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Nielsen MH, Nøhr-Meldgaard J, Møllerhøj MB, Oró D, Pors SE, Andersen MW, Kamzolas I, Petsalaki E, Vacca M, Harder LM, Perfield JW, Veidal S, Hansen HH, Feigh M. Characterization of six clinical drugs and dietary intervention in the nonobese CDAA-HFD mouse model of MASH and progressive fibrosis. Am J Physiol Gastrointest Liver Physiol 2025; 328:G51-G71. [PMID: 39404770 DOI: 10.1152/ajpgi.00110.2024] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/10/2024] [Revised: 09/13/2024] [Accepted: 09/23/2024] [Indexed: 12/17/2024]
Abstract
The choline-deficient l-amino acid defined-high-fat diet (CDAA-HFD) mouse model is widely used in preclinical metabolic dysfunction-associated steatohepatitis (MASH) research. To validate the CDAA-HFD mouse, we evaluated disease progression and responsiveness to dietary and pharmacological interventions with semaglutide, lanifibranor, elafibranor, obeticholic acid (OCA), firsocostat, and resmetirom. Disease phenotyping was performed in C57BL/6J mice fed CDAA-HFD for 3-20 wk and ranked using the MASLD Human Proximity Score (MHPS). Semaglutide, lanifibranor, elafibranor, OCA, firsocostat, or resmetirom were profiled as treatment intervention for 8 wk, starting after 6 wk of CDAA-HFD feeding. Semaglutide and lanifibranor were further evaluated as early (preventive) therapy for 9 wk, starting 3 wk after CDAA-HFD diet feeding. In addition, benefits of dietary intervention (chow reversal) for 8 wk were characterized following 6 wk of CDAA-HFD feeding. CDAA-HFD mice demonstrated a nonobese phenotype with fast onset and progression of MASH and fibrosis, high similarity to human MASH-fibrosis, and tumor development after 20 wk of diet-induction. Semaglutide and lanifibranor partially reversed fibrosis when administered as prevention but not as treatment intervention. Elafibranor was the only interventional drug therapy to improve fibrosis. In comparison, chow-reversal resulted in complete regression of steatosis with improved liver inflammation and fibrosis in CDAA-HFD mice. CDAA-HFD mice recapitulate histological hallmarks of advanced MASH with progressive severe fibrosis, however, in the absence of a clinical translational obese dysmetabolic phenotype. CDAA-HFD mice are suitable for profiling drug candidates directly targeting hepatic lipid metabolism, inflammation, and fibrosis. The timing of pharmacological intervention is critical for determining antifibrotic drug efficacy in the model.NEW & NOTEWORTHY The CDAA-HFD mouse model is widely used in preclinical MASH research, but validation of the model is lacking. This study presents the longitudinal characterization of disease progression. Furthermore, late-stage clinical compounds and dietary intervention (chow reversal) display distinct hepatoprotective effects in the model. Collectively, the study provides critical information guiding the use of the CDAA-HFD mouse model in preclinical drug discovery for MASH and fibrosis.
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Affiliation(s)
| | | | | | | | | | | | - Ioannis Kamzolas
- TVP Lab, WT/MRC Institute of Metabolic Science, University of Cambridge, Cambridge, United Kingdom
- European Molecular Biology Laboratory, European Bioinformatics Institute (EMBL-EBI), Hinxton, United Kingdom
| | - Evangelia Petsalaki
- European Molecular Biology Laboratory, European Bioinformatics Institute (EMBL-EBI), Hinxton, United Kingdom
| | - Michele Vacca
- TVP Lab, WT/MRC Institute of Metabolic Science, University of Cambridge, Cambridge, United Kingdom
- Interdisciplinary Department of Medicine, University of Bari "Aldo Moro", Bari, Italy
- Laboratory of Liver Metabolism and MASLD, Roger Williams Institute of Hepatology, London, United Kingdom
| | - Lea Mørch Harder
- Research and Early Development, Novo Nordisk A/S, Måløv, Denmark
| | - James W Perfield
- Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana, United States
| | - Sanne Veidal
- Research and Early Development, Novo Nordisk A/S, Måløv, Denmark
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Bushong A, Sepúlveda M, Scherer M, Valachovic AC, Neill CM, Horn S, Choi Y, Lee LS, Baloni P, Hoskins T. Effects of Perfluorinated Alkyl Substances (PFAS) on Amphibian Body and Liver Conditions: Is Lipid Metabolism Being Perturbed throughout Metamorphosis? TOXICS 2024; 12:732. [PMID: 39453152 PMCID: PMC11510839 DOI: 10.3390/toxics12100732] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/30/2024] [Revised: 09/29/2024] [Accepted: 10/03/2024] [Indexed: 10/26/2024]
Abstract
Per- and polyfluoroalkyl substances (PFAS) may interact with peroxisome proliferator activated receptors (PPARs) and alter lipid homeostasis. Using Xenopus laevis, we investigated the effect of PFAS on (a) lipid homeostasis and whether this correlated to changes in body and hepatic condition; (b) the expression of hepatic genes regulated by PPAR; and (c) the hepatic lipidome. We chronically exposed tadpoles to 0.5 µg/L of either PFOS, PFHxS, PFOA, PFHxA, a binary mixture of PFOS and PFHxS (0.5 µg/L of each), or a control, from NF stage 52 through metamorphic climax. Growth, development, and survival were not affected, but we detected a sex-specific decrease in body condition at NF 66 (6.8%) and in hepatic condition (16.6%) across metamorphic climax for male tadpoles exposed to PFOS. We observed weak evidence for the transient downregulation of apolipoprotein-V (apoa5) at NF 62 in tadpoles exposed to PFHxA. Acyl-CoA oxidase 1 (acox1) was downregulated only in males exposed to PFHxS (Ln(Fold Change) = -0.54). We detected PFAS-specific downregulation of structural glycerophospholipids, while semi-quantitative profiling detected the upregulation in numerous glycerophospholipids, sphingomyelins, and diglycerides. Overall, our findings indicate that PFAS can induce sex-specific effects that change across larval development and metamorphosis. We demonstrate that PFAS alter lipid metabolism at environmentally relevant concentrations through divergent mechanisms that may not be related to PPARs, with an absence of effects on body condition, demonstrating the need for more molecular studies to elucidate mechanisms of PFAS-induced lipid dysregulation in amphibians and in other taxa.
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Affiliation(s)
- Anna Bushong
- Department of Forestry and Natural Resources, Purdue University, West Lafayette, IN 47907, USA; (M.S.)
| | - Maria Sepúlveda
- Department of Forestry and Natural Resources, Purdue University, West Lafayette, IN 47907, USA; (M.S.)
- Faculty of Life Sciences, Universidad Andres Bello, Santiago 8370146, Chile
| | - Meredith Scherer
- Department of Forestry and Natural Resources, Purdue University, West Lafayette, IN 47907, USA; (M.S.)
| | - Abigail C. Valachovic
- Department of Forestry and Natural Resources, Purdue University, West Lafayette, IN 47907, USA; (M.S.)
| | - C. Melman Neill
- Department of Forestry and Natural Resources, Purdue University, West Lafayette, IN 47907, USA; (M.S.)
| | - Sophia Horn
- Department of Forestry and Natural Resources, Purdue University, West Lafayette, IN 47907, USA; (M.S.)
| | - Youn Choi
- Department of Agronomy and Environmental & Ecological Engineering, Interdisciplinary Ecological Sciences and Engineering, Purdue University, West Lafayette, IN 47907, USA; (Y.C.); (L.S.L.)
| | - Linda S. Lee
- Department of Agronomy and Environmental & Ecological Engineering, Interdisciplinary Ecological Sciences and Engineering, Purdue University, West Lafayette, IN 47907, USA; (Y.C.); (L.S.L.)
| | - Priyanka Baloni
- College of Health Sciences, Purdue University, West Lafayette, IN 47907, USA;
| | - Tyler Hoskins
- Department of Forestry and Natural Resources, Purdue University, West Lafayette, IN 47907, USA; (M.S.)
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Nasimi Doost Azgomi R, Karimi A, Moini Jazani A. The favorable impacts of cardamom on related complications of diabetes: A comprehensive literature systematic review. Diabetes Metab Syndr 2024; 18:102947. [PMID: 38325073 DOI: 10.1016/j.dsx.2024.102947] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/12/2023] [Revised: 01/07/2024] [Accepted: 01/14/2024] [Indexed: 02/09/2024]
Abstract
BACKGROUND AND AIM Complementary and alternative medicine plays an increasing role in preventing, and regulatory, complications associated with diabetes. There are plenty of polyphenolic compounds found in Elettaria cardamomum (Cardamom) such as luteolin, limonene, pelargonidin, caffeic acid, kaempferol, gallic acid, and quercetin which can be used in many metabolic diseases. METHOD The objective of this systematic review was to appraise evidence from clinical and in vivo studies on the effects of cardamom on inflammation, blood glucose, oxidative stress and dyslipidemia of diabetes mellitus. According to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statements, the present study was carried out. Studies were conducted by searching databases such as EMBASE, Scopus, PubMed, Google Scholar, web of sciences, and Cochrane Library from the commencement until April 2022. RESULTS All available human and animal studies examining the effects of cardamom on diabetes were published in the form of English articles. Finally, only 14 of the 241 articles met the criteria for analysis. Of the 14 articles, 8 were in vivo studies, and 6 were clinical trial studies. Most studies have indicated the beneficial effects of cardamom on insulin resistance, oxidative stress and inflammation. Cardamom also improved dyslipidemia, but had no substantial effect on weight loss. CONCLUSION According to most studies, cardamom supplementation enhanced antioxidant enzyme production and activity in diabetes mellitus and decreased oxidative stress and inflammatory factors. Despite this, the exact mechanism of the disease needs to be identified through more clinical trials.
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Affiliation(s)
- Ramin Nasimi Doost Azgomi
- Traditional Medicine and Hydrotherapy Research Center, Ardabil University of Medical Sciences, Ardabil, Iran
| | - Arash Karimi
- Traditional Medicine and Hydrotherapy Research Center, Ardabil University of Medical Sciences, Ardabil, Iran; Department of Clinical Nutrition, Faculty of Nutrition and Food Science, Tabriz University of Medical Sciences, Tabriz, Iran.
| | - Arezoo Moini Jazani
- Traditional Medicine and Hydrotherapy Research Center, Ardabil University of Medical Sciences, Ardabil, Iran.
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Souza-Tavares H, Miranda CS, Vasques-Monteiro IML, Sandoval C, Santana-Oliveira DA, Silva-Veiga FM, Fernandes-da-Silva A, Souza-Mello V. Peroxisome proliferator-activated receptors as targets to treat metabolic diseases: Focus on the adipose tissue, liver, and pancreas. World J Gastroenterol 2023; 29:4136-4155. [PMID: 37475842 PMCID: PMC10354577 DOI: 10.3748/wjg.v29.i26.4136] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/21/2023] [Revised: 05/26/2023] [Accepted: 06/13/2023] [Indexed: 07/10/2023] Open
Abstract
The world is experiencing reflections of the intersection of two pandemics: Obesity and coronavirus disease 2019. The prevalence of obesity has tripled since 1975 worldwide, representing substantial public health costs due to its comorbidities. The adipose tissue is the initial site of obesity impairments. During excessive energy intake, it undergoes hyperplasia and hypertrophy until overt inflammation and insulin resistance turn adipocytes into dysfunctional cells that send lipotoxic signals to other organs. The pancreas is one of the organs most affected by obesity. Once lipotoxicity becomes chronic, there is an increase in insulin secretion by pancreatic beta cells, a surrogate for type 2 diabetes mellitus (T2DM). These alterations threaten the survival of the pancreatic islets, which tend to become dysfunctional, reaching exhaustion in the long term. As for the liver, lipotoxicity favors lipogenesis and impairs beta-oxidation, resulting in hepatic steatosis. This silent disease affects around 30% of the worldwide population and can evolve into end-stage liver disease. Although therapy for hepatic steatosis remains to be defined, peroxisome proliferator-activated receptors (PPARs) activation copes with T2DM management. Peroxisome PPARs are transcription factors found at the intersection of several metabolic pathways, leading to insulin resistance relief, improved thermogenesis, and expressive hepatic steatosis mitigation by increasing mitochondrial beta-oxidation. This review aimed to update the potential of PPAR agonists as targets to treat metabolic diseases, focusing on adipose tissue plasticity and hepatic and pancreatic remodeling.
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Affiliation(s)
| | | | | | - Cristian Sandoval
- Escuela de Tecnología Médica, Facultad de Salud, Universidad Santo Tomás, Osorno 5310431, Chile
- Departamento de Ciencias Preclínicas, Universidad de la Frontera, Temuco 4780000, Chile
| | | | | | | | - Vanessa Souza-Mello
- Department of Anatomy, Rio de Janeiro State University, Rio de Janeiro 20551030, Brazil
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Lin CY, Yeh KY, Lai HH, Her GM. AgRP Neuron-Specific Ablation Represses Appetite, Energy Intake, and Somatic Growth in Larval Zebrafish. Biomedicines 2023; 11:biomedicines11020499. [PMID: 36831035 PMCID: PMC9953713 DOI: 10.3390/biomedicines11020499] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2022] [Revised: 02/01/2023] [Accepted: 02/06/2023] [Indexed: 02/11/2023] Open
Abstract
Neuronal circuits regulating appetite are dominated by arcuate nucleus neurons, which include appetite-promoting and -suppressing neurons that release the orexigenic neuropeptide agouti-related protein (AgRP) and anorexigenic neuropeptide pro-opiomelanocortin, respectively, to compete for melanocortin receptors to modulate feeding behavior. In this study, we expressed novel agrp promoters, including different lengths of the 5' flanking regions of the agrp gene (4749 bp) in the zebrafish genome. We used the agrp promoter to derive the enhanced green fluorescent protein (EGFP)-nitroreductase (NTR) fusion protein, allowing expression of the green fluorescence signal in the AgRP neurons. Then, we treated the transgenic zebrafish AgRP4.7NTR (Tg [agrp-EGFP-NTR]) with metronidazole to ablate the AgRP neurons in the larvae stage and observed a decline in their appetite and growth. The expression of most orexigenic and growth hormone/insulin-like growth factor axis genes decreased, whereas that of several anorexigenic genes increased. Our findings demonstrate that AgRP is a critical regulator of neuronal signaling for zebrafish appetite and energy intake control. Thus, AgRP4.7NTR can be used as a drug-screening platform for therapeutic targets to treat human appetite disorders, including obesity. Furthermore, the unique agrp promoter we identified can be a powerful tool for research on AgRP neurons, especially AgRP neuron-mediated pathways in the hypothalamus, and appetite.
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Affiliation(s)
- Chiu-Ya Lin
- Department of Bioscience and Biotechnology, National Taiwan Ocean University, Keelung City 202, Taiwan
- Institute of Biopharmaceutical Sciences, National Yang Ming Chiao Tung University, Taipei 112, Taiwan
| | - Kun-Yun Yeh
- Division of Hemato-Oncology, Department of Internal Medicine, Chang Gung Memorial Hospital, Keelung City 204, Taiwan
| | - Hsin-Hung Lai
- Institute of Biopharmaceutical Sciences, National Yang Ming Chiao Tung University, Taipei 112, Taiwan
| | - Guor Mour Her
- Institute of Biopharmaceutical Sciences, National Yang Ming Chiao Tung University, Taipei 112, Taiwan
- Correspondence: ; Tel.: +886-2-2826-7000 (ext. 67990)
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Princiotta Cariddi L, Mauri M, Cosentino M, Versino M, Marino F. Alzheimer's Disease: From Immune Homeostasis to Neuroinflammatory Condition. Int J Mol Sci 2022; 23:13008. [PMID: 36361799 PMCID: PMC9658357 DOI: 10.3390/ijms232113008] [Citation(s) in RCA: 24] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2022] [Revised: 10/12/2022] [Accepted: 10/14/2022] [Indexed: 08/13/2023] Open
Abstract
Alzheimer's Disease is the most common cause in the world of progressive cognitive decline. Although many modifiable and non-modifiable risk factors have been proposed, in recent years, neuroinflammation has been hypothesized to be an important contributing factor of Alzheimer's Disease pathogenesis. Neuroinflammation can occur through the combined action of the Central Nervous System resident immune cells and adaptive peripheral immune system. In the past years, immunotherapies for neurodegenerative diseases have focused wrongly on targeting protein aggregates Aβ plaques and NFT treatment. The role of both innate and adaptive immune cells has not been fully clarified, but several data suggest that immune system dysregulation plays a key role in neuroinflammation. Recent studies have focused especially on the role of the adaptive immune system and have shown that inflammatory markers are characterized by increased CD4+ Teff cells' activities and reduced circulating CD4+ Treg cells. In this review, we discuss the key role of both innate and adaptive immune systems in the degeneration and regeneration mechanisms in the pathogenesis of Alzheimer's Disease, with a focus on how the crosstalk between these two systems is able to sustain brain homeostasis or shift it to a neurodegenerative condition.
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Affiliation(s)
- Lucia Princiotta Cariddi
- PhD Program in Clinical and Experimental Medicine and Medical Humanities, University of Insubria, 21100 Varese, Italy
- Neurology and Stroke Unit, ASST Sette Laghi Hospital, 21100 Varese, Italy
| | - Marco Mauri
- Neurology and Stroke Unit, ASST Sette Laghi Hospital, 21100 Varese, Italy
- Department of Biotechnology and Life Sciences, University of Insubria, 21100 Varese, Italy
| | - Marco Cosentino
- Center of Research in Medical Pharmacology, University of Insubria, 21100 Varese, Italy
| | - Maurizio Versino
- Neurology and Stroke Unit, ASST Sette Laghi Hospital, 21100 Varese, Italy
- Department of Medicine and Surgery, University of Insubria, 21100 Varese, Italy
| | - Franca Marino
- Center of Research in Medical Pharmacology, University of Insubria, 21100 Varese, Italy
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Jacques V, Bolze S, Hallakou-Bozec S, Czarnik AW, Divakaruni AS, Fouqueray P, Murphy AN, Van der Ploeg LHT, DeWitt S. Deuterium-Stabilized ( R)-Pioglitazone (PXL065) Is Responsible for Pioglitazone Efficacy in NASH yet Exhibits Little to No PPARγ Activity. Hepatol Commun 2021; 5:1412-1425. [PMID: 34430785 PMCID: PMC8369945 DOI: 10.1002/hep4.1723] [Citation(s) in RCA: 25] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/11/2020] [Revised: 02/19/2021] [Accepted: 03/12/2021] [Indexed: 02/04/2023] Open
Abstract
The antidiabetic drug pioglitazone is, to date, the most efficacious oral drug recommended off-label for the treatment of nondiabetic or diabetic patients with biopsy-proven nonalcoholic steatohepatitis (NASH). However, weight gain and edema side effects have limited its use for NASH. Pioglitazone is a mixture of two stereoisomers ((R)-pioglitazone and (S)-pioglitazone) that interconvert in vitro and in vivo. We aimed to characterize their individual pharmacology to develop a safer and potentially more potent drug for NASH. We stabilized the stereoisomers of pioglitazone with deuterium at the chiral center. Preclinical studies with deuterium-stabilized (R)-pioglitazone (PXL065) and (S)-pioglitazone demonstrated that (R)-pioglitazone retains the efficacy of pioglitazone in NASH, including reduced hepatic triglycerides, free fatty acids, cholesterol, steatosis, inflammation, hepatocyte enlargement, and fibrosis. Although both stereoisomers inhibit the mitochondrial pyruvate carrier, PXL065 shows limited to no peroxisome proliferator-activated receptor gamma (PPARγ) activity, whereas (S)-pioglitazone appears responsible for the PPARγ activity and associated weight gain. Nonetheless, in preclinical models, both stereoisomers reduce plasma glucose and hepatic fibrosis to the same extent as pioglitazone, suggesting that these benefits may also be mediated by altered mitochondrial metabolism. In a phase 1a clinical study, we demonstrated safety and tolerability of single 7.5-mg, 22.5-mg, and 30-mg doses of PXL065 as well as preferential exposure to the (R)-stereoisomer in comparison to 45-mg pioglitazone. Conclusion: PXL065 at a dose lower than 22.5 mg is predicted to exhibit efficacy for NASH equal to, or greater than, 45-mg pioglitazone without the potentially detrimental weight gain and edema. The development of PXL065 for NASH represents a unique opportunity to leverage the therapeutic benefits of pioglitazone, while reducing or eliminating PPARγ-related side effects.
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Affiliation(s)
| | | | | | | | - Ajit S Divakaruni
- Department of PharmacologyUniversity of California, San DiegoLa JollaCAUSA.,Department of Molecular and Medical PharmacologyUniversity of California, Los AngelesLos AngelesCAUSA
| | | | - Anne N Murphy
- Department of PharmacologyUniversity of California, San DiegoLa JollaCAUSA.,Cytokinetics IncSouth San FranciscoCAUSA
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High-Intensity Interval Training and α-Linolenic Acid Supplementation Improve DHA Conversion and Increase the Abundance of Gut Mucosa-Associated Oscillospira Bacteria. Nutrients 2021; 13:nu13030788. [PMID: 33673609 PMCID: PMC7997329 DOI: 10.3390/nu13030788] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2021] [Revised: 02/10/2021] [Accepted: 02/23/2021] [Indexed: 12/12/2022] Open
Abstract
Obesity, a major public health problem, is the consequence of an excess of body fat and biological alterations in the adipose tissue. Our aim was to determine whether high-intensity interval training (HIIT) and/or α-linolenic acid supplementation (to equilibrate the n-6/n-3 polyunsaturated fatty acids (PUFA) ratio) might prevent obesity disorders, particularly by modulating the mucosa-associated microbiota. Wistar rats received a low fat diet (LFD; control) or high fat diet (HFD) for 16 weeks to induce obesity. Then, animals in the HFD group were divided in four groups: HFD (control), HFD + linseed oil (LO), HFD + HIIT, HFD + HIIT + LO. In the HIIT groups, rats ran on a treadmill, 4 days.week-1. Erythrocyte n-3 PUFA content, body composition, inflammation, and intestinal mucosa-associated microbiota composition were assessed after 12 weeks. LO supplementation enhanced α-linolenic acid (ALA) to docosahexaenoic acid (DHA) conversion in erythrocytes, and HIIT potentiated this conversion. Compared with HFD, HIIT limited weight gain, fat mass accumulation, and adipocyte size, whereas LO reduced systemic inflammation. HIIT had the main effect on gut microbiota β-diversity, but the HIIT + LO association significantly increased Oscillospira relative abundance. In our conditions, HIIT had a major effect on body fat mass, whereas HIIT + LO improved ALA conversion to DHA and increased the abundance of Oscillospira bacteria in the microbiota.
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Abstract
Adipose, or fat, tissue (AT) was once considered an inert tissue that primarily existed to store lipids, and was not historically recognized as an important organ in the regulation and maintenance of health. With the rise of obesity and more rigorous research, AT is now recognized as a highly complex metabolic organ involved in a host of important physiological functions, including glucose homeostasis and a multitude of endocrine capabilities. AT dysfunction has been implicated in several disease states, most notably obesity, metabolic syndrome and type 2 diabetes. The study of AT has provided useful insight in developing strategies to combat these highly prevalent metabolic diseases. This review highlights the major functions of adipose tissue and the consequences that can occur when disruption of these functions leads to systemic metabolic dysfunction.
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Affiliation(s)
- Innocence Harvey
- Adipocyte Biology Laboratory, Pennington Biomedical Research Center, Baton Rouge, LA 70808, USA
| | - Anik Boudreau
- Adipocyte Biology Laboratory, Pennington Biomedical Research Center, Baton Rouge, LA 70808, USA
| | - Jacqueline M Stephens
- Adipocyte Biology Laboratory, Pennington Biomedical Research Center, Baton Rouge, LA 70808, USA.,Department of Biological Sciences, Louisiana State University, Baton Rouge, LA 70803, USA
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Dávalos-Salas M, Mariadason JM, Watt MJ, Montgomery MK. Molecular regulators of lipid metabolism in the intestine - Underestimated therapeutic targets for obesity? Biochem Pharmacol 2020; 178:114091. [PMID: 32535104 DOI: 10.1016/j.bcp.2020.114091] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2020] [Revised: 06/08/2020] [Accepted: 06/09/2020] [Indexed: 02/07/2023]
Abstract
The incidence of obesity and type 2 diabetes continues to rise across the globe necessitating the need to identify new therapeutic approaches to manage these diseases. In this review, we explore the potential for therapeutic interventions focussed on the intestinal epithelium, by targeting the role of this tissue in lipid uptake, lipid-mediated cross talk and lipid oxidation. We focus initially on ongoing strategies to manage obesity by targeting the essential role of the intestinal epithelium in lipid uptake, and in mediating tissue cross talk to regulate food intake. Subsequently, we explore a previously underestimated capacity of intestinal epithelial cells to oxidize fatty acids. In this context, we describe recent findings which have unveiled a key role for the peroxisome proliferator-activated receptor (PPAR) family of nuclear receptors and histone deacetylases (HDACs) in the regulation of lipid oxidation genes in enterocytes and how targeted genetic manipulation of these factors in enterocytes reduces weight gain, identifying intestinal PPARs and HDACs as potential therapeutic targets in the management of obesity.
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Affiliation(s)
- Mercedes Dávalos-Salas
- Olivia Newton John Cancer Research Institute, Melbourne, Victoria, Australia; La Trobe University School of Cancer Medicine, Melbourne, Victoria, Australia
| | - John M Mariadason
- Olivia Newton John Cancer Research Institute, Melbourne, Victoria, Australia; La Trobe University School of Cancer Medicine, Melbourne, Victoria, Australia
| | - Matthew J Watt
- Department of Physiology, Faculty of Medicine Dentistry and Health Sciences, University of Melbourne, Parkville, Victoria, Australia
| | - Magdalene K Montgomery
- Department of Physiology, Faculty of Medicine Dentistry and Health Sciences, University of Melbourne, Parkville, Victoria, Australia.
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Evans LW, Stratton MS, Ferguson BS. Dietary natural products as epigenetic modifiers in aging-associated inflammation and disease. Nat Prod Rep 2020; 37:653-676. [PMID: 31993614 PMCID: PMC7577396 DOI: 10.1039/c9np00057g] [Citation(s) in RCA: 40] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Covering: up to 2020Chronic, low-grade inflammation is linked to aging and has been termed "inflammaging". Inflammaging is considered a key contributor to the development of metabolic dysfunction and a broad spectrum of diseases or disorders including declines in brain and heart function. Genome-wide association studies (GWAS) coupled with epigenome-wide association studies (EWAS) have shown the importance of diet in the development of chronic and age-related diseases. Moreover, dietary interventions e.g. caloric restriction can attenuate inflammation to delay and/or prevent these diseases. Common themes in these studies entail the use of phytochemicals (plant-derived compounds) or the production of short chain fatty acids (SCFAs) as epigenetic modifiers of DNA and histone proteins. Epigenetic modifications are dynamically regulated and as such, serve as potential therapeutic targets for the treatment or prevention of age-related disease. In this review, we will focus on the role for natural products that include phytochemicals and short chain fatty acids (SCFAs) as regulators of these epigenetic adaptations. Specifically, we discuss regulators of methylation, acetylation and acylation, in the protection from chronic inflammation driven metabolic dysfunction and deterioration of neurocognitive and cardiac function.
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Affiliation(s)
- Levi W Evans
- Department of Nutrition, University of Nevada, Reno, NV 89557, USA.
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Shekarchizadeh-Esfahani P, Arab A, Ghaedi E, Hadi A, Jalili C. Effects of cardamom supplementation on lipid profile: A systematic review and meta-analysis of randomized controlled clinical trials. Phytother Res 2019; 34:475-485. [PMID: 31755188 DOI: 10.1002/ptr.6543] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2019] [Revised: 10/15/2019] [Accepted: 10/19/2019] [Indexed: 12/11/2022]
Abstract
Cardiovascular disease is a highly prevalent issue worldwide and one of its main manifestations, dyslipidemia, needs more attention. Recent studies have suggested that cardamom has favorable effects beyond lipid lowering, but the result are contradictory. Our objective was to conduct a systematic review and meta-analysis on randomized controlled trials (RCTs) that assessed the effect of cardamom on lipids. The search included PubMed, Scopus, ISI Web of Science, Google Scholar, and the Cochrane library (up to March, 2019) to identify RCTs investigating the effects of cardamom supplementation on serum lipid parameters. Weighted mean differences (WMDs) were pooled using a random-effect model. Meta-analysis of data from five eligible RCTs showed that cardamom supplementation did not significantly change the concentrations of total cholesterol (WMD: -6.11 mg/dl, 95% CI [-13.06, 0.83], I2 = 0.0%), low-density lipoprotein cholesterol (WMD: -4.31 mg/dl, 95% CI [-9.75, 1.13], I2 = 0.0%), or high-density lipoprotein cholesterol (WMD: 1.75 mg/dl, 95% CI [-1.95 to 5.46], I2 = 71.4%). However, a significant reduction was observed in serum triglyceride (TG; WMD: -20.55 mg/dl, 95% CI [-32.48, -8.63], I2 = 0.0%) levels after cardamom supplementation. Cardamom might be able to change TG, but for confirming the results, more studies exclusively on dyslipidemia patients and considering the intake of lipid lowering agents as exclusion criteria are necessary.
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Affiliation(s)
- Parivash Shekarchizadeh-Esfahani
- Department of General Courses, School of Management and Medical Information Sciences, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Arman Arab
- Department of Community Nutrition, School of Nutrition and Food Science, Food Security Research Center, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Ehsan Ghaedi
- Students' Scientific Research Center (SSRC), Tehran University of Medical Sciences (TUMS), Tehran, Iran.,Department of Cellular and Molecular Nutrition, School of Nutritional Sciences and Dietetics, Tehran University of Medical Sciences, Tehran, Iran
| | - Amir Hadi
- Halal Research Center of IRI, FDA, Tehran, Iran
| | - Cyrus Jalili
- Medical Biology Research Center, Health Technology Institute, Kermanshah University of Medical Sciences, Kermanshah, Iran
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Roth JD, Veidal SS, Fensholdt LKD, Rigbolt KTG, Papazyan R, Nielsen JC, Feigh M, Vrang N, Young M, Jelsing J, Adorini L, Hansen HH. Combined obeticholic acid and elafibranor treatment promotes additive liver histological improvements in a diet-induced ob/ob mouse model of biopsy-confirmed NASH. Sci Rep 2019; 9:9046. [PMID: 31227742 PMCID: PMC6588626 DOI: 10.1038/s41598-019-45178-z] [Citation(s) in RCA: 38] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2019] [Accepted: 05/29/2019] [Indexed: 12/13/2022] Open
Abstract
Obeticholic acid (OCA) and elafibranor (ELA) are selective and potent agonists for the farnesoid X receptor (FXR) and dual peroxisome proliferator-activated receptor α/δ (PPAR-α/δ), respectively. Both agents have demonstrated clinical efficacy in nonalcoholic steatohepatitis (NASH). The present study used OCA and ELA to compare the effects of mono- and combination therapies on metabolic and histological endpoints in Lepob/ob mice with established diet-induced and biopsy-confirmed NASH (ob/ob-NASH). ob/ob-NASH mice were fed the AMLN diet high in trans-fat, fructose and cholesterol for 15 weeks, whereafter they received vehicle, OCA (30 mg/kg, PO, QD), ELA (3, 10 mg/kg, PO, QD), or combinations (OCA + ELA) for eight weeks. Within-subject comparisons were performed on histomorphometric changes, including fractional area of liver fat, galectin-3 and Col1a1. OCA and ELA monotherapies improved all quantitative histopathological parameters and OCA + ELA combinations exerted additive effects on metabolic and histological endpoints. In agreement with their different molecular mechanisms of action, OCA and ELA monotherapies elicited distinct hepatic gene expression profiles and their combination led to profound transcriptome changes associated with further improvements in lipid handling and insulin signaling, suppression of immune responses and reduced extracellular matrix formation. In conclusion, these findings provide preclinical proof-of-concept for combined FXR and PPAR-α/δ agonist-based therapies in NASH.
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Affiliation(s)
| | | | | | | | | | | | | | | | - Mark Young
- Intercept Pharmaceuticals, San Diego, CA, USA
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Strand E, Lysne V, Grinna ML, Bohov P, Svardal A, Nygård O, Berge RK, Bjørndal B. Short-Term Activation of Peroxisome Proliferator-Activated Receptors α and γ Induces Tissue-Specific Effects on Lipid Metabolism and Fatty Acid Composition in Male Wistar Rats. PPAR Res 2019; 2019:8047627. [PMID: 31308847 PMCID: PMC6594300 DOI: 10.1155/2019/8047627] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2019] [Revised: 04/28/2019] [Accepted: 05/19/2019] [Indexed: 12/11/2022] Open
Abstract
Dietary fatty acids (FAs) affect certain metabolic routes, including pathways controlled by the peroxisome proliferator-activated receptors (PPARs), but tissue-specific effects are not well-defined. Thus, the aim was to compare the metabolic response in hepatic, adipose, and cardiac tissues after treatment with specific PPAR agonists. Male Wistar rats were randomized into three groups: a control group receiving placebo (n=8); a PPARα agonist group receiving WY-14,643 (n=6); and a PPARγ agonist group receiving rosiglitazone (n=6) for 12 days. All animals received a low-fat standard chow diet and were given a daily dose of placebo or agonist orally. Lipids and FA methyl esters were measured in plasma, liver, and heart and gene expression was measured in liver and adipose tissue, while enzyme activities were measured in liver. Treatment with the PPARα agonist was associated with higher liver mass relative to body weight (liver index), lower plasma, and hepatic total cholesterol, as well as lower plasma carnitine and acylcarnitines, compared with control. In heart, PPARα activation leads to overall lower levels of free FAs and specific changes in certain FAs, compared with control. Furthermore, β-oxidation in liver and the enzymatic activities of well-known PPARα targeted genes were higher following PPARα administration. Overall, rats treated with the PPARα agonist had higher hepatic saturated FAs (SFAs) and monounsaturated FAs (MUFAs) and lower n-6 and n-3 PUFAs, compared to control. Treatment with the PPARγ agonist was associated with a lower liver index, lower plasma triglycerides (TAG) and phospholipids, and higher hepatic phospholipids, compared with control. PPARγ target genes were increased specifically in adipose tissue. Moreover, lower total cardiac FAs and SFA and higher cardiac n-6 PUFA were also associated with PPARγ activation. Altogether, there were characteristic effects of PPARα activation in liver and heart, as well as in plasma. PPARγ effects were not only confined to adipose tissue, but specific effects were also seen in liver, heart, and plasma. In conclusion, short-term treatment with PPAR agonists induced tissue-specific effects on FA composition in liver and heart. Moreover, both PPARα and PPARγ activation lowered plasma TAG and phospholipids, most likely through effects on liver and adipose tissue, respectively. In future studies we aim to reveal whether similar patterns can be found through diet-induced activation of specific pathways.
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Affiliation(s)
- Elin Strand
- Department of Clinical Science, University of Bergen, Bergen, Norway
- Department of Immunology and Transfusion Medicine, Haukeland University Hospital, Bergen, Norway
| | - Vegard Lysne
- Centre for Nutrition, Department of Clinical Science, University of Bergen, Bergen, Norway
| | | | - Pavol Bohov
- Department of Clinical Science, University of Bergen, Bergen, Norway
| | - Asbjørn Svardal
- Department of Clinical Science, University of Bergen, Bergen, Norway
| | - Ottar Nygård
- Department of Heart Disease, Haukeland University Hospital, Bergen, Norway
- Mohn Nutrition Research Laboratory, Department of Clinical Science, University of Bergen, Bergen, Norway
| | - Rolf K. Berge
- Department of Clinical Science, University of Bergen, Bergen, Norway
- Department of Heart Disease, Haukeland University Hospital, Bergen, Norway
| | - Bodil Bjørndal
- Department of Clinical Science, University of Bergen, Bergen, Norway
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Aghasi M, Koohdani F, Qorbani M, Nasli-Esfahani E, Ghazi-Zahedi S, Khoshamal H, Keshavarz A, Sotoudeh G. Beneficial effects of green cardamom on serum SIRT1, glycemic indices and triglyceride levels in patients with type 2 diabetes mellitus: a randomized double-blind placebo controlled clinical trial. JOURNAL OF THE SCIENCE OF FOOD AND AGRICULTURE 2019; 99:3933-3940. [PMID: 30701554 DOI: 10.1002/jsfa.9617] [Citation(s) in RCA: 29] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/17/2018] [Revised: 01/18/2019] [Accepted: 01/26/2019] [Indexed: 06/09/2023]
Abstract
BACKGROUND Cardamom has antioxidant and anti-inflammatory effects which may help to remedy diseases. Studies on the health benefits of cardamom in diabetic patients are very limited. Thus, this study is designed to determine the effect of cardamom supplementation on blood lipids and glycemic indices in type 2 diabetic patients. To investigate the mechanism of cardamom effect on blood glucose and lipid levels, serum sirtuin-1 (SIRT1) was assessed. RESULTS In a parallel, double-blind randomized, placebo-controlled clinical trial, 83 overweight or obese type 2 diabetic patients were randomly allocated into an intervention (n = 41) or a control group (n = 42). The intervention and the placebo group received 3 g of green cardamom or rusk powder, respectively for 10 weeks. Physical activity level, dietary intake, anthropometric measurements (weight, height and waist circumference), glycemic indices [glucose, insulin, hemoglobin A1c (HbA1c)], blood lipids [triglyceride (TG), total cholesterol (TC), high-density lipoprotein cholesterol (HDL-c) and low-density lipoprotein cholesterol (LDL-c)] and SIRT1 levels were measured. Body mass index and homeostasis model assessment as an index of insulin resistance (HOMA-IR) were calculated before and after intervention. Compared to the control group, a significant decrease in serum HbA1C (-0.4%), insulin (-2.8 µIU dL-1 ), HOMA-IR (-1.7) and TG (-39.9 mg dL-1 ), and an increase in SIRT1 (2.3 ng mL-1 ) was observed in cardamom group. There were no significant changes in serum TC, HDL-c and LDL-c levels between the two groups before and after adjustment for potential confounders including glyclaside dose, duration of disease and weight. CONCLUSION Our results showed that cardamom can decrease HbA1c, insulin level, HOMA-IR and TG level via increase in SIRT1 concentration in type 2 diabetes mellitus patients. © 2019 Society of Chemical Industry.
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Affiliation(s)
- Mohadeseh Aghasi
- Department of Community Nutrition, School of Nutritional Sciences and Dietetics, Tehran University of Medical Sciences, Tehran, Iran
| | - Fariba Koohdani
- Department of Cellular and Molecular Nutrition, School of Nutritional Sciences and Dietetics, Tehran University of Medical Sciences, Tehran, Iran
| | - Mostafa Qorbani
- Non-communicable Disease Research Center, Alborz University of Medical Sciences, Karaj, Iran
| | - Ensieh Nasli-Esfahani
- Diabetes Research Center, Endocrinology and Metabolism Clinical Sciences Institute, Tehran University of Medical Sciences, Tehran, Iran
| | - Shohreh Ghazi-Zahedi
- Department of Community Nutrition, School of Nutritional Sciences and Dietetics, Tehran University of Medical Sciences, Tehran, Iran
| | - Hoorieh Khoshamal
- Department of Community Nutrition, School of Nutritional Sciences and Dietetics, Tehran University of Medical Sciences, Tehran, Iran
| | - Ali Keshavarz
- Department of Clinical Nutrition, School of Nutritional Sciences and Dietetics, Tehran University of Medical Sciences, Tehran, Iran
| | - Gity Sotoudeh
- Department of Community Nutrition, School of Nutritional Sciences and Dietetics, Tehran University of Medical Sciences, Tehran, Iran
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Choudhary NS, Kumar N, Duseja A. Peroxisome Proliferator-Activated Receptors and Their Agonists in Nonalcoholic Fatty Liver Disease. J Clin Exp Hepatol 2019; 9:731-739. [PMID: 31889755 PMCID: PMC6926194 DOI: 10.1016/j.jceh.2019.06.004] [Citation(s) in RCA: 53] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/23/2019] [Accepted: 06/23/2019] [Indexed: 02/06/2023] Open
Abstract
Nonalcoholic fatty liver disease (NAFLD) is one of the most common liver diseases worldwide. In addition to the liver-related morbidity and mortality, NAFLD is now also associated with various extrahepatic diseases. Pathogenesis of NAFLD is multifactorial with limited pharmacotherapy options for the treatment of patients with NAFLD. Peroxisome proliferator-activated receptors (PPARs) are ligand-activated transcription factors that are involved in the transcriptional regulation of lipid metabolism, glucose homeostasis, energy balance, inflammation, and atherosclerosis. PPAR agonists are attractive options for treatment of NAFLD as they can act at multiple targets involved in the pathogenesis of NAFLD. We reviewed the available literature on the pathophysiological role of PPARs and use of PPAR agonists in the treatment of NAFLD. Original studies and review articles available on PubMed regarding the role of PPARs in the pathogenesis and utility of PPAR agonists in the treatment of NAFLD were included in this review article. ClinicalTrials.gov and Clinical Trials Registry-India sites were searched for ongoing studies on saroglitazar. The available literature suggests that PPARs play an important role in the pathogenesis of NAFLD. Use of PPAR gamma agonists is associated with histological improvement in NAFLD. Dual PPAR agonists with no or minimal PPAR gamma activity are being explored in the treatment of NAFLD. Because of the pathophysiological role of PPARs in NAFLD, PPAR agonists are attractive options for the treatment of patients with NAFLD. Dual PPAR agonists without significant gamma activity appear promising for the treatment of NAFLD.
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Affiliation(s)
- Narendra S. Choudhary
- Institute of Liver Transplantation and Regenerative Medicine, Medanta the Medicity, Gurugram, India
| | | | - Ajay Duseja
- Department of Hepatology, Postgraduate Institute of Medical Education and Research, Chandigarh, India,Address for correspondence: Dr. Ajay Duseja MD, DM, FAMS, FAASLD, FACG, FSGEI Professor, Department of Hepatology, Sector 12, Postgraduate Institute of Medical Education and Research, Chandigarh, 160012, India.
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Oliveira GB, Regitano LCA, Cesar ASM, Reecy JM, Degaki KY, Poleti MD, Felício AM, Koltes JE, Coutinho LL. Integrative analysis of microRNAs and mRNAs revealed regulation of composition and metabolism in Nelore cattle. BMC Genomics 2018; 19:126. [PMID: 29415651 PMCID: PMC5804041 DOI: 10.1186/s12864-018-4514-3] [Citation(s) in RCA: 29] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2016] [Accepted: 01/31/2018] [Indexed: 01/01/2023] Open
Abstract
BACKGROUND The amount of intramuscular fat can influence the sensory characteristics and nutritional value of beef, thus the selection of animals with adequate fat deposition is important to the consumer. There is growing knowledge about the genes and pathways that control the biological processes involved in fat deposition in muscle. MicroRNAs (miRNAs) belong to a well-conserved class of non-coding small RNAs that modulate gene expression across a range of biological functions in animal development and physiology. The aim of this study was to identify differentially expressed (DE) miRNAs, regulatory candidate genes and co-expression networks related to intramuscular fat (IMF) deposition. To achieve this, we used mRNA and miRNA expression data from the Longissimus dorsi muscle of 30 Nelore steers with high (H) and low (L) genomic estimated breeding values (GEBV) for IMF deposition. RESULTS Differential miRNA expression analysis between animals with extreme GEBV values for IMF identified six DE miRNAs (FDR 10%). Functional annotation of the target genes for these microRNAs indicated that the PPARs signaling pathway is involved with IMF deposition. Candidate regulatory genes such as SDHAF4, FBXO17, ALDOA and PKM were identified by partial correlation with information theory (PCIT), phenotypic impact factor (PIF) and regulatory impact factor (RIF) co-expression approaches from integrated miRNA-mRNA expression data. Two DE miRNAs (FDR 10%), bta-miR-143 and bta-miR-146b, which were upregulated in the Low IMF group, were correlated with regulatory candidate genes, which were functionally enriched for fatty acid oxidation GO terms. Co-expression patterns obtained by weighted correlation network analysis (WGCNA), which showed possible interaction and regulation between mRNAs and miRNAs, identified several modules related to immune system function, protein metabolism, energy metabolism and glucose catabolism according to in silico analysis performed herein. CONCLUSION In this study, several genes and miRNAs were identified as candidate regulators of IMF by analyzing DE miRNAs using two different miRNA-mRNA co-expression network methods. This study contributes to the understanding of potential regulatory mechanisms of gene signaling networks involved in fat deposition processes measured in muscle. Glucose metabolism and inflammation processes were the main pathways found in silico to influence intramuscular fat deposition in beef cattle in the integrative mRNA-miRNA co-expression analysis.
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Affiliation(s)
- Gabriella B. Oliveira
- Department of Animal Science, University of São Paulo, Piracicaba, SP 13418-900 Brazil
| | | | - Aline S. M. Cesar
- Department of Animal Science, University of São Paulo, Piracicaba, SP 13418-900 Brazil
| | - James M. Reecy
- Department of Animal Science, Iowa State University, Ames, IA 50011 USA
| | - Karina Y. Degaki
- Department of Animal Science, University of São Paulo, Piracicaba, SP 13418-900 Brazil
| | - Mirele D. Poleti
- Department of Animal Science, University of São Paulo, Piracicaba, SP 13418-900 Brazil
| | - Andrezza M. Felício
- Department of Animal Science, University of São Paulo, Piracicaba, SP 13418-900 Brazil
| | - James E. Koltes
- Department of Animal Science, University of Arkansas, Fayetteville, AR 72701 USA
| | - Luiz L. Coutinho
- Department of Animal Science, University of São Paulo, Piracicaba, SP 13418-900 Brazil
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Differential actions of PPAR-α and PPAR-β/δ on beige adipocyte formation: A study in the subcutaneous white adipose tissue of obese male mice. PLoS One 2018; 13:e0191365. [PMID: 29351550 PMCID: PMC5774787 DOI: 10.1371/journal.pone.0191365] [Citation(s) in RCA: 36] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2017] [Accepted: 01/03/2018] [Indexed: 12/18/2022] Open
Abstract
Background and aims Obesity compromises adipocyte physiology. PPARs are essential to adipocyte plasticity, but its isolated role in the browning phenomenon is not clear. This study aimed to examine whether activation of PPAR-α or PPAR-β/δ could induce beige cell depots in the subcutaneous white adipose tissue of diet-induced obese mice. Material and methods Sixty animals were randomly assigned to receive a control diet (C, 10% lipids) or a high-fat diet (HF, 50% lipids) for ten weeks. Then each group was re-divided to begin the treatments that lasted 4 weeks, totalizing six groups: C, C-α (C plus PPAR-α agonist, 2.5 mg/kg BM), C-β (C plus PPAR-β/δ agonist, 1 mg/kg BM), HF, HF-α (HF plus PPAR-α agonist), HF-β (HF plus PPAR-β/δ agonist). Results HF animals presented with overweight, glucose intolerance and subcutaneous white adipocyte hypertrophy. Both treatments significantly attenuated these parameters. Browning, verified by UCP1 positive beige cells and enhanced body temperature, was just observed in PPAR-α treated groups. PPAR-α agonism also elicited an enhanced gene expression of the thermogenesis effector UCP1, the beige-selective gene TMEM26 and the PRDM16, an essential gene for brown-like phenotype maintenance in the beige adipocytes when compared to their counterparts. The enhanced CIDEA and the reduced UCP1 gene levels might justify the white phenotype predominance after the treatment with the PPAR-β/δ agonist. Conclusions This work provides evidence that the PPAR-β/δ agonist ameliorated metabolic disorders through enhanced beta-oxidation and better tolerance to glucose, whereas the PPAR-α agonism was confirmed as a promising therapeutic target for treating metabolic diseases via beige cell induction and enhanced thermogenesis.
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19
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Tølbøl KS, Kristiansen MNB, Hansen HH, Veidal SS, Rigbolt KTG, Gillum MP, Jelsing J, Vrang N, Feigh M. Metabolic and hepatic effects of liraglutide, obeticholic acid and elafibranor in diet-induced obese mouse models of biopsy-confirmed nonalcoholic steatohepatitis. World J Gastroenterol 2018; 24:179-194. [PMID: 29375204 PMCID: PMC5768937 DOI: 10.3748/wjg.v24.i2.179] [Citation(s) in RCA: 105] [Impact Index Per Article: 15.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/25/2017] [Revised: 11/24/2017] [Accepted: 12/04/2017] [Indexed: 02/06/2023] Open
Abstract
AIM To evaluate the pharmacodynamics of compounds in clinical development for nonalcoholic steatohepatitis (NASH) in obese mouse models of biopsy-confirmed NASH.
METHODS Male wild-type C57BL/6J mice (DIO-NASH) and Lepob/ob (ob/ob-NASH) mice were fed a diet high in trans-fat (40%), fructose (20%) and cholesterol (2%) for 30 and 21 wk, respectively. Prior to treatment, all mice underwent liver biopsy for confirmation and stratification of liver steatosis and fibrosis, using the nonalcoholic fatty liver disease activity score (NAS) and fibrosis staging system. The mice were kept on the diet and received vehicle, liraglutide (0.2 mg/kg, SC, BID), obeticholic acid (OCA, 30 mg/kg PO, QD), or elafibranor (30 mg/kg PO, QD) for eight weeks. Within-subject comparisons were performed on changes in steatosis, inflammation, ballooning degeneration, and fibrosis scores. In addition, compound effects were evaluated by quantitative liver histology, including percent fractional area of liver fat, galectin-3, and collagen 1a1.
RESULTS Liraglutide and elafibranor, but not OCA, reduced body weight in both models. Liraglutide improved steatosis scores in DIO-NASH mice only. Elafibranor and OCA reduced histopathological scores of hepatic steatosis and inflammation in both models, but only elafibranor reduced fibrosis severity. Liraglutide and OCA reduced total liver fat, collagen 1a1, and galectin-3 content, driven by significant reductions in liver weight. The individual drug effects on NASH histological endpoints were supported by global gene expression (RNA sequencing) and liver lipid biochemistry.
CONCLUSION DIO-NASH and ob/ob-NASH mouse models show distinct treatment effects of liraglutide, OCA, and elafibranor, being in general agreement with corresponding findings in clinical trials for NASH. The present data therefore further supports the clinical translatability and utility of DIO-NASH and ob/ob-NASH mouse models of NASH for probing the therapeutic efficacy of compounds in preclinical drug development for NASH.
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Affiliation(s)
- Kirstine S Tølbøl
- Gubra Aps, Hørsholm DK-2970, Denmark
- Department of Biomedical Sciences, Faculty of Health Sciences, University of Copenhagen, Copenhagen DK-2200, Denmark
- Section for Metabolic Imaging and Liver Metabolism, The Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health Sciences, University of Copenhagen, Copenhagen DK-2200, Denmark
| | - Maria NB Kristiansen
- Gubra Aps, Hørsholm DK-2970, Denmark
- Department of Biomedical Sciences, Faculty of Health Sciences, University of Copenhagen, Copenhagen DK-2200, Denmark
| | | | | | | | - Matthew P Gillum
- Section for Metabolic Imaging and Liver Metabolism, The Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health Sciences, University of Copenhagen, Copenhagen DK-2200, Denmark
| | | | - Niels Vrang
- Gubra Aps, Hørsholm DK-2970, Denmark
- Department of Chemistry, Faculty of Science, University of Copenhagen, Copenhagen DK-2200, Denmark
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Gellrich L, Merk D. Therapeutic Potential of Peroxisome Proliferator-Activated Receptor Modulation in Non-Alcoholic Fatty Liver Disease and Non-Alcoholic Steatohepatitis. NUCLEAR RECEPTOR RESEARCH 2017. [DOI: 10.11131/2017/101310] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
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21
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Silveira LS, Pimentel GD, Souza CO, Biondo LA, Teixeira AAS, Lima EA, Batatinha HAP, Rosa Neto JC, Lira FS. Effect of an acute moderate-exercise session on metabolic and inflammatory profile of PPAR-α knockout mice. Cell Biochem Funct 2017; 35:510-517. [DOI: 10.1002/cbf.3308] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2017] [Revised: 06/23/2017] [Accepted: 09/17/2017] [Indexed: 11/05/2022]
Affiliation(s)
- Loreana S. Silveira
- Exercise and Immunometabolism Research Group, Department of Physical Education; Universidade Estadual Paulista; Presidente Prudente SP Brazil
| | - Gustavo D. Pimentel
- Clinical and Sports Nutrition Research Laboratory (Labince); Nutrition Faculty (FANUT)-Federal University of Goiás (UFG); Goiânia GO Brazil
| | - Camila O. Souza
- Immunometabolism Research Group, Institute of Biomedical Sciences; University of São Paulo (USP); São Paulo SP Brazil
| | - Luana A. Biondo
- Immunometabolism Research Group, Institute of Biomedical Sciences; University of São Paulo (USP); São Paulo SP Brazil
| | - Alexandre Abílio S. Teixeira
- Immunometabolism Research Group, Institute of Biomedical Sciences; University of São Paulo (USP); São Paulo SP Brazil
| | - Edson A. Lima
- Immunometabolism Research Group, Institute of Biomedical Sciences; University of São Paulo (USP); São Paulo SP Brazil
| | - Helena A. P. Batatinha
- Immunometabolism Research Group, Institute of Biomedical Sciences; University of São Paulo (USP); São Paulo SP Brazil
| | - José C. Rosa Neto
- Immunometabolism Research Group, Institute of Biomedical Sciences; University of São Paulo (USP); São Paulo SP Brazil
| | - Fábio S. Lira
- Exercise and Immunometabolism Research Group, Department of Physical Education; Universidade Estadual Paulista; Presidente Prudente SP Brazil
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High Fat Diet with a High Monounsaturated Fatty Acid and Polyunsaturated/Saturated Fatty Acid Ratio Suppresses Body Fat Accumulation and Weight Gain in Obese Hamsters. Nutrients 2017; 9:nu9101148. [PMID: 29048361 PMCID: PMC5691764 DOI: 10.3390/nu9101148] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2017] [Revised: 10/07/2017] [Accepted: 10/16/2017] [Indexed: 12/11/2022] Open
Abstract
The aim of this study was to investigate the effect of a high fat diet with experimental oil consisting of 60% MUFAs (monounsaturated fatty acids) with a P/S ratio of 5 on fat deposition and lipid metabolism in obese hamsters. Hamsters were randomly assigned to a control group and a diet-induced obesity group for nine weeks. Then an additional eight-week experimental period began, during which obese hamsters were randomly divided into three groups and fed different amounts of the experimental oil mixture in their diets as follows: 5%, 15%, and 20% w/w (OB-M5, OB-M15, and OB-M20 groups, respectively). The results showed that the OB-M15 and OB-M20 groups had significantly lower blood cholesterol and higher insulin levels. Compared to the control group, the three obese groups exhibited higher hepatic fatty acid synthase activity; however, the acyl-CoA oxidase activities were also enhanced. Although dietary fat content differed, there were no differences in energy intake, final body weights, and epididymal fat weights among the four groups. These results suggest that regardless of whether the specimens had a high fat intake or not, dietary fat containing high MUFAs with a high P/S ratio had beneficial effects on maintaining blood lipid profiles and may not result in body fat accumulation in obese hamsters, possibly by promoting lipolytic enzyme activities.
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Duteil D, Tosic M, Schüle R. Lsd1, a metabolic sensor of environment requirements that prevents adipose tissue from aging. Adipocyte 2017; 6:298-303. [PMID: 28700271 DOI: 10.1080/21623945.2017.1345831] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/28/2022] Open
Abstract
Understanding development and maintenance of beige adipocytes provide exciting insights in establishing novel therapies against obesity and obesity-associated disorders. Lysine-specific demethylase 1 (Lsd1) is an epigenetic eraser required for differentiation and function of adipocytes. Lsd1 is involved in early commitment of preadipocytes, but dispensable for terminal differentiation of white adipose tissue (WAT). In mature adipocytes, Lsd1 responds to different environmental stimuli to alter metabolic function and enable proper thermogenic and oxidative response. Exposure to cold leads to Lsd1 upregulation and subsequent beiging of WAT. Oppositely, Lsd1 levels decline during aging resulting in a conversion of beige into white adipocytes, associated with loss of thermogenic properties of WAT. Lsd1 maintains beige adipocytes by controlling the expression of the nuclear receptor peroxisome proliferator-activated receptor α. In summary, our studies not only provided insights into the mechanism of age-related beige-to-white adipocyte transition, but also established Lsd1 as a sensor that enables thermogenic response in WAT.
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Affiliation(s)
- Delphine Duteil
- Urologische Klinik und Zentrale Klinische Forschung, Klinikum der Universität Freiburg, Freiburg, Germany
| | - Milica Tosic
- Urologische Klinik und Zentrale Klinische Forschung, Klinikum der Universität Freiburg, Freiburg, Germany
| | - Roland Schüle
- Urologische Klinik und Zentrale Klinische Forschung, Klinikum der Universität Freiburg, Freiburg, Germany
- BIOSS Centre of Biological Signalling Studies, Albert-Ludwigs-University, Freiburg, Germany
- Deutsche Konsortium für Translationale Krebsforschung (DKTK), Standort Freiburg, Germany
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Chen Z, Zhang Y, Guo L, Dosoky N, de Ferra L, Peters S, Niswender KD, Davies SS. Leptogenic effects of NAPE require activity of NAPE-hydrolyzing phospholipase D. J Lipid Res 2017; 58:1624-1635. [PMID: 28596183 DOI: 10.1194/jlr.m076513] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2017] [Revised: 06/04/2017] [Indexed: 12/21/2022] Open
Abstract
Food intake induces synthesis of N-acylphosphatidylethanolamines (NAPEs) in the intestinal tract. While NAPEs exert leptin-like (leptogenic) effects, including reduced weight gain and food intake, the mechanisms by which NAPEs induce these leptogenic effects remain unclear. One key question is whether intestinal NAPEs act directly on cognate receptors or first require conversion to N-acylethanolamides (NAEs) by NAPE-hydrolyzing phospholipase D (NAPE-PLD). Previous studies using Nape-pld-/- mice were equivocal because intraperitoneal injection of NAPEs led to nonspecific aversive effects. To avoid the aversive effects of injection, we delivered NAPEs and NAEs intestinally using gut bacteria synthesizing these compounds. Unlike in wild-type mice, increasing intestinal levels of NAPE using NAPE-synthesizing bacteria in Nape-pld-/- mice failed to reduce food intake and weight gain or alter gene expression. In contrast, increasing intestinal NAE levels in Nape-pld-/- mice using NAE-synthesizing bacteria induced all of these effects. These NAE-synthesizing bacteria also markedly increased NAE levels and decreased inflammatory gene expression in omental adipose tissue. These results demonstrate that intestinal NAPEs require conversion to NAEs by the action of NAPE-PLD to exert their various leptogenic effects, so that the reduced intestinal NAPE-PLD activity found in obese subjects may directly contribute to excess food intake and obesity.
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Affiliation(s)
- Zhongyi Chen
- Division of Clinical Pharmacology, Vanderbilt University, Nashville, TN
| | - Yongqin Zhang
- Division of Clinical Pharmacology, Vanderbilt University, Nashville, TN
| | - Lilu Guo
- Division of Clinical Pharmacology, Vanderbilt University, Nashville, TN
| | - Noura Dosoky
- Division of Clinical Pharmacology, Vanderbilt University, Nashville, TN
| | | | | | - Kevin D Niswender
- Veterans Administration Tennessee Valley Healthcare System, Nashville, TN; Division of Diabetes, Endocrinology, and Metabolism, Department of Medicine, Vanderbilt University, Nashville, TN; Department of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, TN
| | - Sean S Davies
- Division of Clinical Pharmacology, Vanderbilt University, Nashville, TN; Department of Pharmacology, Vanderbilt University, Nashville, TN; Vanderbilt Institute for Chemical Biology, Vanderbilt University, Nashville, TN.
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Hsu WCJ, Wildburger NC, Haidacher SJ, Nenov MN, Folorunso O, Singh AK, Chesson BC, Franklin WF, Cortez I, Sadygov RG, Dineley KT, Rudra JS, Taglialatela G, Lichti CF, Denner L, Laezza F. PPARgamma agonists rescue increased phosphorylation of FGF14 at S226 in the Tg2576 mouse model of Alzheimer's disease. Exp Neurol 2017; 295:1-17. [PMID: 28522250 DOI: 10.1016/j.expneurol.2017.05.005] [Citation(s) in RCA: 28] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2017] [Revised: 04/13/2017] [Accepted: 05/13/2017] [Indexed: 12/13/2022]
Abstract
BACKGROUND Cognitive impairment in humans with Alzheimer's disease (AD) and in animal models of Aβ-pathology can be ameliorated by treatments with the nuclear receptor peroxisome proliferator-activated receptor-gamma (PPARγ) agonists, such as rosiglitazone (RSG). Previously, we demonstrated that in the Tg2576 animal model of AD, RSG treatment rescued cognitive deficits and reduced aberrant activity of granule neurons in the dentate gyrus (DG), an area critical for memory formation. METHODS We used a combination of mass spectrometry, confocal imaging, electrophysiology and split-luciferase assay and in vitro phosphorylation and Ingenuity Pathway Analysis. RESULTS Using an unbiased, quantitative nano-LC-MS/MS screening, we searched for potential molecular targets of the RSG-dependent rescue of DG granule neurons. We found that S226 phosphorylation of fibroblast growth factor 14 (FGF14), an accessory protein of the voltage-gated Na+ (Nav) channels required for neuronal firing, was reduced in Tg2576 mice upon treatment with RSG. Using confocal microscopy, we confirmed that the Tg2576 condition decreased PanNav channels at the AIS of the DG, and that RSG treatment of Tg2576 mice reversed the reduction in PanNav channels. Analysis from previously published data sets identified correlative changes in action potential kinetics in RSG-treated T2576 compared to untreated and wildtype controls. In vitro phosphorylation and mass spectrometry confirmed that the multifunctional kinase GSK-3β, a downstream target of insulin signaling highly implicated in AD, phosphorylated FGF14 at S226. Assembly of the FGF14:Nav1.6 channel complex and functional regulation of Nav1.6-mediated currents by FGF14 was impaired by a phosphosilent S226A mutation. Bioinformatics pathway analysis of mass spectrometry and biochemistry data revealed a highly interconnected network encompassing PPARγ, FGF14, SCN8A (Nav 1.6), and the kinases GSK-3 β, casein kinase 2β, and ERK1/2. CONCLUSIONS These results identify FGF14 as a potential PPARγ-sensitive target controlling Aβ-induced dysfunctions of neuronal activity in the DG underlying memory loss in early AD.
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Affiliation(s)
- Wei-Chun J Hsu
- Department of Pharmacology & Toxicology, University of Texas Medical Branch, 301 University Blvd, Galveston, TX 77555, United States; Biochemistry and Molecular Biology Graduate Program, Graduate School of Biomedical Sciences, University of Texas Medical Branch, 301 University Blvd, Galveston, TX 77555, United States; M.D./Ph.D. Combined Degree Program, Graduate School of Biomedical Sciences, University of Texas Medical Branch, 301 University Blvd, Galveston, TX 77555, United States
| | - Norelle C Wildburger
- Department of Pharmacology & Toxicology, University of Texas Medical Branch, 301 University Blvd, Galveston, TX 77555, United States; Neuroscience Graduate Program, Graduate School of Biomedical Sciences, University of Texas Medical Branch, 301 University Blvd, Galveston, TX 77555, United States; Department of Neurology, Washington University School of Medicine, 660 S. Euclid Avenue, St. Louis, MO 63110, United States
| | - Sigmund J Haidacher
- Department of Internal Medicine, University of Texas Medical Branch, 301 University Blvd, Galveston, TX 77555, United States
| | - Miroslav N Nenov
- Department of Pharmacology & Toxicology, University of Texas Medical Branch, 301 University Blvd, Galveston, TX 77555, United States; Mitchell Center for Neurodegenerative Diseases, University of Texas Medical Branch, 301 University Blvd, Galveston, TX 77555, United States
| | - Oluwarotimi Folorunso
- Department of Pharmacology & Toxicology, University of Texas Medical Branch, 301 University Blvd, Galveston, TX 77555, United States
| | - Aditya K Singh
- Department of Pharmacology & Toxicology, University of Texas Medical Branch, 301 University Blvd, Galveston, TX 77555, United States
| | - Brent C Chesson
- Department of Pharmacology & Toxicology, University of Texas Medical Branch, 301 University Blvd, Galveston, TX 77555, United States
| | - Whitney F Franklin
- Neuroscience Graduate Program, Graduate School of Biomedical Sciences, University of Texas Medical Branch, 301 University Blvd, Galveston, TX 77555, United States; Department of Neurology, University of Texas Medical Branch, 301 University Blvd, Galveston, TX 77555, United States; Mitchell Center for Neurodegenerative Diseases, University of Texas Medical Branch, 301 University Blvd, Galveston, TX 77555, United States
| | - Ibdanelo Cortez
- Neuroscience Graduate Program, Graduate School of Biomedical Sciences, University of Texas Medical Branch, 301 University Blvd, Galveston, TX 77555, United States; Mitchell Center for Neurodegenerative Diseases, University of Texas Medical Branch, 301 University Blvd, Galveston, TX 77555, United States
| | - Rovshan G Sadygov
- Biochemistry and Molecular Biology Graduate Program, Graduate School of Biomedical Sciences, University of Texas Medical Branch, 301 University Blvd, Galveston, TX 77555, United States; Sealy Center for Molecular Medicine, University of Texas Medical Branch, 301 University Blvd, Galveston, TX 77555, United States
| | - Kelly T Dineley
- Mitchell Center for Neurodegenerative Diseases, University of Texas Medical Branch, 301 University Blvd, Galveston, TX 77555, United States; Department of Neurology, University of Texas Medical Branch, 301 University Blvd, Galveston, TX 77555, United States; Center for Addiction Research, University of Texas Medical Branch, 301 University Blvd, Galveston, TX 77555, United States
| | - Jay S Rudra
- Department of Pharmacology & Toxicology, University of Texas Medical Branch, 301 University Blvd, Galveston, TX 77555, United States
| | - Giulio Taglialatela
- Mitchell Center for Neurodegenerative Diseases, University of Texas Medical Branch, 301 University Blvd, Galveston, TX 77555, United States; Department of Neurology, University of Texas Medical Branch, 301 University Blvd, Galveston, TX 77555, United States
| | - Cheryl F Lichti
- Department of Pharmacology & Toxicology, University of Texas Medical Branch, 301 University Blvd, Galveston, TX 77555, United States
| | - Larry Denner
- Sealy Center for Molecular Medicine, University of Texas Medical Branch, 301 University Blvd, Galveston, TX 77555, United States; Department of Internal Medicine, University of Texas Medical Branch, 301 University Blvd, Galveston, TX 77555, United States; Mitchell Center for Neurodegenerative Diseases, University of Texas Medical Branch, 301 University Blvd, Galveston, TX 77555, United States; Center for Addiction Research, University of Texas Medical Branch, 301 University Blvd, Galveston, TX 77555, United States
| | - Fernanda Laezza
- Department of Pharmacology & Toxicology, University of Texas Medical Branch, 301 University Blvd, Galveston, TX 77555, United States; Mitchell Center for Neurodegenerative Diseases, University of Texas Medical Branch, 301 University Blvd, Galveston, TX 77555, United States; Center for Addiction Research, University of Texas Medical Branch, 301 University Blvd, Galveston, TX 77555, United States; Center for Biomedical Engineering, University of Texas Medical Branch, 301 University Blvd, Galveston, TX 77555, United States.
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Abstract
Aging is accompanied by major changes in adipose tissue distribution and function. In particular, with time, thermogenic-competent beige adipocytes progressively gain a white adipocyte morphology. However, the mechanisms controlling the age-related transition of beige adipocytes to white adipocytes remain unclear. Lysine-specific demethylase 1 (Lsd1) is an epigenetic eraser enzyme positively regulating differentiation and function of adipocytes. Here we show that Lsd1 levels decrease in aging inguinal white adipose tissue concomitantly with beige fat cell decline. Accordingly, adipocyte-specific increase of Lsd1 expression is sufficient to rescue the age-related transition of beige adipocytes to white adipocytes in vivo, whereas loss of Lsd1 precipitates it. Lsd1 maintains beige adipocytes by controlling the expression of peroxisome proliferator-activated receptor α (Ppara), and treatment with a Ppara agonist is sufficient to rescue the loss of beige adipocytes caused by Lsd1 ablation. In summary, our data provide insights into the mechanism controlling the age-related beige-to-white adipocyte transition and identify Lsd1 as a regulator of beige fat cell maintenance.
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Tan CK, Zhuang Y, Wahli W. Synthetic and natural Peroxisome Proliferator-Activated Receptor (PPAR) agonists as candidates for the therapy of the metabolic syndrome. Expert Opin Ther Targets 2017; 21:333-348. [PMID: 28092722 DOI: 10.1080/14728222.2017.1280467] [Citation(s) in RCA: 53] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
INTRODUCTION Peroxisome proliferator-activated receptors (PPARs) are the molecular targets of hypolipidemic and insulin-sensitizing drugs and implicated in a multitude of processes that fine-tune the functions of all organs in vertebrates. As transcription factors they sense endogenous and exogenous lipid signaling molecules and convert these signals into intricate gene responses that impact health and disease. The PPARs act as modulators of cellular, organ, and systemic processes, such as lipid and carbohydrate metabolism, making them valuable for understanding body homeostasis influenced by nutrition and exercise. Areas covered: This review concentrates on synthetic and natural PPAR ligands and how they have helped reveal many aspects of the transcriptional control of complex processes important in health. Expert opinion: The three PPARs have complementary roles in the fine-tuning of most fundamental body functions, especially energy metabolism. Understanding their inter-relatedness using ligands that simultaneously modulate the activity of more than one of these receptors is a major goal. This approach may provide essential knowledge for the development of dual or pan-PPAR agonists or antagonists as potential new health-promoting agents and for nutritional approaches to prevent metabolic diseases.
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Affiliation(s)
- Chek Kun Tan
- a Lee Kong Chian School of Medicine , Nanyang Technological University , Singapore , Singapore
| | - Yan Zhuang
- a Lee Kong Chian School of Medicine , Nanyang Technological University , Singapore , Singapore
| | - Walter Wahli
- a Lee Kong Chian School of Medicine , Nanyang Technological University , Singapore , Singapore.,b Center for Integrative Genomics , University of Lausanne , Lausanne , Switzerland
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Gonzalez-Franquesa A, Patti ME. Insulin Resistance and Mitochondrial Dysfunction. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2017; 982:465-520. [DOI: 10.1007/978-3-319-55330-6_25] [Citation(s) in RCA: 84] [Impact Index Per Article: 10.5] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
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Chronic peroxisome proliferator-activated receptorβ/δ agonist GW0742 prevents hypertension, vascular inflammatory and oxidative status, and endothelial dysfunction in diet-induced obesity. J Hypertens 2016; 33:1831-44. [PMID: 26147382 DOI: 10.1097/hjh.0000000000000634] [Citation(s) in RCA: 30] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/29/2022]
Abstract
OBJECTIVE Endothelial dysfunction plays a key role in obesity-induced risk of cardiovascular disease. The aim of the present study was to analyze the effect of chronic peroxisome proliferator-activated receptor (PPAR)β/δ agonist GW0742 treatment on endothelial function in obese mice fed a high-fat diet (HFD). METHODS AND RESULTS Five-week-old male mice were allocated to one of the following groups: control, control-treated (GW0742, 3 mg/kg per day, by oral gavage), HFD, HFD + GW0742, HFD + GSK0660 (1 mg/kg/day, intraperitoneal) or HFD-GW0742-GSK0660 and followed for 11 or 13 weeks. GW0742 administration to mice fed HFD prevented the gain of body weight, heart and kidney hypertrophy, and fat accumulation. The increase in plasma levels of fasting glucose, glucose tolerance test, homeostatic model assessment of insulin resistance, and triglyceride found in the HFD group was suppressed by GW0742. This agonist increased plasma HDL in HFD-fed mice and restored the levels of tumor necrosis factor-α and adiponectin in fat. GW0742 prevented the impaired nitric oxide-dependent vasodilatation induced by acetylcholine in aortic rings from mice fed HFD. Moreover, GW0742 increased both aortic Akt and endothelial nitric oxide synthase phosphorylation, and inhibited the increase in caveolin-1/endothelial nitric oxide synthase interaction, ethidium fluorescence, NOX-1, Toll-like receptor 4, tumor necrosis factor-α, and interleukin-6 expression, and IκBα phosphorylation found in aortae from the HFD group. GSK0660 prevented all changes induced by GW0742. CONCLUSION PPARβ/δ activation prevents obesity and exerts protective effects on hypertension and on the early manifestations of atherosclerosis, that is, endothelial dysfunction and the vascular pro-oxidant and pro-inflammatory status, in HFD-fed mice.
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Chevy Q, Heubl M, Goutierre M, Backer S, Moutkine I, Eugène E, Bloch-Gallego E, Lévi S, Poncer JC. KCC2 Gates Activity-Driven AMPA Receptor Traffic through Cofilin Phosphorylation. J Neurosci 2015; 35:15772-86. [PMID: 26631461 PMCID: PMC6605455 DOI: 10.1523/jneurosci.1735-15.2015] [Citation(s) in RCA: 47] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2015] [Revised: 09/01/2015] [Accepted: 09/26/2015] [Indexed: 12/31/2022] Open
Abstract
Expression of the neuronal K/Cl transporter KCC2 is tightly regulated throughout development and by both normal and pathological neuronal activity. Changes in KCC2 expression have often been associated with altered chloride homeostasis and GABA signaling. However, recent evidence supports a role of KCC2 in the development and function of glutamatergic synapses through mechanisms that remain poorly understood. Here we show that suppressing KCC2 expression in rat hippocampal neurons precludes long-term potentiation of glutamatergic synapses specifically by preventing activity-driven membrane delivery of AMPA receptors. This effect is independent of KCC2 transporter function and can be accounted for by increased Rac1/PAK- and LIMK-dependent cofilin phosphorylation and actin polymerization in dendritic spines. Our results demonstrate that KCC2 plays a critical role in the regulation of spine actin cytoskeleton and gates long-term plasticity at excitatory synapses in cortical neurons.
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Affiliation(s)
- Quentin Chevy
- Institut National de la Santé et de la Recherche Médicale, Unité Mixte de Recherche-S 839, F-75005, Paris, France, Sorbonne Universités, Université Pierre et Marie Curie Université Paris 06, Unité Mixte de Recherche-S 839, F-75005, Paris, France, Institut du Fer a Moulin, F-75005, Paris, France, and
| | - Martin Heubl
- Institut National de la Santé et de la Recherche Médicale, Unité Mixte de Recherche-S 839, F-75005, Paris, France, Sorbonne Universités, Université Pierre et Marie Curie Université Paris 06, Unité Mixte de Recherche-S 839, F-75005, Paris, France, Institut du Fer a Moulin, F-75005, Paris, France, and
| | - Marie Goutierre
- Institut National de la Santé et de la Recherche Médicale, Unité Mixte de Recherche-S 839, F-75005, Paris, France, Sorbonne Universités, Université Pierre et Marie Curie Université Paris 06, Unité Mixte de Recherche-S 839, F-75005, Paris, France, Institut du Fer a Moulin, F-75005, Paris, France, and
| | - Stéphanie Backer
- Institut Cochin, Institut National de la Santé et de la Recherche Médicale, U 1016, Centre National de la Recherche Scientifique, Unité Mixte de Recherche 8104, Université Paris Descartes, F-75014, Paris, France
| | - Imane Moutkine
- Institut National de la Santé et de la Recherche Médicale, Unité Mixte de Recherche-S 839, F-75005, Paris, France, Sorbonne Universités, Université Pierre et Marie Curie Université Paris 06, Unité Mixte de Recherche-S 839, F-75005, Paris, France, Institut du Fer a Moulin, F-75005, Paris, France, and
| | - Emmanuel Eugène
- Institut National de la Santé et de la Recherche Médicale, Unité Mixte de Recherche-S 839, F-75005, Paris, France, Sorbonne Universités, Université Pierre et Marie Curie Université Paris 06, Unité Mixte de Recherche-S 839, F-75005, Paris, France, Institut du Fer a Moulin, F-75005, Paris, France, and
| | - Evelyne Bloch-Gallego
- Institut Cochin, Institut National de la Santé et de la Recherche Médicale, U 1016, Centre National de la Recherche Scientifique, Unité Mixte de Recherche 8104, Université Paris Descartes, F-75014, Paris, France
| | - Sabine Lévi
- Institut National de la Santé et de la Recherche Médicale, Unité Mixte de Recherche-S 839, F-75005, Paris, France, Sorbonne Universités, Université Pierre et Marie Curie Université Paris 06, Unité Mixte de Recherche-S 839, F-75005, Paris, France, Institut du Fer a Moulin, F-75005, Paris, France, and
| | - Jean Christophe Poncer
- Institut National de la Santé et de la Recherche Médicale, Unité Mixte de Recherche-S 839, F-75005, Paris, France, Sorbonne Universités, Université Pierre et Marie Curie Université Paris 06, Unité Mixte de Recherche-S 839, F-75005, Paris, France, Institut du Fer a Moulin, F-75005, Paris, France, and
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Poon K, Alam M, Karatayev O, Barson JR, Leibowitz SF. Regulation of the orexigenic neuropeptide, enkephalin, by PPARδ and fatty acids in neurons of the hypothalamus and forebrain. J Neurochem 2015; 135:918-31. [PMID: 26332891 DOI: 10.1111/jnc.13298] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2015] [Revised: 07/28/2015] [Accepted: 08/23/2015] [Indexed: 11/28/2022]
Abstract
Ingestion of a high-fat diet composed mainly of the saturated fatty acid, palmitic (PA), and the unsaturated fatty acid, oleic (OA), stimulates transcription in the brain of the opioid neuropeptide, enkephalin (ENK), which promotes intake of substances of abuse. To understand possible underlying mechanisms, this study examined the nuclear receptors, peroxisome proliferator-activated receptors (PPARs), and tested in hypothalamic and forebrain neurons from rat embryos whether PPARs regulate endogenous ENK and the fatty acids themselves affect these PPARs and ENK. The first set of experiments demonstrated that knocking down PPARδ, but not PPARα or PPARγ, increased ENK transcription, activation of PPARδ by an agonist decreased ENK levels, and PPARδ neurons coexpressed ENK, suggesting that PPARδ negatively regulates ENK. In the second set of experiments, PA treatment of hypothalamic and forebrain neurons had no effect on PPARδ protein while stimulating ENK mRNA and protein, whereas OA increased both mRNA and protein levels of PPARδ in forebrain neurons while having no effect on ENK mRNA and increasing ENK levels. These findings show that PA has a strong, stimulatory effect on ENK and weak effect on PPARδ protein, whereas OA has a strong stimulatory effect on PPARδ and weak effect on ENK, consistent with the inhibitory effect of PPARδ on ENK. They suggest a function for PPARδ, perhaps protective in nature, in embryonic neurons exposed to fatty acids from a fat-rich diet and provide evidence for a mechanism contributing to differential effects of saturated and monounsaturated fatty acids on neurochemical systems involved in consummatory behavior. Our findings show that PPARδ in forebrain and hypothalamic neurons negatively regulates enkephalin (ENK), a peptide known to promote ingestive behavior. This inverse relationship is consistent with our additional findings, that a saturated (palmitic; PA) compared to a monounsaturated fatty acid (oleic; OA) has a strong stimulatory effect on ENK and weak effect on PPARδ. These results suggest that PPARδ protects against the neuronal effects of fatty acids, which differentially affect neurochemical systems involved in ingestive behavior.
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Affiliation(s)
- Kinning Poon
- Laboratory of Behavioral Neurobiology, The Rockefeller University, New York City, New York, USA
| | - Mohammad Alam
- Laboratory of Behavioral Neurobiology, The Rockefeller University, New York City, New York, USA
| | - Olga Karatayev
- Laboratory of Behavioral Neurobiology, The Rockefeller University, New York City, New York, USA
| | - Jessica R Barson
- Laboratory of Behavioral Neurobiology, The Rockefeller University, New York City, New York, USA
| | - Sarah F Leibowitz
- Laboratory of Behavioral Neurobiology, The Rockefeller University, New York City, New York, USA
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Kuo KK, Wu BN, Liu CP, Yang TY, Kao LP, Wu JR, Lai WT, Chen IJ. Xanthine-based KMUP-1 improves HDL via PPARγ/SR-B1, LDL via LDLRs, and HSL via PKA/PKG for hepatic fat loss. J Lipid Res 2015; 56:2070-84. [PMID: 26351364 PMCID: PMC4617394 DOI: 10.1194/jlr.m057547] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2015] [Indexed: 12/21/2022] Open
Abstract
The phosphodiesterase inhibitor (PDEI)/eNOS enhancer KMUP-1, targeting G-protein coupled receptors (GPCRs), improves dyslipidemia. We compared its lipid-lowering effects with simvastatin and explored hormone-sensitive lipase (HSL) translocation in hepatic fat loss. KMUP-1 HCl (1, 2.5, and 5 mg/kg/day) and simvastatin (5 mg/kg/day) were administered in C57BL/6J male mice fed a high-fat diet (HFD) by gavage for 8 weeks. KMUP-1 inhibited HFD-induced plasma/liver TG, total cholesterol, and LDL; increased HDL/3-hydroxy-3-methylglutaryl-CoA reductase (HMGR)/Rho kinase II (ROCK II)/PPARγ/ABCA1; and decreased liver and body weight. KMUP-1 HCl in drinking water (2.5 mg/200 ml tap water) for 1–14 or 8–14 weeks decreased HFD-induced liver and body weight and scavenger receptor class B type I expression and increased protein kinase A (PKA)/PKG/LDLRs/HSL expression and immunoreactivity. In HepG2 cells incubated with serum or exogenous mevalonate, KMUP-1 (10−7∼10−5 M) reversed HMGR expression by feedback regulation, colocalized expression of ABCA1/apolipoprotein A-I/LXRα/PPARγ, and reduced exogenous geranylgeranyl pyrophosphate/farnesyl pyrophosphate (FPP)-induced RhoA/ROCK II expression. A guanosine 3′,5′-cyclic monophosphate (cGMP) antagonist reversed KMUP-1-induced ROCK II reduction, indicating cGMP/eNOS involvement. KMUP-1 inceased PKG and LDLRs surrounded by LDL and restored oxidized LDL-induced PKA expresion. Unlike simvastatin, KMUP-1 could not inhibit 14C mevalonate formation. KMUP-1 could, but simvastatin could not, decrease ROCK II expression by exogenous FPP/CGPP. KMUP-1 improves HDL via PPARγ/LXRα/ABCA1/Apo-I expression and increases LDLRs/PKA/PKG/HSL expression and immunoreactivity, leading to TG hydrolysis to lower hepatic fat and body weight.
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Affiliation(s)
- Kung-Kai Kuo
- Division of Hepatobiliopancreatic Surgery, Kaohsiung Medical University Hospital
| | - Bin-Nan Wu
- Department of Pharmacology, School of Medicine, College of Medicine
| | - Chung-Pin Liu
- Department of Cardiology, Yuan's General Hospital, Kaohsiung, Taiwan
| | - Tzu-Yang Yang
- Department of Pharmacology, School of Medicine, College of Medicine
| | - Li-Pin Kao
- Department of Pharmacology, School of Medicine, College of Medicine
| | - Jiunn-Ren Wu
- Department of Pedatrics, Kaohsiung Medical University Hospital
| | - Wen-Ter Lai
- Division of Cardiology, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Ing-Jun Chen
- Department of Pharmacology, School of Medicine, College of Medicine
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Souza-Mello V. Peroxisome proliferator-activated receptors as targets to treat non-alcoholic fatty liver disease. World J Hepatol 2015; 7:1012-1019. [PMID: 26052390 PMCID: PMC4450178 DOI: 10.4254/wjh.v7.i8.1012] [Citation(s) in RCA: 130] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/27/2015] [Revised: 02/21/2015] [Accepted: 03/30/2015] [Indexed: 02/06/2023] Open
Abstract
Lately, the world has faced tremendous progress in the understanding of non-alcoholic fatty liver disease (NAFLD) pathogenesis due to rising obesity rates. Peroxisome proliferator-activated receptors (PPARs) are transcription factors that modulate the expression of genes involved in lipid metabolism, energy homeostasis and inflammation, being altered in diet-induced obesity. Experimental evidences show that PPAR-alpha is the master regulator of hepatic beta-oxidation (mitochondrial and peroxisomal) and microsomal omega-oxidation, being markedly decreased by high-fat (HF) intake. PPAR-beta/delta is crucial to the regulation of forkhead box-containing protein O subfamily-1 expression and, hence, the modulation of enzymes that trigger hepatic gluconeogenesis. In addition, PPAR-beta/delta can activate hepatic stellate cells aiming to the hepatic recovery from chronic insult. On the contrary, PPAR-gamma upregulation by HF diets maximizes NAFLD through the induction of lipogenic factors, which are implicated in the fatty acid synthesis. Excessive dietary sugars also upregulate PPAR-gamma, triggering de novo lipogenesis and the consequent lipid droplets deposition within hepatocytes. Targeting PPARs to treat NAFLD seems a fruitful approach as PPAR-alpha agonist elicits expressive decrease in hepatic steatosis by increasing mitochondrial beta-oxidation, besides reduced lipogenesis. PPAR-beta/delta ameliorates hepatic insulin resistance by decreasing hepatic gluconeogenesis at postprandial stage. Total PPAR-gamma activation can exert noxious effects by stimulating hepatic lipogenesis. However, partial PPAR-gamma activation leads to benefits, mainly mediated by increased adiponectin expression and decreased insulin resistance. Further studies are necessary aiming at translational approaches useful to treat NAFLD in humans worldwide by targeting PPARs.
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Affiliation(s)
- Vanessa Souza-Mello
- Vanessa Souza-Mello, Biomedical Centre, Institute of Biology, Department of Anatomy, State University of Rio de Janeiro, Rio de Janeiro 20551-030, Brazil
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Rachid TL, Penna-de-Carvalho A, Bringhenti I, Aguila MB, Mandarim-de-Lacerda CA, Souza-Mello V. Fenofibrate (PPARalpha agonist) induces beige cell formation in subcutaneous white adipose tissue from diet-induced male obese mice. Mol Cell Endocrinol 2015; 402:86-94. [PMID: 25576856 DOI: 10.1016/j.mce.2014.12.027] [Citation(s) in RCA: 109] [Impact Index Per Article: 10.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/27/2014] [Revised: 12/07/2014] [Accepted: 12/30/2014] [Indexed: 12/18/2022]
Abstract
Browning is characterized by the formation of beige/brite fat depots in subcutaneous white adipose tissue (sWAT). This study aimed to examine whether the chronic activation of PPARalpha by fenofibrate could induce beige cell depots in the sWAT of diet-induced obese mice. High-fat fed animals presented overweight, insulin resistance and displayed adverse sWAT remodeling. Fenofibrate significantly attenuated these parameters. Treated groups demonstrated active UCP-1 beige cell clusters within sWAT, confirmed through higher gene expression of PPARalpha, PPARbeta, PGC1alpha, BMP8B, UCP-1, PRDM16 and irisin in treated groups. PPARalpha activation seems to be pivotal to trigger browning through irisin induction and UCP-1 transcription, indicating that fenofibrate increased the expression of genes typical of brown adipose tissue (BAT) in the sWAT, characterizing the formation of beige cells. These findings put forward a possible role of PPARalpha as a promising therapeutic for metabolic diseases via beige cell induction.
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Affiliation(s)
- Tamiris Lima Rachid
- Laboratory of Morphometry, Metabolism, and Cardiovascular Diseases, Biomedical Center, Institute of Biology, State University of Rio de Janeiro, Brazil
| | - Aline Penna-de-Carvalho
- Laboratory of Morphometry, Metabolism, and Cardiovascular Diseases, Biomedical Center, Institute of Biology, State University of Rio de Janeiro, Brazil
| | - Isabele Bringhenti
- Laboratory of Morphometry, Metabolism, and Cardiovascular Diseases, Biomedical Center, Institute of Biology, State University of Rio de Janeiro, Brazil
| | - Marcia B Aguila
- Laboratory of Morphometry, Metabolism, and Cardiovascular Diseases, Biomedical Center, Institute of Biology, State University of Rio de Janeiro, Brazil
| | - Carlos A Mandarim-de-Lacerda
- Laboratory of Morphometry, Metabolism, and Cardiovascular Diseases, Biomedical Center, Institute of Biology, State University of Rio de Janeiro, Brazil
| | - Vanessa Souza-Mello
- Laboratory of Morphometry, Metabolism, and Cardiovascular Diseases, Biomedical Center, Institute of Biology, State University of Rio de Janeiro, Brazil.
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Rafraf M, Zemestani M, Asghari-Jafarabadi M. Effectiveness of chamomile tea on glycemic control and serum lipid profile in patients with type 2 diabetes. J Endocrinol Invest 2015; 38:163-70. [PMID: 25194428 DOI: 10.1007/s40618-014-0170-x] [Citation(s) in RCA: 40] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/08/2014] [Accepted: 08/21/2014] [Indexed: 12/18/2022]
Abstract
AIMS This study aimed at assessing the effects of chamomile tea consumption on glycemic control and serum lipid profile in patients with type 2 diabetes mellitus (T2DM). METHODS This single-blind randomized controlled clinical trial was conducted on 64 individuals with T2DM (males and females) aged between 30 and 60 years. The intervention group (n = 32) consumed chamomile tea (3 g/150 mL hot water) three times per day immediately after meals for 8 weeks. The control group (n = 32) followed a water regimen for the same intervention period. Fasting blood samples, anthropometric measurements, and 3-day, 24-h dietary recalls were collected at the baseline and at the end of the trial. Data were analyzed by independent t test, paired t test, Pearson correlation test, and analysis of covariance. RESULTS Chamomile tea significantly decreased concentration of HbA1C (p = 0.03), serum insulin levels (p < 0.001), homeostatic model assessment for insulin resistance (p < 0.001), total cholesterol (p = 0.001), triglyceride (p < 0.001), and low-density lipoprotein cholesterol (p = 0.05) compared with control group. No significant changes were shown in serum high-density lipoprotein cholesterol levels in both groups. CONCLUSION Chamomile tea has some beneficial effects on glycemic control and serum lipid profile in T2DM patients.
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Affiliation(s)
- M Rafraf
- Department of Nutrition in Community, Faculty of Nutrition, Nutrition Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - M Zemestani
- Students' Research Committee, Faculty of Nutrition, Tabriz University of Medical Sciences, Tabriz, Iran.
| | - M Asghari-Jafarabadi
- Department of Statistics and Epidemiology, Faculty of Health, Tabriz Health Service Management Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
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Nenov MN, Tempia F, Denner L, Dineley KT, Laezza F. Impaired firing properties of dentate granule neurons in an Alzheimer's disease animal model are rescued by PPARγ agonism. J Neurophysiol 2014; 113:1712-26. [PMID: 25540218 PMCID: PMC4359997 DOI: 10.1152/jn.00419.2014] [Citation(s) in RCA: 35] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/02/2022] Open
Abstract
Early cognitive impairment in Alzheimer's disease (AD) correlates with medial temporal lobe dysfunction, including two areas essential for memory formation: the entorhinal cortex and dentate gyrus (DG). In the Tg2576 animal model for AD amyloidosis, activation of the peroxisome proliferator-activated receptor-gamma (PPARγ) with rosiglitazone (RSG) ameliorates hippocampus-dependent cognitive impairment and restores aberrant synaptic activity at the entorhinal cortex to DG granule neuron inputs. It is unknown, however, whether intrinsic firing properties of DG granule neurons in these animals are affected by amyloid-β pathology and if they are sensitive to RSG treatment. Here, we report that granule neurons from 9-mo-old wild-type and Tg2576 animals can be segregated into two cell types with distinct firing properties and input resistance that correlate with less mature type I and more mature type II neurons. The DG type I cell population was greater than type II in wild-type littermates. In the Tg2576 animals, the type I and type II cell populations were nearly equal but could be restored to wild-type levels through cognitive enhancement with RSG. Furthermore, Tg2576 cell firing frequency and spike after depolarization were decreased in type I and increased in type II cells, both of which could also be restored to wild-type levels upon RSG treatment. That these parameters were restored by PPARγ activation emphasizes the therapeutic value of RSG against early AD cognitive impairment.
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Affiliation(s)
- Miroslav N Nenov
- Department of Pharmacology and Toxicology, The University of Texas Medical Branch, Galveston, Texas
| | - Filippo Tempia
- Department of Pharmacology and Toxicology, The University of Texas Medical Branch, Galveston, Texas
| | - Larry Denner
- Department of Internal Medicine, The University of Texas Medical Branch, Galveston, Texas; Center for Addiction Research, The University of Texas Medical Branch, Galveston, Texas; Mitchell Center for Neurodegenerative Diseases, The University of Texas Medical Branch, Galveston, Texas; and
| | - Kelly T Dineley
- Department of Neurology, The University of Texas Medical Branch, Galveston, Texas; Center for Addiction Research, The University of Texas Medical Branch, Galveston, Texas; Mitchell Center for Neurodegenerative Diseases, The University of Texas Medical Branch, Galveston, Texas; and
| | - Fernanda Laezza
- Department of Pharmacology and Toxicology, The University of Texas Medical Branch, Galveston, Texas; Center for Addiction Research, The University of Texas Medical Branch, Galveston, Texas; Mitchell Center for Neurodegenerative Diseases, The University of Texas Medical Branch, Galveston, Texas; and Center for Biomedical Engineering, The University of Texas Medical Branch, Galveston, Texas
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Chen Z, Guo L, Zhang Y, Walzem RL, Pendergast JS, Printz RL, Morris LC, Matafonova E, Stien X, Kang L, Coulon D, McGuinness OP, Niswender KD, Davies SS. Incorporation of therapeutically modified bacteria into gut microbiota inhibits obesity. J Clin Invest 2014; 124:3391-406. [PMID: 24960158 DOI: 10.1172/jci72517] [Citation(s) in RCA: 189] [Impact Index Per Article: 17.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2013] [Accepted: 05/08/2014] [Indexed: 12/30/2022] Open
Abstract
Metabolic disorders, including obesity, diabetes, and cardiovascular disease, are widespread in Westernized nations. Gut microbiota composition is a contributing factor to the susceptibility of an individual to the development of these disorders; therefore, altering a person's microbiota may ameliorate disease. One potential microbiome-altering strategy is the incorporation of modified bacteria that express therapeutic factors into the gut microbiota. For example, N-acylphosphatidylethanolamines (NAPEs) are precursors to the N-acylethanolamide (NAE) family of lipids, which are synthesized in the small intestine in response to feeding and reduce food intake and obesity. Here, we demonstrated that administration of engineered NAPE-expressing E. coli Nissle 1917 bacteria in drinking water for 8 weeks reduced the levels of obesity in mice fed a high-fat diet. Mice that received modified bacteria had dramatically lower food intake, adiposity, insulin resistance, and hepatosteatosis compared with mice receiving standard water or control bacteria. The protective effects conferred by NAPE-expressing bacteria persisted for at least 4 weeks after their removal from the drinking water. Moreover, administration of NAPE-expressing bacteria to TallyHo mice, a polygenic mouse model of obesity, inhibited weight gain. Our results demonstrate that incorporation of appropriately modified bacteria into the gut microbiota has potential as an effective strategy to inhibit the development of metabolic disorders.
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Mansour M. The Roles of Peroxisome Proliferator-Activated Receptors in the Metabolic Syndrome. PROGRESS IN MOLECULAR BIOLOGY AND TRANSLATIONAL SCIENCE 2014; 121:217-66. [DOI: 10.1016/b978-0-12-800101-1.00007-7] [Citation(s) in RCA: 58] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
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Moon KS, Lee JE, Lee HS, Hwang IC, Kim DH, Park HK, Choi HJ, Jo W, Son WC, Yun HI. CKD-501, a novel selective PPARγ agonist, shows no carcinogenic potential in ICR mice following oral administration for 104 weeks. J Appl Toxicol 2013; 34:1271-84. [PMID: 24026970 DOI: 10.1002/jat.2918] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/10/2013] [Revised: 07/11/2013] [Accepted: 07/11/2013] [Indexed: 12/31/2022]
Abstract
CKD-501 is a peroxisome proliferator-activated receptor gamma (PPARγ) agonist that is effective for the treatment of diabetes. However, its carcinogenic potential remains controversial. The current carcinogenicity study was conducted over a period of 104 weeks in ICR mice. Three groups, each consisting of 60 male and 60 female mice, received oral CKD-501 dosages of 0.2, 1.0 or 6.0 mg kg(-1) day(-1). The mortality rates of the male control, 0.2, 1.0 and 6.0 mg kg(-1) day(-1) treated groups were 60%, 68%, 58% and 67%, respectively and 57%, 68% and 67% in the female control, 0.2 and 1.0 mg kg(-1) day(-1) treated groups. It was 67% in the female 6.0 mg kg(-1) day(-1) treated group, which was terminated at week 98 due to its increased mortality rate. No significant treatment-related effects were observed on the survival rates, with the exception of females in the 6.0 mg kg(-1) day(-1) group. Body weights increased in females receiving 1.0 and 6.0 mg kg(-1) day(-1) due to the class effects of the PPARγ agonist. Differences were not found in hematology parameters between the CKD-501-treated groups and their corresponding controls, but the histopathological evidence did not reveal any findings attributed to CKD-501. Treated animals exhibited non-neoplastic findings (adipocyte proliferation, bone marrow hypoplasia cardiomyopathy), but all of these were expected changes for this class of compound. There were no treatment-related neoplastic changes in this study. The results of this study therefore demonstrate a lack of carcinogenicity following oral administration of CKD-501 to ICR mice for 104 weeks.
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Affiliation(s)
- Kyoung-Sik Moon
- Division of Non-clinical Studies, Korea Institute of Toxicology (KIT), Daejeon, Korea; Department of Veterinary Pharmacology and Toxicology, College of Veterinary Medicine, Chungnam National University, Daejeon, Korea
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Nandhikonda P, Yasgar A, Baranowski AM, Sidhu PS, McCallum MM, Pawlak AJ, Teske K, Feleke B, Yuan NY, Kevin C, Bikle DD, Ayers SD, Webb P, Rai G, Simeonov A, Jadhav A, Maloney D, Arnold LA. Peroxisome proliferation-activated receptor δ agonist GW0742 interacts weakly with multiple nuclear receptors, including the vitamin D receptor. Biochemistry 2013; 52:4193-203. [PMID: 23713684 DOI: 10.1021/bi400321p] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/29/2022]
Abstract
A high-throughput screening campaign was conducted to identify small molecules with the ability to inhibit the interaction between the vitamin D receptor (VDR) and steroid receptor coactivator 2. These inhibitors represent novel molecular probes for modulating gene regulation mediated by VDR. Peroxisome proliferator-activated receptor (PPAR) δ agonist GW0742 was among the identified VDR-coactivator inhibitors and has been characterized herein as a pan nuclear receptor antagonist at concentrations of > 12.1 μM. The highest antagonist activity for GW0742 was found for VDR and the androgen receptor. Surprisingly, GW0742 behaved as a PPAR agonist and antagonist, activating transcription at lower concentrations and inhibiting this effect at higher concentrations. A unique spectroscopic property of GW0742 was identified as well. In the presence of rhodamine-derived molecules, GW0742 increased the fluorescence intensity and level of fluorescence polarization at an excitation wavelength of 595 nm and an emission wavelength of 615 nm in a dose-dependent manner. The GW0742-inhibited NR-coactivator binding resulted in a reduced level of expression of five different NR target genes in LNCaP cells in the presence of agonist. Especially VDR target genes CYP24A1, IGFBP-3, and TRPV6 were negatively regulated by GW0742. GW0742 is the first VDR ligand inhibitor lacking the secosteroid structure of VDR ligand antagonists. Nevertheless, the VDR-meditated downstream process of cell differentiation was antagonized by GW0742 in HL-60 cells that were pretreated with the endogenous VDR agonist 1,25-dihydroxyvitamin D3.
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Affiliation(s)
- Premchendar Nandhikonda
- Department of Chemistry and Biochemistry, University of Wisconsin-Milwaukee, Milwaukee, Wisconsin 53211, USA
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Carracedo A, Weiss D, Leliaert AK, Bhasin M, de Boer VCJ, Laurent G, Adams AC, Sundvall M, Song SJ, Ito K, Finley LS, Egia A, Libermann T, Gerhart-Hines Z, Puigserver P, Haigis MC, Maratos-Flier E, Richardson AL, Schafer ZT, Pandolfi PP. A metabolic prosurvival role for PML in breast cancer. J Clin Invest 2012; 122:3088-100. [PMID: 22886304 DOI: 10.1172/jci62129] [Citation(s) in RCA: 219] [Impact Index Per Article: 16.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2011] [Accepted: 07/05/2012] [Indexed: 12/26/2022] Open
Abstract
Cancer cells exhibit an aberrant metabolism that facilitates more efficient production of biomass and hence tumor growth and progression. However, the genetic cues modulating this metabolic switch remain largely undetermined. We identified a metabolic function for the promyelocytic leukemia (PML) gene, uncovering an unexpected role for this bona fide tumor suppressor in breast cancer cell survival. We found that PML acted as both a negative regulator of PPARγ coactivator 1A (PGC1A) acetylation and a potent activator of PPAR signaling and fatty acid oxidation. We further showed that PML promoted ATP production and inhibited anoikis. Importantly, PML expression allowed luminal filling in 3D basement membrane breast culture models, an effect that was reverted by the pharmacological inhibition of fatty acid oxidation. Additionally, immunohistochemical analysis of breast cancer biopsies revealed that PML was overexpressed in a subset of breast cancers and enriched in triple-negative cases. Indeed, PML expression in breast cancer correlated strikingly with reduced time to recurrence, a gene signature of poor prognosis, and activated PPAR signaling. These findings have important therapeutic implications, as PML and its key role in fatty acid oxidation metabolism are amenable to pharmacological suppression, a potential future mode of cancer prevention and treatment.
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Affiliation(s)
- Arkaitz Carracedo
- Cancer Genetics Program, Beth Israel Deaconess Cancer Center, Department of Medicine, Harvard Medical School, and Department of Pathology, Brigham and Women's Hospital, Boston, MA 02215, USA
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Ochman AR, Lipinski CA, Handler JA, Reaume AG, Saporito MS. The Lyn kinase activator MLR-1023 is a novel insulin receptor potentiator that elicits a rapid-onset and durable improvement in glucose homeostasis in animal models of type 2 diabetes. J Pharmacol Exp Ther 2012; 342:23-32. [PMID: 22431203 DOI: 10.1124/jpet.112.192187] [Citation(s) in RCA: 32] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/08/2025] Open
Abstract
MLR-1023 [Tolimidone; CP-26154; 2(1H)-pyrimidinone, 5-(3-methylphenoxy)] is an allosteric Lyn kinase activator that reduces blood glucose levels in mice subjected to an oral glucose tolerance test (J Pharmacol Exp Ther 342:15-22, 2012). The current studies were designed to define the role of insulin in MLR-1023-mediated blood glucose lowering, to evaluate it in animal models of type 2 diabetes, and to compare it to the activities of selected existing diabetes therapeutics. Results from these studies show that in an acute oral glucose tolerance test MLR-1023 evoked a dose-dependent blood glucose-lowering response that was equivalent in magnitude to that of metformin without eliciting a hypoglycemic response. In streptozotocin-treated, insulin-depleted mice, MLR-1023 administration did not affect blood glucose levels. However, MLR-1023 potentiated the glucose-lowering activity of exogenously administered insulin, showing that MLR-1023-mediated blood glucose lowering was insulin-dependent. In a hyperinsulinemic/euglycemic clamp study, orally administered MLR-1023 increased the glucose infusion rate required to sustain blood glucose levels, demonstrating that MLR-1023 increased insulin receptor sensitivity. In chronically treated db/db mice, MLR-1023 elicited a dose-dependent and durable glucose-lowering effect, reduction in HbA1c levels and preservation of pancreatic β-cells. The magnitude of effect was equivalent to that seen with rosiglitazone but with a faster onset of action and without causing weight gain. These studies show that MLR-1023 is an insulin receptor-potentiating agent that produces a rapid-onset and durable blood glucose-lowering activity in diabetic animals.
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Bouchard-Mercier A, Paradis AM, Pérusse L, Vohl MC. Associations between polymorphisms in genes involved in fatty acid metabolism and dietary fat intakes. JOURNAL OF NUTRIGENETICS AND NUTRIGENOMICS 2012; 5:1-12. [PMID: 22414759 DOI: 10.1159/000336511] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/13/2011] [Accepted: 01/16/2012] [Indexed: 12/17/2022]
Abstract
BACKGROUND Obesity prevalence is growing in our population. Twin studies have estimated the heritability of dietary intakes to about 30%. The objective of this study was to verify whether polymorphisms in genes involved in fatty acid metabolism are associated with dietary fat intakes. METHODS Seven hundred participants were recruited. A validated food frequency questionnaire was used to assess dietary intakes. PCR-RFLP and TAQMAN methodology were used to genotype PPARα Leu162Val, PPARγ Pro12Ala, PPARδ -87T>C, PPARGC1α Gly482Ser, FASN Val1483Ile and SREBF1 c.*619C>G. Statistical analyses were executed with SAS statistical package. RESULTS Carriers of the Ala12 allele of PPARγ Pro12Ala polymorphism had higher intakes of total fat (p = 0.04). For FASN Val1483Ile polymorphism, significant gene-sex interaction effects were found for total fat and saturated fat intakes (p = 0.02 and p = 0.002, respectively). No significant difference in fat intakes was observed for PPARα Leu162Val, PPARδ -87T>C, PPARGC1α Gly482Ser and SREBF1 c.*619C>G polymorphisms. CONCLUSIONS Polymorphisms in PPARγ and FASN seem to be associated with dietary fat intakes. Genetic variants are important to take into account when studying dietary intakes.
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Coelho DF, Pereira-Lancha LO, Chaves DS, Diwan D, Ferraz R, Campos-Ferraz PL, Poortmans JR, Lancha Junior AH. Effect of high-fat diets on body composition, lipid metabolism and insulin sensitivity, and the role of exercise on these parameters. Braz J Med Biol Res 2011; 44:966-72. [PMID: 21876873 DOI: 10.1590/s0100-879x2011007500107] [Citation(s) in RCA: 41] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/19/2011] [Accepted: 08/10/2011] [Indexed: 12/25/2022] Open
Abstract
Dietary fat composition can interfere in the development of obesity due to the specific roles of some fatty acids that have different metabolic activities, which can alter both fat oxidation and deposition rates, resulting in changes in body weight and/or composition. High-fat diets in general are associated with hyperphagia, but the type of dietary fat seems to be more important since saturated fats are linked to a positive fat balance and omental adipose tissue accumulation when compared to other types of fat, while polyunsaturated fats, omega-3 and omega-6, seem to increase energy expenditure and decrease energy intake by specific mechanisms involving hormone-sensitive lipase, activation of peroxisome proliferator-activated receptor α (PPARα) and others. Saturated fat intake can also impair insulin sensitivity compared to omega-3 fat, which has the opposite effect due to alterations in cell membranes. Obesity is also associated with impaired mitochondrial function. Fat excess favors the production of malonyl-CoA, which reduces GLUT4 efficiency. The tricarboxylic acid cycle and beta-oxidation are temporarily uncoupled, forming metabolite byproducts that augment reactive oxygen species production. Exercise can restore mitochondrial function and insulin sensitivity, which may be crucial for a better prognosis in treating or preventing obesity.
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Affiliation(s)
- D F Coelho
- Departamento de Biologia Celular e Desenvolvimento, Instituto de Ciências Biomédicas, Universidade de São Paulo, São Paulo, SP, Brasil.
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Effects of Glycyrrhizic Acid on Peroxisome Proliferator-Activated Receptor Gamma (PPARgamma), Lipoprotein Lipase (LPL), Serum Lipid and HOMA-IR in Rats. PPAR Res 2011; 2010:530265. [PMID: 20011054 PMCID: PMC2786009 DOI: 10.1155/2010/530265] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2009] [Accepted: 08/28/2009] [Indexed: 11/17/2022] Open
Abstract
Studies on ligand binding potential of glycyrrhizic acid, a potential agonist to PPARgamma, displayed encouraging results in amelioration of metabolic syndrome. The regulation of gene cassettes by PPARgamma affects glucose homeostasis, lipid, lipoprotein metabolism and adipogenesis. This study was performed to determine the effects of GA on total PPARgamma and LPL expression levels, lipid parameters and HOMA-IR. Oral administration of 100 mg/kg GA for 24 hours resulted in an increase in insulin sensitivity with decreases in blood glucose, serum insulin and HOMA-IR. Improvement in serum lipid parameters was also observed with a decrease in triacylglycerol, total cholesterol and LDL-cholesterol and an elevation in HDL-cholesterol. GA administration also resulted in up-regulation of total PPARgamma and LPL expression levels in the visceral and subcutaneous adipose tissues, abdominal and quadriceps femoris muscles, as well as liver and kidney, with a significant up-regulation only in the visceral adipose tissue, abdominal and quadriceps femoris muscles. Thus, oral administration of 100 mg/kg GA for 24 hours improved insulin sensitivity and lipid profiles and induced upregulation of total PPARgamma and LPL expression levels in all studied tissues.
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PPAR Regulation of Inflammatory Signaling in CNS Diseases. PPAR Res 2011; 2008:658520. [PMID: 18670616 PMCID: PMC2490815 DOI: 10.1155/2008/658520] [Citation(s) in RCA: 99] [Impact Index Per Article: 7.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2007] [Revised: 04/22/2008] [Accepted: 05/12/2008] [Indexed: 12/25/2022] Open
Abstract
Central nervous system (CNS) is an immune privileged site, nevertheless inflammation associates with many CNS diseases. Peroxisome proliferator-activated receptors (PPARs) are a family of nuclear hormone receptors that regulate immune and inflammatory responses. Specific ligands for PPARα, γ, and δ isoforms have proven effective in the animal models of multiple sclerosis (MS), Alzheimer's disease, Parkinson's disease, and trauma/stroke, suggesting their use in the treatment of neuroinflammatory diseases. The activation of NF-κB and Jak-Stat signaling pathways and secretion of inflammatory cytokines are critical in the pathogenesis of CNS diseases. Interestingly, PPAR agonists mitigate CNS disease by modulating inflammatory signaling network in immune cells. In this manuscript, we review the current knowledge on how PPARs regulate neuroinflammatory signaling networks in CNS diseases.
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Abstract
Exercise, together with a low-energy diet, is the first-line treatment for type 2 diabetes type 2 diabetes . Exercise improves insulin sensitivity insulin sensitivity by increasing the number or function of muscle mitochondria mitochondria and the capacity for aerobic metabolism, all of which are low in many insulin-resistant subjects. Cannabinoid 1-receptor antagonists and β-adrenoceptor agonists improve insulin sensitivity in humans and promote fat oxidation in rodents independently of reduced food intake. Current drugs for the treatment of diabetes are not, however, noted for their ability to increase fat oxidation, although the thiazolidinediones increase the capacity for fat oxidation in skeletal muscle, whilst paradoxically increasing weight gain.There are a number of targets for anti-diabetic drugs that may improve insulin sensitivity insulin sensitivity by increasing the capacity for fat oxidation. Their mechanisms of action are linked, notably through AMP-activated protein kinase, adiponectin, and the sympathetic nervous system. If ligands for these targets have obvious acute thermogenic activity, it is often because they increase sympathetic activity. This promotes fuel mobilisation, as well as fuel oxidation. When thermogenesis thermogenesis is not obvious, researchers often argue that it has occurred by using the inappropriate device of treating animals for days or weeks until there is weight (mainly fat) loss and then expressing energy expenditure energy expenditure relative to body weight. In reality, thermogenesis may have occurred, but it is too small to detect, and this device distracts us from really appreciating why insulin sensitivity has improved. This is that by increasing fatty acid oxidation fatty acid oxidation more than fatty acid supply, drugs lower the concentrations of fatty acid metabolites that cause insulin resistance. Insulin sensitivity improves long before any anti-obesity effect can be detected.
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Affiliation(s)
- Jonathan R S Arch
- Clore Laboratory, University of Buckingham, Buckingham, MK18 1EG, UK
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Huang HJ, Lee KJ, Yu HW, Chen HY, Tsai FJ, Chen CYC. A novel strategy for designing the selective PPAR agonist by the "sum of activity" model. J Biomol Struct Dyn 2010; 28:187-200. [PMID: 20645652 DOI: 10.1080/07391102.2010.10507352] [Citation(s) in RCA: 53] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/28/2022]
Abstract
Peroxisome proliferator-activated receptors alpha, delta and gamma are a collection of ligand-activated transcription factors crucial in lipid and glucose homeostasis. The involvement of these receptors in lipid metabolism makes them perfect therapeutic target for treating obesity and stroke. In this study, 'sum of activity' model was employed to design multi-target agonists. We used a new strategy to design agonists that fit both alpha and delta but not gamma, to avoid side effect. The CoMFA and CoMSIA models were used to explore the pharmacophore features by constructing three individual models: (a) alpha-model, (b) delta-model and (c) gamma-model, and two sum models: (d) alpha, delta- model, and (e) alpha, delta and gamma-model. The CoMFA model yielded a significant cross validation value, q(2), of 0.729 and non-cross validation value, r(2), of 0.933 in the alpha, delta-model. The CoMSIA studies yielded the best predictive models with q(2) of 0.622 in A+S and with r(2) of 0.911 in the alpha, delta-model. Finally, we proposed that distinct features shown in models (a), (b), (d) but not (c) and (e) should be accounted in designing weight-controlling drugs.
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Affiliation(s)
- Hung-Jin Huang
- Laboratory of Computational and Systems Biology, School of Chinese Medicine, China Medical University, Taichung, 40402, Taiwan, ROC
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Chen H, Dardik B, Qiu L, Ren X, Caplan SL, Burkey B, Boettcher BR, Gromada J. Cevoglitazar, a novel peroxisome proliferator-activated receptor-alpha/gamma dual agonist, potently reduces food intake and body weight in obese mice and cynomolgus monkeys. Endocrinology 2010; 151:3115-24. [PMID: 20484464 DOI: 10.1210/en.2009-1366] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
Abstract
Cevoglitazar is a dual agonist for the peroxisome proliferator-activated receptor (PPAR)-alpha and -gamma subtypes. Dual activation of PPARalpha and -gamma is a therapeutic approach in development for the treatment of type 2 diabetes mellitus and diabetic dyslipidemia. In this report, we show that, in addition to improving insulin sensitivity and lipid metabolism like other dual PPAR agonists, cevoglitazar also elicits beneficial effects on energy homeostasis in two animal models of obesity. In leptin-deficient ob/ob mice, administration of cevoglitazar at 0.5, 1, or 2 mg/kg for 18 d led to acute and sustained, dose-dependent reduction of food intake and body weight. Furthermore, plasma levels of glucose and insulin were normalized after 7 d of cevoglitazar treatment at 0.5 mg/kg. Plasma levels of free fatty acids and triglycerides were dose-dependently reduced. In obese and insulin-resistant cynomolgus monkeys, treatment with cevoglitazar at 50 and 500 mug/kg for 4 wk lowered food intake and body weight in a dose-dependent manner. In these animals, cevoglitazar also reduced fasting plasma insulin and, at the highest dose, reduced hemoglobin A1c levels by 0.4%. These preclinical results demonstrate that cevoglitazar holds promise for the treatment of diabetes and obesity-related disorders because of its unique beneficial effect on energy balance in addition to improving glycemic and metabolic control.
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Affiliation(s)
- Hong Chen
- Novartis Institutes for BioMedical Research, Inc., 100 Technology Square, Cambridge, MA 02139, USA.
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Perreault M, Will S, Panza D, Gareski T, Harding K, Kubasiak D, Jalenak M, Gartrell K, Wang S, Bollag G, Artis DR, Ibrahim PN, Womack P, Lin JJ, Saiah E, Mansour TS, Vlasuk GP, Erbe DV, Tobin JF. Modulation of nutrient sensing nuclear hormone receptors promotes weight loss through appetite suppression in mice. Diabetes Obes Metab 2010; 12:234-45. [PMID: 20152000 DOI: 10.1111/j.1463-1326.2009.01157.x] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/28/2022]
Abstract
AIM Peroxisome proliferator activated receptors (PPARs) are nuclear receptors involved in glucose and lipid metabolism. Three isoforms of PPARs have been identified with different tissue distribution and biological functions. Although the pharmacology of each receptor is well studied, the physiological effect of simultaneous activation of PPARalpha, gamma and delta is only starting to emerge. We sought to determine the biological effects of a novel PPAR pan activator and elucidate the physiological mechanisms involved. METHODS Ob/ob, diet-induced obese (DIO) or PPARalpha knockout mice were administered a novel agonist that activates all PPARs to various degrees to determine the effect on body weight, body composition, food intake and energy expenditure. In addition, serum parameters including glucose, insulin, triglycerides and ketone bodies as well as tissue acylcarnitine were evaluated. The effect of the novel agonist on liver and skeletal muscle histopathology was also studied. RESULTS We report that simultaneous activation of all PPARs resulted in substantial weight loss in ob/ob and DIO mice. Consistent with known PPAR pharmacology, we observed that agonist treatment increased lipid oxidation, although appetite suppression was mainly responsible for the weight loss. Agonist-induced weight loss was completely absent in PPARalpha knockout mice suggesting that PPARalpha pharmacology was the major contributor to weight regulation in mice. CONCLUSIONS Our work provides evidence that simultaneous activation of PPARalpha, gamma and delta decreases body weight by regulating appetite. These effects of the pan agonist were completely absent in PPARalpha knockout mice, suggesting that PPARalpha pharmacology was the major contributor to weight loss.
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Affiliation(s)
- M Perreault
- Metabolic Disease and Hemophilia Research, Wyeth Research, Cambridge, MA 02140, USA.
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