Toxicol 2011; 32:85-92. [PMID: 21679764 DOI: 10.1016/j.reprotox.2011.05.006] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2011] [Revised: 04/22/2011] [Accepted: 05/12/2011] [Indexed: 12/20/2022]
Abstract
Resveratrol (trans-3,5,4'-trihydroxystilbene), a polyphenol found in red wine, has multiple beneficial activities that are similar to caloric restriction. In this study, we analyzed the effect of resveratrol on the gonadotropin genes, follicle-stimulating hormone (FSHβ) and luteinizing hormone (LHβ) in LβT2 immortalized mouse gonadotrope cells. Resveratrol specifically inhibited activin-induced FSHβ mRNA and protein expression, and reduced activin-stimulated Smad2/3 phosphorylation. Knockdown of SirT1 gene expression or SirT1 inhibition did not block repression of FSHβ expression or suppression of Smad2/3 phosphorylation, but did increase p53 acetylation. Taken together, our results suggest that resveratrol down-regulates Smad2/3 phosphorylation and suppresses FSHβ expression via a SirT1-independent pathway.
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Affiliation(s)
- Debin Lan
- Department of Medicine, University of California, 9500 Gilman Drive, La Jolla, San Diego, CA 92093, USA
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Hommelberg PPH, Plat J, Remels AHV, van Essen ALM, Kelders MCJM, Mensink RP, Schols AMWJ, Langen RCJ. Trans-10, cis-12 conjugated linoleic acid inhibits skeletal muscle differentiation and GLUT4 expression independently from NF-κB activation. Mol Nutr Food Res 2011; 54:1763-72. [PMID: 20568237 DOI: 10.1002/mnfr.201000103] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/29/2023]
Abstract
SCOPE The capacity of skeletal muscle to contribute to glucose homeostasis depends on muscular insulin sensitivity. The expression of glucose transporter (GLUT)-4 is increased during myoblast differentiation, a process essential in maintenance of adult muscle. Therefore, processes that affect muscle differentiation may influence insulin dependent glucose homeostasis. Conjugated linoleic acids, and in particular trans-10, cis-12 CLA (t10, c12-CLA), are potent inducers of NF-kB in cultured skeletal myotubes, and NF-kB activation inhibits muscle differentiation. The aims of this study were to evaluate whether CLAs inhibit myogenic differentiation and lower GLUT4 mRNA expression and to address the involvement of NF-kB activation in potential effects of CLA on these processes. METHODS AND RESULTS Incubation of C2C12 cells with t10, c12-CLA blocked the formation of myotubes, which was accompanied by reduced expression of the muscle specific genes creatine kinase, myogenin, myosin heavy chain perinatal and myosin heavy chain IIB, as well as decreased GLUT4 mRNA levels. However, genetic blockade of NF-kB was not sufficient to restore reduced myosin heavy chain protein expression following t10, c12-CLA treatment. Surprisingly, in contrast to myotubes, t10, c12-CLA was not able to activate NF-kB transcriptional activity in myoblasts. CONCLUSION In conclusion, t10, c12-CLA inhibits myogenic differentiation and GLUT4 expression, independently from NF-kB activation.
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Affiliation(s)
- Pascal P H Hommelberg
- Department of Human Biology, Maastricht University Medical Centre+, Maastricht, The Netherlands
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