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Yang G, Li C, Wang S, Liang X, Yang B, Zhang Y, Zhang X, Chang X, Meng X. Molecular characterization of the grass carp bscl2 gene and its expression response to lipid accumulation, nutritional status, insulin and glucagon. Comp Biochem Physiol B Biochem Mol Biol 2024; 270:110931. [PMID: 38070669 DOI: 10.1016/j.cbpb.2023.110931] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2023] [Revised: 12/03/2023] [Accepted: 12/03/2023] [Indexed: 01/10/2024]
Abstract
Bscl2 plays a role in lipid metabolism of mammals, however its role in teleost fish remains unclear. Using the grass carp (Ctenopharyngodon idella) as a model, the bscl2 gene was isolated from the brain and characterized. Thereafter, the tissue distribution of the gene was examined, before expression was analyzed as a function of fasting, refeeding, oral glucose administration and overfeeding. In addition, bscl2 mRNA levels were evaluated in grass carp primary hepatocytes treated with glucagon, insulin, oleic acid, and glucose. Results showed that the cloned bscl2 gene was 1341 bp, encoding 446 amino acids, and was highly expressed in the brain, heart, and gonad. Following oral glucose administration, bscl2 expression increased. Expression of bscl2 decreased in fasted fish but increased following refeeding. Overfeeding, which resulted in elevated lipid accumulation, also stimulated bscl2 expression. In primary hepatocytes, bscl2 levels were increased by glucose, oleic acid, and insulin treatments, and reduced by glucagon treatment. These data suggest that bscl2 may play an important role in nutrient metabolism in teleost fish.
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Affiliation(s)
- Guokun Yang
- College of Fisheries, Henan Normal University, Xinxiang 453007, PR China; Engineering Technology Research Center of Henan Province for Aquatic Animal Cultivation, Henan Normal University, Xinxiang 453007, PR China
| | - Chengquan Li
- College of Fisheries, Henan Normal University, Xinxiang 453007, PR China
| | - Sunan Wang
- College of Fisheries, Henan Normal University, Xinxiang 453007, PR China
| | - Xiaomin Liang
- College of Fisheries, Henan Normal University, Xinxiang 453007, PR China
| | - Boya Yang
- College of Fisheries, Henan Normal University, Xinxiang 453007, PR China
| | - Yanmin Zhang
- College of Fisheries, Henan Normal University, Xinxiang 453007, PR China; Engineering Technology Research Center of Henan Province for Aquatic Animal Cultivation, Henan Normal University, Xinxiang 453007, PR China
| | - Xindang Zhang
- College of Fisheries, Henan Normal University, Xinxiang 453007, PR China; Engineering Technology Research Center of Henan Province for Aquatic Animal Cultivation, Henan Normal University, Xinxiang 453007, PR China
| | - Xulu Chang
- College of Fisheries, Henan Normal University, Xinxiang 453007, PR China; Engineering Technology Research Center of Henan Province for Aquatic Animal Cultivation, Henan Normal University, Xinxiang 453007, PR China
| | - Xiaolin Meng
- College of Fisheries, Henan Normal University, Xinxiang 453007, PR China; Engineering Technology Research Center of Henan Province for Aquatic Animal Cultivation, Henan Normal University, Xinxiang 453007, PR China.
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Huang Z, Ye Y, Long Z, Qin H, Liu L, Xu A, Li Z. Lycium barbarum polysaccharides improve lipid metabolism disorders of spotted sea bass Lateolabrax maculatus induced by high lipid diet. Int J Biol Macromol 2023; 242:125122. [PMID: 37263324 DOI: 10.1016/j.ijbiomac.2023.125122] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2023] [Revised: 05/16/2023] [Accepted: 05/24/2023] [Indexed: 06/03/2023]
Abstract
This experiment explored the effects of Lycium barbarum polysaccharides (LBP) on lipid metabolism of spotted sea bass Lateolabrax maculatus. Blank and experimental control diets with 100 and 150 g/kg lipid were designed, respectively, and three dosages of LBP (0.75, 1.00, 1.25 g/kg) were supplemented in the experimental control diet. A total 375 of spotted sea bass (19.33 ± 0.15) g were divided into 5 groups, and were given experimental diets for 56 days, respectively. Results showed fish were induced to lipid metabolism disorders with dietary 150 g/kg lipid intake, which manifested in reduced feeding, oxidative stress, elevated serum lipid, and more severe hepatic damage. Dietary LBP improved the lipid metabolism disorders of fish, as indicated by significant enhancements in weight gain, digestion, superoxide dismutase activity, and decreases in malonaldehyde content, and activity of alanine aminotransferase and aspartate aminotransferase. Accordingly, an improvement in the hepatic morphological and expression of lipid metabolism related genes, including FAS, PPAR-α, CPT1 and ATGL, was observed. Nevertheless, no significant variation in serum triglyceride and total cholesterol was observed. Overall, dietary LBP can improve the growth, digestion, antioxidant capacity, and liver health of spotted sea bass, thereby improving the lipid metabolism disorders induced by 150 g/kg dietary lipid intake.
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Affiliation(s)
- Zhangfan Huang
- Fisheries College, Jimei University, Xiamen, China; Fujian Provincial Key Laboratory of Marine Fishery Resources and Eco-environment, Xiamen, China
| | - Youling Ye
- Fisheries College, Jimei University, Xiamen, China; Fujian Provincial Key Laboratory of Marine Fishery Resources and Eco-environment, Xiamen, China
| | - Zhongying Long
- Fisheries College, Jimei University, Xiamen, China; Fujian Provincial Key Laboratory of Marine Fishery Resources and Eco-environment, Xiamen, China
| | - Huihui Qin
- Fisheries College, Jimei University, Xiamen, China; Fujian Provincial Key Laboratory of Marine Fishery Resources and Eco-environment, Xiamen, China
| | - Longhui Liu
- Fisheries College, Jimei University, Xiamen, China; Fujian Provincial Key Laboratory of Marine Fishery Resources and Eco-environment, Xiamen, China
| | - Anle Xu
- Fisheries College, Jimei University, Xiamen, China; Fujian Provincial Key Laboratory of Marine Fishery Resources and Eco-environment, Xiamen, China
| | - Zhongbao Li
- Fisheries College, Jimei University, Xiamen, China; Fujian Provincial Key Laboratory of Marine Fishery Resources and Eco-environment, Xiamen, China.
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Yang G, Liang X, Jiang Y, Li C, Zhang Y, Zhang X, Chang X, Shen Y, Meng X. Molecular Characterization of Grass Carp GIPR and Effect of Nutrition States, Insulin, and Glucagon on Its Expression. AQUACULTURE NUTRITION 2022; 2022:4330251. [PMID: 36860432 PMCID: PMC9973162 DOI: 10.1155/2022/4330251] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 09/11/2022] [Revised: 10/08/2022] [Accepted: 10/25/2022] [Indexed: 06/18/2023]
Abstract
GIP plays an important regulatory role in glucose and lipid metabolism. As the specific receptor, GIPR is involved in this physiological process. To assess the roles of GIPR in teleost, the GIPR gene was cloned from grass carp. The ORF of cloned GIPR gene was 1560 bp, encoding 519 amino acids. The grass carp GIPR was the G-protein-coupled receptor which contains seven predicted transmembrane domains. In addition, two predicted glycosylation sites were contained in the grass carp GIPR. The grass carp GIPR expression is in multiple tissues and is highly expressed in the kidney, brain regions, and visceral fat tissue. In the OGTT experiment, the GIPR expression is markedly decreased in the kidney, visceral fat, and brain by treatment with glucose for 1 and 3 h. In the fast and refeeding experiment, the GIPR expression in the kidney and visceral fat tissue was significantly induced in the fast groups. In addition, the GIPR expression levels were markedly decreased in the refeeding groups. In the present study, the visceral fat accumulation of grass carp was induced by overfed. The GIPR expression was significantly decreased in the brain, kidney, and visceral fat tissue of overfed grass carp. In primary hepatocytes, the GIPR expression was promoted by treatment with oleic acid and insulin. The GIPR mRNA levels were significantly reduced by treatment with glucose and glucagon in the grass carp primary hepatocytes. To our knowledge, this is the first time the biological role of GIPR is unveiled in teleost.
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Affiliation(s)
- Guokun Yang
- College of Fisheries, Henan Normal University, Xinxiang 453007, China
- Engineering Technology Research Center of Henan Province for Aquatic Animal Cultivation, Henan Normal University, Xinxiang 453007, China
| | - Xiaomin Liang
- College of Fisheries, Henan Normal University, Xinxiang 453007, China
| | - Yanle Jiang
- College of Fisheries, Henan Normal University, Xinxiang 453007, China
| | - Chengquan Li
- College of Fisheries, Henan Normal University, Xinxiang 453007, China
| | - Yanmin Zhang
- College of Fisheries, Henan Normal University, Xinxiang 453007, China
- Engineering Technology Research Center of Henan Province for Aquatic Animal Cultivation, Henan Normal University, Xinxiang 453007, China
| | - Xindang Zhang
- College of Fisheries, Henan Normal University, Xinxiang 453007, China
- Engineering Technology Research Center of Henan Province for Aquatic Animal Cultivation, Henan Normal University, Xinxiang 453007, China
| | - Xulu Chang
- College of Fisheries, Henan Normal University, Xinxiang 453007, China
- Engineering Technology Research Center of Henan Province for Aquatic Animal Cultivation, Henan Normal University, Xinxiang 453007, China
| | - Yawei Shen
- College of Fisheries, Henan Normal University, Xinxiang 453007, China
- Engineering Technology Research Center of Henan Province for Aquatic Animal Cultivation, Henan Normal University, Xinxiang 453007, China
| | - Xiaolin Meng
- College of Fisheries, Henan Normal University, Xinxiang 453007, China
- Engineering Technology Research Center of Henan Province for Aquatic Animal Cultivation, Henan Normal University, Xinxiang 453007, China
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Anwer H, O'Dea RE, Mason D, Zajitschek S, Klinke A, Reid M, Hesselson D, Noble DWA, Morris MJ, Lagisz M, Nakagawa S. The effects of an obesogenic diet on behavior and cognition in zebrafish ( Danio rerio): Trait average, variability, repeatability, and behavioral syndromes. Ecol Evol 2022; 12:e9511. [PMID: 36407899 PMCID: PMC9666915 DOI: 10.1002/ece3.9511] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2022] [Revised: 10/20/2022] [Accepted: 10/24/2022] [Indexed: 11/17/2022] Open
Abstract
The obesity epidemic, largely driven by the accessibility of ultra-processed high-energy foods, is one of the most pressing public health challenges of the 21st century. Consequently, there is increasing concern about the impacts of diet-induced obesity on behavior and cognition. While research on this matter continues, to date, no study has explicitly investigated the effect of obesogenic diet on variance and covariance (correlation) in behavioral traits. Here, we examined how an obesogenic versus control diet impacts means and (co-)variances of traits associated with body condition, behavior, and cognition in a laboratory population of ~160 adult zebrafish (Danio rerio). Overall, an obesogenic diet increased variation in several zebrafish traits. Zebrafish on an obesogenic diet were significantly heavier and displayed higher body weight variability; fasting blood glucose levels were similar between control and treatment zebrafish. During behavioral assays, zebrafish on the obesogenic diet displayed more exploratory behavior and were less reactive to video stimuli with conspecifics during a personality test, but these significant differences were sex-specific. Zebrafish on an obesogenic diet also displayed repeatable responses in aversive learning tests whereas control zebrafish did not, suggesting an obesogenic diet resulted in more consistent, yet impaired, behavioral responses. Where behavioral syndromes existed (inter-class correlations between personality traits), they did not differ between obesogenic and control zebrafish groups. By integrating a multifaceted, holistic approach that incorporates components of (co-)variances, future studies will greatly benefit by quantifying neglected dimensions of obesogenic diets on behavioral changes.
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Affiliation(s)
- Hamza Anwer
- Evolution & Ecology Research Centre and School of Biological, Earth and Environmental SciencesUniversity of New South WalesSydneyNew South WalesAustralia
- Diabetes and Metabolism DivisionGarvan Institute of Medical ResearchSydneyNew South WalesAustralia
| | - Rose E. O'Dea
- Evolution & Ecology Research Centre and School of Biological, Earth and Environmental SciencesUniversity of New South WalesSydneyNew South WalesAustralia
| | - Dominic Mason
- Evolution & Ecology Research Centre and School of Biological, Earth and Environmental SciencesUniversity of New South WalesSydneyNew South WalesAustralia
- Diabetes and Metabolism DivisionGarvan Institute of Medical ResearchSydneyNew South WalesAustralia
| | - Susanne Zajitschek
- Evolution & Ecology Research Centre and School of Biological, Earth and Environmental SciencesUniversity of New South WalesSydneyNew South WalesAustralia
- Diabetes and Metabolism DivisionGarvan Institute of Medical ResearchSydneyNew South WalesAustralia
- Liverpool John Moores UniversitySchool of Biological and Environmental SciencesLiverpoolUK
| | - Annabell Klinke
- Evolution & Ecology Research Centre and School of Biological, Earth and Environmental SciencesUniversity of New South WalesSydneyNew South WalesAustralia
| | - Madeleine Reid
- Diabetes and Metabolism DivisionGarvan Institute of Medical ResearchSydneyNew South WalesAustralia
| | - Daniel Hesselson
- Diabetes and Metabolism DivisionGarvan Institute of Medical ResearchSydneyNew South WalesAustralia
- Centenary Institute and Faculty of Medicine and HealthUniversity of SydneySydneyNew South WalesAustralia
| | - Daniel W. A. Noble
- Division of Ecology and Evolution, Research School of BiologyThe Australian National UniversityCanberraAustralian Capital TerritoryAustralia
| | - Margaret J. Morris
- Department of Pharmacology, School of Medical SciencesUniversity of New South WalesSydneyNew South WalesAustralia
| | - Malgorzata Lagisz
- Evolution & Ecology Research Centre and School of Biological, Earth and Environmental SciencesUniversity of New South WalesSydneyNew South WalesAustralia
- Diabetes and Metabolism DivisionGarvan Institute of Medical ResearchSydneyNew South WalesAustralia
| | - Shinichi Nakagawa
- Evolution & Ecology Research Centre and School of Biological, Earth and Environmental SciencesUniversity of New South WalesSydneyNew South WalesAustralia
- Diabetes and Metabolism DivisionGarvan Institute of Medical ResearchSydneyNew South WalesAustralia
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Balbuena E, Cheng J, Eroglu A. Carotenoids in orange carrots mitigate non-alcoholic fatty liver disease progression. Front Nutr 2022; 9:987103. [PMID: 36225879 PMCID: PMC9549209 DOI: 10.3389/fnut.2022.987103] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2022] [Accepted: 09/02/2022] [Indexed: 11/23/2022] Open
Abstract
Background Carotenoids are abundant in colored fruits and vegetables. Non-alcoholic fatty liver disease (NAFLD) is a global burden and risk factor for end-stage hepatic diseases. This study aims to compare the anti-NAFLD efficacy between carotenoid-rich and carotenoid-deficient vegetables. Materials and methods Male C57BL/6J mice were randomized to one of four experimental diets for 15 weeks (n = 12 animals/group): Low-fat diet (LFD, 10% calories from fat), high-fat diet (HFD, 60% calories from fat), HFD with 20% white carrot powders (HFD + WC), or with 20% orange carrot powders (HFD + OC). Results We observed that carotenoids in the orange carrots reduced HFD-induced weight gain, better than white carrots. Histological and triglyceride (TG) analyses revealed significantly decreased HFD-induced hepatic lipid deposition and TG content in the HFD + WC group, which was further reduced in the HFD + OC group. Western blot analysis demonstrated inconsistent changes of fatty acid synthesis-related proteins but significantly improved ACOX-1 and CPT-II, indicating that orange carrot carotenoids had the potential to inhibit NAFLD by improving β-oxidation. Further investigation showed significantly higher mRNA and protein levels of PPARα and its transcription factor activity. Conclusion Carotenoid-rich foods may display more potent efficacy in mitigating NAFLD than those with low carotenoid levels.
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Affiliation(s)
- Emilio Balbuena
- Plants for Human Health Institute, North Carolina State University, Kannapolis, NC, United States
- Department of Molecular and Structural Biochemistry, College of Agriculture and Life Sciences, North Carolina State University, Raleigh, NC, United States
| | - Junrui Cheng
- Plants for Human Health Institute, North Carolina State University, Kannapolis, NC, United States
| | - Abdulkerim Eroglu
- Plants for Human Health Institute, North Carolina State University, Kannapolis, NC, United States
- Department of Molecular and Structural Biochemistry, College of Agriculture and Life Sciences, North Carolina State University, Raleigh, NC, United States
- *Correspondence: Abdulkerim Eroglu,
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6
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Zhou D, Fu Y, Li F, Yang D, Wei L, Yue H, Dai Y, Jeon Y. Treatment of obese zebrafish with saringosterol acetate through AMP activated protein kinase pathway. Chem Biodivers 2022; 19:e202200495. [PMID: 35856892 DOI: 10.1002/cbdv.202200495] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2022] [Accepted: 07/18/2022] [Indexed: 11/06/2022]
Abstract
OBJECT Edible Brown Seaweed Sargassum fusiforme (Harvey) Setchell, 1931 abbreviated as Sargassum fusiforme was used for folk medical therapy in East Asia countries over five hundred years. Saringosterol acetate (SA) was isolated from S. fusiforme in our previous study and indicated various effects. However, anti-obesity activity of SA and its mechanism still unknown. Method: The inhibitory effect of SA, isolated from S. fusiforme , on adipogenesis in 3T3-L1 adipocytes was investigated in vitro and in zebrafish model. Cell toxicity, differentiation, signaling pathway, and lipid accumulation of SA treated 3T3-L1 adipocytes were determined. The body weight and triglyceride content of diet-induced obese (DIO) adult male zebrafish were measured from 12 to 17 weeks after fertilization. Result: SA attenuated the differentiation of cells and reduced lipid accumulation, and triglyceride content in the 3T3-L1 adipocytes. During the differentiation of adipocytes, SA suppressed fat accumulation and decreased the expression of signal factors responsible for adipogenesis. In SA-treated adipocytes, while fatty acid synthetase was downregulated, AMP-activated protein kinase (AMPK) was upregulated. Furthermore, SA suppressed body weight and triglyceride content in DIO zebrafish. CONCLUSION SA is a potential therapeutic agent in the management of metabolic disorders, such as obesity.
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Affiliation(s)
- DongYue Zhou
- Changchun University of Chinese Medicine, Jilin Ginseng Academy, Changchun 130117, Changchun, CHINA
| | - YunHua Fu
- Changchun University of Chinese Medicine, Jilin Ginseng Academy, Changchun 130117, Changchun, CHINA
| | - FangTong Li
- Changchun University of Chinese Medicine, Jilin Ginseng Academy, Changchun 130117, Changchun, CHINA
| | - Di Yang
- Changchun University of Chinese Medicine, Jilin Ginseng Academy, Changchun 130117, Changchun, CHINA
| | - LiNa Wei
- Changchun University of Chinese Medicine, Jilin Ginseng Academy, Changchun 130117, Changchun, CHINA
| | - Hao Yue
- Changchun University of Chinese Medicine, Jilin Ginseng Academy, Changchun 130117, Changchun, CHINA
| | - Yulin Dai
- Changchun University of Chinese Medicine, jilin ginseng academy, 1035# boshuo raod, 130117, Changchun, CHINA
| | - YouJin Jeon
- Jeju National University, Marine Science Institute, Jeju 63333, Jeju, KOREA, REPUBLIC OF
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7
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Matsuoka I, Hata K, Katsuzaki H, Nakayama H, Zang L, Ota M, Kim Y, Chu DC, Juneja LR, Nishimura N, Shimada Y. Zebrafish obesogenic test identifies anti-adipogenic fraction in Moringa oreifera leaf extracts. Food Sci Nutr 2022; 10:1248-1256. [PMID: 35432980 PMCID: PMC9007296 DOI: 10.1002/fsn3.2758] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2021] [Revised: 12/08/2021] [Accepted: 12/22/2021] [Indexed: 12/12/2022] Open
Abstract
The zebrafish obesogenic test (ZOT) is a powerful tool for identifying anti-adipogenic compounds for in vivo screening. In our previous study, we found that Moringa oleifera (MO) leaf powder suppressed the accumulation of visceral adipose tissue (VAT) in ZOT. MO demonstrates a wide range of pharmacological effects; however, little is known about its functional constituents. To identify the anti-adipogenic components of MO leaves, we prepared extracts using different extraction methods and tested the obtained extracts and fractions using ZOT. We found that the dichloromethane extract and its hexane:EtOAc = 8:2 fraction reduced VAT accumulation in young zebrafish fed a high-fat diet. We also performed gene expression analysis in the zebrafish VAT and found that CCAAT/enhancer-binding protein beta and CCAAT/enhancer-binding protein delta (associated with early stages of adipogenesis) gene expression was downregulated after fraction 2 administration. We identified a new MO fraction that suppressed VAT accumulation by inhibiting early adipogenesis using the ZOT. Phenotype-driven zebrafish screening is a reasonable strategy for identifying bioactive components in natural products.
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Affiliation(s)
- Izumi Matsuoka
- Graduate School of Regional Innovation Studies Mie University Tsu Japan
| | - Kanae Hata
- Graduate School of Regional Innovation Studies Mie University Tsu Japan
| | | | - Hiroko Nakayama
- Graduate School of Regional Innovation Studies Mie University Tsu Japan.,Mie University Zebrafish Drug Screening Center Tsu Japan
| | - Liqing Zang
- Graduate School of Regional Innovation Studies Mie University Tsu Japan.,Mie University Zebrafish Drug Screening Center Tsu Japan
| | - Mizuho Ota
- Graduate School of Bioresources Mie University Tsu Japan
| | | | | | | | - Norihiro Nishimura
- Graduate School of Regional Innovation Studies Mie University Tsu Japan.,Mie University Zebrafish Drug Screening Center Tsu Japan
| | - Yasuhito Shimada
- Mie University Zebrafish Drug Screening Center Tsu Japan.,Department of Bioinformatics Mie University Advanced Science Research Promotion Center Tsu Japan.,Department of Integrative Pharmacology Mie University Graduate School of Medicine Tsu Japan
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8
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Zang L, Shimada Y, Nakayama H, Matsuoka I, Kim Y, Chu DC, Juneja LR, Tsuruta R, Sasakawa Y, Kuroyanagi J, Nishimura N. Globin Digest Improves Visceral Adiposity Through UCP1 Upregulation in Diet-Induced Obese Zebrafish and Mice. Front Nutr 2021; 8:650975. [PMID: 34646848 PMCID: PMC8502801 DOI: 10.3389/fnut.2021.650975] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2021] [Accepted: 08/12/2021] [Indexed: 11/13/2022] Open
Abstract
Globin digest (GD), a bioactive oligopeptide derived from porcine hemoglobin proteins, has been demonstrated to have beneficial effects on improving postprandial hyperlipidemia, hyperglycemia, and liver injury. We previously reported the lipid-lowering effects of GD using a zebrafish obesogenic test. Here, we sought to evaluate the effect of GD on visceral adiposity and the underlying molecular mechanisms using zebrafish and mouse obesity models. GD ameliorated dyslipidemia and suppressed the accumulation of visceral adipose tissue (VAT) in adult obese zebrafish. Transcriptomic analysis by RNA sequencing of GD-treated adult zebrafish revealed that GD upregulated UCP1-related pathways. Further, we performed mouse experiments and found that GD intake (2 mg/g body weight/day) was associated with lowered plasma triglyceride and total cholesterol levels, decreased VAT accumulation, and improved adipocyte hypertrophy with the upregulation of Ucp1 expression in white adipose tissue at both the mRNA and protein levels. Taken together, these results indicate that GD improves visceral adiposity by upregulating UCP1 expression, providing a novel perspective on combating obesity.
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Affiliation(s)
- Liqing Zang
- Graduate School of Regional Innovation Studies, Mie University, Tsu, Japan
- Mie University Zebrafish Drug Screening Center, Tsu, Japan
| | - Yasuhito Shimada
- Mie University Zebrafish Drug Screening Center, Tsu, Japan
- Department of Integrative Pharmacology, Mie University Graduate School of Medicine, Tsu, Japan
- Department of Bioinformatics, Mie University Advanced Science Research Promotion Center, Tsu, Japan
| | - Hiroko Nakayama
- Graduate School of Regional Innovation Studies, Mie University, Tsu, Japan
- Mie University Zebrafish Drug Screening Center, Tsu, Japan
| | - Izumi Matsuoka
- Graduate School of Regional Innovation Studies, Mie University, Tsu, Japan
| | - Youngil Kim
- Rohto Pharmaceutical Co., Ltd., Osaka, Japan
| | | | - Lekh Raj Juneja
- Rohto Pharmaceutical Co., Ltd., Osaka, Japan
- MG Pharma Inc., Osaka, Japan
| | | | | | | | - Norihiro Nishimura
- Graduate School of Regional Innovation Studies, Mie University, Tsu, Japan
- Mie University Zebrafish Drug Screening Center, Tsu, Japan
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9
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Luzio A, Figueiredo M, Matos MM, Coimbra AM, Álvaro AR, Monteiro SM. Effects of short-term exposure to genistein and overfeeding diet on the neural and retinal progenitor competence of adult zebrafish (Danio rerio). Neurotoxicol Teratol 2021; 88:107030. [PMID: 34506931 DOI: 10.1016/j.ntt.2021.107030] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2021] [Revised: 09/01/2021] [Accepted: 09/01/2021] [Indexed: 12/25/2022]
Abstract
Neurogenesis is a process that occurs throughout the life of a vertebrate. Among the different factors that may affect the natural occurrence of neurogenesis, obesity seems to decrease the proliferation capacity of progenitor neuronal cells. Conversely, the phytoestrogen genistein is known to attenuate some obesity effects beyond its neuroprotective action. Aiming to improve the understanding of how obesity and genistein trigger an impact on the neural and retinal progenitor competence of adult zebrafish, fish were exposed to genistein (GEN - 2 μg L-1) alone or combined with two dietary groups (control and overfeed - OFD) for up to 9 weeks. Zebrafish were fed once per day with Artemia sp. in the control and GEN (2% of BW, control diet), and three times per day in the OFD and OFD + GEN groups (12% BW, overfeeding diet). To assess obesity induction, BMI, biometric parameters, and PPAR-γ protein were quantified. Afterwards, qRT-PCR and immunohistochemistry were performed to determine the cell proliferation and the presence of stem cells through PCNA and Sox-2. Our findings proved that overfeeding adult zebrafish increased the general growth and induced the development of fatty liver. However, for OFD + GEN, this effect was assuaged through the anti-adipogenic effect of GEN. This finding suggests that phytoestrogens could be beneficial to reduce the negative effects of obesity. Moreover, OF induced negative effects on retinal and brain homeostasis, decreasing the proliferation capacity of progenitor neuronal cells. With regard to retinal progenitor competence, genistein seems to mitigate the negative impacts of obesity, whereas the effects of obesity on the brain were exacerbated by this phytoestrogen which negatively influenced the homeostasis of zebrafish neural progenitor competence. This study highlighted the fact that the effects of phytoestrogens in adult neural progenitor competence are complex and could exhibit dissimilar effects depending on the tissue.
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Affiliation(s)
- A Luzio
- Centre for the Research and Technology of Agro-Environmental and Biological Sciences, CITAB and Inov4Agro - Institute for Innovation, Capacity Building and Sustainability of Agri-food Production, Vila Real, Portugal; Department of Biology and Environment, Life Sciences and Environment School, University of Trás-os-Montes e Alto Douro, Apt. 1013, 5000-801 Vila Real, Portugal
| | - M Figueiredo
- Department of Biology and Environment, Life Sciences and Environment School, University of Trás-os-Montes e Alto Douro, Apt. 1013, 5000-801 Vila Real, Portugal
| | - M M Matos
- Department of Genetics and Biotechnology, Life Sciences and Environment School, University of Trás-os-Montes and Alto Douro (UTAD), Vila Real, Portugal; Biosystems & Integrative Sciences Institute (BioISI), Sciences Faculty, University of Lisbon, Lisbon, Portugal
| | - A M Coimbra
- Centre for the Research and Technology of Agro-Environmental and Biological Sciences, CITAB and Inov4Agro - Institute for Innovation, Capacity Building and Sustainability of Agri-food Production, Vila Real, Portugal; Department of Genetics and Biotechnology, Life Sciences and Environment School, University of Trás-os-Montes and Alto Douro (UTAD), Vila Real, Portugal
| | - A R Álvaro
- Center for Neuroscience and Cell Biology, University of Coimbra (CNBC-UC), 3004-504 Coimbra, Portugal.
| | - S M Monteiro
- Centre for the Research and Technology of Agro-Environmental and Biological Sciences, CITAB and Inov4Agro - Institute for Innovation, Capacity Building and Sustainability of Agri-food Production, Vila Real, Portugal; Department of Biology and Environment, Life Sciences and Environment School, University of Trás-os-Montes e Alto Douro, Apt. 1013, 5000-801 Vila Real, Portugal.
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10
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Su Y, He L, Hu Z, Li Y, Zhang Y, Fan Z, Zhao K, Zhang H, Liu C. Obesity Causes Abrupt Changes in the Testicular Microbiota and Sperm Motility of Zebrafish. Front Immunol 2021; 12:639239. [PMID: 34248933 PMCID: PMC8268156 DOI: 10.3389/fimmu.2021.639239] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2020] [Accepted: 06/04/2021] [Indexed: 12/12/2022] Open
Abstract
Background Obesity is a recognized risk factor for low fertility and is becoming increasingly prevalent in many countries around the world. Obesity changes intestinal microbiota composition, causes inflammation of various organs, and also reduces sperm quality. Several microorganisms are present in the testis. However, whether obesity affects the changes of testicular microbiota and whether these changes are related to reduced fertility in obese men remain to be elucidated. Methods In the present study, a zebrafish obesity model was established by feeding with egg yolk powder. Sperm motility was measured by the Computer Assisted Sperm Analysis system, testicular microbial communities was assessed via 16s RNA sequencing, the immune response in zebrafish testis was quantified by quantitative real-time polymerase chain reaction and enzyme-linked immunosorbent assay, and the testicular tissue structure was detected by electron microscopy and hematoxylin–eosin staining. Results Compared with the control group, zebrafish sperm motility was dramatically reduced, the expression of testicular proinflammatory cytokines in the testes was upregulated, and the blood–testis barrier structure was disrupted in the obese group. In addition, testicular microbiome composition was clearly altered in the obese group. Conclusion Obesity alters testicular microbiota composition, and the reason behind the decreased sperm motility in obese zebrafish may be related to changes in the testicular microbial communities.
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Affiliation(s)
- Yufang Su
- Institute of Reproductive Health, Tongji Medical College, HuaZhong University of Science and Technology, Wuhan, China.,Department of Oncology, Jiangxi Maternal and Child Health Hospital, Nanchang, China
| | - Liting He
- Institute of Reproductive Health, Tongji Medical College, HuaZhong University of Science and Technology, Wuhan, China
| | - Zhiyong Hu
- Institute of Reproductive Health, Tongji Medical College, HuaZhong University of Science and Technology, Wuhan, China
| | - Ying Li
- Prenatal Diagnostic Center, People's Hospital of Guangxi Zhuang Autonomous Region, Nanning, China
| | - Yuan Zhang
- Institute of Reproductive Health, Tongji Medical College, HuaZhong University of Science and Technology, Wuhan, China
| | - Zunpan Fan
- Institute of Reproductive Health, Tongji Medical College, HuaZhong University of Science and Technology, Wuhan, China
| | - Kai Zhao
- Institute of Reproductive Health, Tongji Medical College, HuaZhong University of Science and Technology, Wuhan, China
| | - Huiping Zhang
- Institute of Reproductive Health, Tongji Medical College, HuaZhong University of Science and Technology, Wuhan, China
| | - Chunyan Liu
- Institute of Reproductive Health, Tongji Medical College, HuaZhong University of Science and Technology, Wuhan, China
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11
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Li MX, Qiang J, Bao JW, Tao YF, Zhu HJ, Xu P. Growth performance, physiological parameters, and transcript levels of lipid metabolism-related genes in hybrid yellow catfish (Tachysurus fulvidraco ♀ × Pseudobagrus vachellii ♂) fed diets containing Siberian ginseng. PLoS One 2021; 16:e0246417. [PMID: 33571255 PMCID: PMC7877655 DOI: 10.1371/journal.pone.0246417] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2020] [Accepted: 01/19/2021] [Indexed: 01/20/2023] Open
Abstract
In high-density aquaculture, fish health can suffer because of excessive feeding, which causes fatty liver disease. Siberian ginseng (Acanthopanax senticosus) has been used as a feed additive to promote animal growth, immunity, and lipid metabolism. In this study, we explored the effects of A. senticosus on the physiology of hybrid yellow catfish (Tachysurus fulvidraco ♀ × Pseudobagrus vachellii ♂). A control group and five groups fed diets containing A. senticosus (0.5, 1, 2, 4, and 8 g A. senticosus/kg feed) were established and maintained for 8 weeks. Dietary supplementation with A. senticosus at 4 g/kg promoted growth of the hybrid yellow catfish. Serum total cholesterol (TC) and triacylglycerol (TG) levels at 2 g/kg A. senticosus (TC: 1.31 mmol/L; TG: 1.08 mmol/L) were significantly lower than in the control group (TC: 1.51 mmol/L; TG: 1.41 mmol/L), and 4 g/kg A. senticosus (17.20 μmol/g tissue) reduced the liver TG level compared with the control group (21.36 μmol/g tissue) (P <0.05). Comparative transcriptomic analysis of liver tissue between the control group and the group showing optimum growth (4 g/kg A. senticosus) revealed 820 differentially expressed genes and 44 significantly enriched pathways, especially lipid metabolism pathways such as unsaturated fatty acid and fatty acid metabolism. The transcript levels of five lipid metabolism-related genes were determined by quantitative real-time PCR. The results showed that 2–4 g/kg A. senticosus supplementation reduced the FADS2, ELOVL2, CYP24a, and PLPP3 transcript levels and 4 g/kg A. senticosus increased the DIO2 transcript level (P <0.05), leading to altered synthesis of TG and thyroxine and reduced fat deposition in the liver. Our results show that dietary A. senticosus affects the regulation of fat metabolism and promotes the growth of hybrid yellow catfish. A. senticosus is a healthy feed additive, and the appropriate dietary supplementation rate is 2–4 g/kg.
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Affiliation(s)
- Ming Xiao Li
- Wuxi Fisheries College, Nanjing Agricultural University, Jiangsu, Wuxi, China
| | - Jun Qiang
- Key Laboratory of Freshwater Fishes and Germplasm Resources Utilization, Ministry of Agriculture, Freshwater Fisheries Research Center, Chinese Academy of Fishery Sciences, Jiangsu, Wuxi, China
| | - Jing Wen Bao
- Key Laboratory of Freshwater Fishes and Germplasm Resources Utilization, Ministry of Agriculture, Freshwater Fisheries Research Center, Chinese Academy of Fishery Sciences, Jiangsu, Wuxi, China
| | - Yi Fan Tao
- Key Laboratory of Freshwater Fishes and Germplasm Resources Utilization, Ministry of Agriculture, Freshwater Fisheries Research Center, Chinese Academy of Fishery Sciences, Jiangsu, Wuxi, China
| | - Hao Jun Zhu
- Key Laboratory of Freshwater Fishes and Germplasm Resources Utilization, Ministry of Agriculture, Freshwater Fisheries Research Center, Chinese Academy of Fishery Sciences, Jiangsu, Wuxi, China
| | - Pao Xu
- Wuxi Fisheries College, Nanjing Agricultural University, Jiangsu, Wuxi, China
- Key Laboratory of Freshwater Fishes and Germplasm Resources Utilization, Ministry of Agriculture, Freshwater Fisheries Research Center, Chinese Academy of Fishery Sciences, Jiangsu, Wuxi, China
- * E-mail:
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12
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Shende P, Narvenker R. Herbal nanotherapy: A new paradigm over conventional obesity treatment. J Drug Deliv Sci Technol 2021. [DOI: 10.1016/j.jddst.2020.102291] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
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13
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Matsuura N, Zang L, Nishimura N, Shimada Y. Lacto-Fermented Cauliflower Fungus (Sparassis crispa) Ameliorates Hepatic Steatosis by Activating Beta-Oxidation in Diet-Induced Obese Zebrafish. J Med Food 2020; 23:803-810. [DOI: 10.1089/jmf.2019.4571] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022] Open
Affiliation(s)
- Nobuo Matsuura
- Graduate School of Regional Innovation Studies, Mie University, Tsu, Japan
- Bankyo Pharmaceutical Co., Ltd., Taki, Japan
| | - Liqing Zang
- Graduate School of Regional Innovation Studies, Mie University, Tsu, Japan
- Mie University Zebrafish Drug Screening Center, Tsu, Japan
| | - Norihiro Nishimura
- Graduate School of Regional Innovation Studies, Mie University, Tsu, Japan
- Mie University Zebrafish Drug Screening Center, Tsu, Japan
| | - Yasuhito Shimada
- Graduate School of Regional Innovation Studies, Mie University, Tsu, Japan
- Mie University Zebrafish Drug Screening Center, Tsu, Japan
- Department of Integrative Pharmacology, Mie University Graduate School of Medicine, Tsu, Japan
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14
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Wiggenhauser LM, Kroll J. Vascular Damage in Obesity and Diabetes: Highlighting Links Between Endothelial Dysfunction and Metabolic Disease in Zebrafish and Man. Curr Vasc Pharmacol 2020; 17:476-490. [PMID: 30378499 DOI: 10.2174/1570161116666181031101413] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2018] [Revised: 09/11/2018] [Accepted: 09/25/2018] [Indexed: 02/08/2023]
Abstract
Endothelial dysfunction is an initial pathophysiological mechanism of vascular damage and is further recognized as an independent predictor of negative prognosis in diabetes-induced micro- and macrovascular complications. Insight into the capability of zebrafish to model metabolic disease like obesity and type II diabetes has increased and new evidence on the induction of vascular pathologies in zebrafish through metabolic disease is available. Here, we raise the question, if zebrafish can be utilized to study the initial impairments of vascular complications in metabolic disorders. In this review, we focus on the advances made to develop models of obesity and type II diabetes in zebrafish, discuss the key points and characteristics of these models, while highlighting the available information linked to the development of endothelial dysfunction in zebrafish and man. We show that larval and adult zebrafish develop metabolic dysregulation in the settings of obesity and diabetes, exhibiting pathophysiological mechanisms, which mimic the human condition. The most important genes related to endothelial dysfunction are present in zebrafish and further display similar functions as in mammals. Several suggested contributors to endothelial dysfunction found in these models, namely hyperinsulinaemia, hyperglycaemia, hyperlipidaemia and hyperleptinaemia are highlighted and the available data from zebrafish are summarised. Many underlying processes of endothelial dysfunction in obesity and diabetes are fundamentally present in zebrafish and provide ground for the assumption, that zebrafish can develop endothelial dysfunction. Conservation of basic biological mechanisms is established for zebrafish, but focused investigation on the subject is now needed as validation and particularly more research is necessary to understand the differences between zebrafish and man. The available data demonstrate the relevance of zebrafish as a model for metabolic disease and their ability to become a proponent for the investigation of vascular damage in the settings of obesity and diabetes.
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Affiliation(s)
- Lucas Moritz Wiggenhauser
- Department of Vascular Biology and Tumor Angiogenesis, European Center for Angioscience, Medical Faculty Mannheim, Heidelberg University, 68167 Mannheim, Germany
| | - Jens Kroll
- Department of Vascular Biology and Tumor Angiogenesis, European Center for Angioscience, Medical Faculty Mannheim, Heidelberg University, 68167 Mannheim, Germany
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15
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Yamada Y, Chensom S, Yonemoto H, Nakayama H, Zang L, Nishimura N, Mishima T, Shimada Y. Water Extract of Yamato Tachibana (Citrus tachibana) Induces Food Intake in Adult and Larval Zebrafish. J Med Food 2020; 23:65-71. [DOI: 10.1089/jmf.2019.4484] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/25/2023] Open
Affiliation(s)
- Yuka Yamada
- Graduate School of Regional Innovation Studies, Mie University, Tsu, Mie, Japan
| | - Sasicha Chensom
- Graduate School of Regional Innovation Studies, Mie University, Tsu, Mie, Japan
| | - Hisataka Yonemoto
- Department of Integrative Pharmacology, Graduate School of Medicine, Mie University, Tsu, Mie, Japan
| | - Hiroko Nakayama
- Graduate School of Regional Innovation Studies, Mie University, Tsu, Mie, Japan
- Zebrafish Drug Screening Center, Mie University, Tsu, Mie, Japan
| | - Liqing Zang
- Graduate School of Regional Innovation Studies, Mie University, Tsu, Mie, Japan
- Zebrafish Drug Screening Center, Mie University, Tsu, Mie, Japan
| | - Norihiro Nishimura
- Graduate School of Regional Innovation Studies, Mie University, Tsu, Mie, Japan
- Zebrafish Drug Screening Center, Mie University, Tsu, Mie, Japan
| | - Takashi Mishima
- Graduate School of Regional Innovation Studies, Mie University, Tsu, Mie, Japan
- Graduate School of Bioresources, Mie University, Tsu, Mie, Japan
| | - Yasuhito Shimada
- Department of Integrative Pharmacology, Graduate School of Medicine, Mie University, Tsu, Mie, Japan
- Zebrafish Drug Screening Center, Mie University, Tsu, Mie, Japan
- Department of Bioinformatics, Advanced Science Research Promotion Center, Mie University, Tsu, Mie, Japan
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16
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Williams MB, Watts SA. Current basis and future directions of zebrafish nutrigenomics. GENES AND NUTRITION 2019; 14:34. [PMID: 31890052 PMCID: PMC6935144 DOI: 10.1186/s12263-019-0658-2] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 09/04/2019] [Accepted: 12/16/2019] [Indexed: 12/19/2022]
Abstract
This review investigates the current state of nutrigenomics in the zebrafish animal models. The zebrafish animal model has been used extensively in the study of disease onset and progression and associated molecular changes. In this review, we provide a synopsis of nutrigenomics using the zebrafish animal model. Obesity and dyslipidemia studies describe the genomics of dietary-induced obesity in relation to high-fat/high-calorie diets. Inflammation and cardiovascular studies describe dietary effects on the expression of acute inflammatory markers and resulting chronic inflammatory issues including atherosclerosis. We also evaluated the genomic response to bioactive dietary compounds associated with metabolic disorders. Carbohydrate metabolism and β-cell function studies describe the impacts of high-carbohydrate dietary challenges on nutritional programming. We also report tumorigenesis in relation to dietary carcinogen exposure studies that can result in permanent genomic changes. Vitamin and mineral deficiency studies demonstrate transgenerational genomic impacts of micronutrients in the diet and temporal expression changes. Circadian rhythm studies describe the relation between metabolism and natural temporal cycles of gene expression that impacts health. Bone formation studies describe the role of dietary composition that influences bone reabsorption regulation. Finally, this review provides future directions in the use of the zebrafish model for nutrigenomic and nutrigenetic research.
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Affiliation(s)
- Michael B Williams
- Department of Biology, University of Alabama at Birmingham, Birmingham, AL 35294 USA
| | - Stephen A Watts
- Department of Biology, University of Alabama at Birmingham, Birmingham, AL 35294 USA
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17
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Tanaka T, Koiwa J. [Next generation zebrafish-based drug discovery and precision medicine]. Nihon Yakurigaku Zasshi 2019; 154:78-83. [PMID: 31406047 DOI: 10.1254/fpj.154.78] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/26/2022]
Abstract
Even after entering the era of genomic drug discovery in the 21st century, development of a breakthrough therapeutic drug (first-in-class) for intractable diseases (unmet medical needs) has been extremely difficult, but to the US FDA 62% of the approved first-in-class drugs are found by phenotypic screening. The next-generation zebrafish drug discovery enables high-throughput quantitative live in vivo phenotypic screening, and has been impacting global drug discovery strategies now. Compared to severe immunodeficient mice, zebrafish is expected to become a true individualized medical tool as a clinical ex vivo diagnostic system because of the high efficiency and speed of engraftment of patient-derived cancer xenotransplantation. Phenomics-based personalized medicine with the patient-derived cancer xenograft zebrafish in addition to conventional omics platform of individualized medicine is a true next-generation precision medicine to utilize for selection of therapeutic drugs and decision of their doses for the patient, and emerging paradigm shift is realizing in this century.
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Affiliation(s)
- Toshio Tanaka
- Department of Systems Pharmacology, Mie University Graduate School of Medicine.,Mie University Medical Zebrafish Research Center
| | - Junko Koiwa
- Department of Systems Pharmacology, Mie University Graduate School of Medicine
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18
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Zang L, Shimada Y, Nakayama H, Chen W, Okamoto A, Koide H, Oku N, Dewa T, Shiota M, Nishimura N. Therapeutic Silencing of Centromere Protein X Ameliorates Hyperglycemia in Zebrafish and Mouse Models of Type 2 Diabetes Mellitus. Front Genet 2019; 10:693. [PMID: 31417608 PMCID: PMC6681619 DOI: 10.3389/fgene.2019.00693] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2019] [Accepted: 07/02/2019] [Indexed: 01/17/2023] Open
Abstract
Type 2 diabetes mellitus (T2DM) is characterized by persistent hyperglycemia and is influenced by genetic and environmental factors. Optimum T2DM management involves early diagnosis and effective glucose-lowering therapies. Further research is warranted to improve our understanding of T2DM pathophysiology and reveal potential roles of genetic predisposition. We have previously developed an obesity-induced diabetic zebrafish model that shares common pathological pathways with humans and may be used to identify putative pharmacological targets of diabetes. Additionally, we have previously identified several candidate genes with altered expression in T2DM zebrafish. Here, we performed a small-scale zebrafish screening for these genes and discovered a new therapeutic target, centromere protein X (CENPX), which was further validated in a T2DM mouse model. In zebrafish, cenpx knockdown by morpholino or knockout by CRISPR/Cas9 system ameliorated overfeeding-induced hyperglycemia and upregulated insulin level. In T2DM mice, small-interfering RNA-mediated Cenpx knockdown decreased hyperglycemia and upregulated insulin synthesis in the pancreas. Gene expression analysis revealed insulin, mechanistic target of rapamycin, leptin, and insulin-like growth factor 1 pathway activation following Cenpx silencing in pancreas tissues. Thus, CENPX inhibition exerted antidiabetic effects via increased insulin expression and related pathways. Therefore, T2DM zebrafish may serve as a powerful tool in the discovery of new therapeutic gene targets.
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Affiliation(s)
- Liqing Zang
- Graduate School of Regional Innovation Studies, Mie University, Tsu, Japan.,Mie University Zebrafish Drug Screening Center, Tsu, Japan
| | - Yasuhito Shimada
- Mie University Zebrafish Drug Screening Center, Tsu, Japan.,Department of Integrative Pharmacology, Mie University Graduate School of Medicine, Tsu, Japan.,Department of Bioinformatics, University Advanced Science Research Promotion Centre, Tsu, Mie, Japan
| | - Hiroko Nakayama
- Graduate School of Regional Innovation Studies, Mie University, Tsu, Japan.,Mie University Zebrafish Drug Screening Center, Tsu, Japan
| | - Wenbiao Chen
- Department of Molecular Physiology & Biophysics, Vanderbilt University School of Medicine, Nashville, TN, United States
| | - Ayaka Okamoto
- Department of Medical Biochemistry, School of Pharmaceutical Sciences, University of Shizuoka, Shizuoka, Japan
| | - Hiroyuki Koide
- Department of Medical Biochemistry, School of Pharmaceutical Sciences, University of Shizuoka, Shizuoka, Japan
| | - Naoto Oku
- Department of Medical Biochemistry, School of Pharmaceutical Sciences, University of Shizuoka, Shizuoka, Japan
| | - Takehisa Dewa
- Department of Frontier Materials, Graduate School of Engineering, Nagoya Institute of Technology, Nagoya, Japan
| | - Masayuki Shiota
- Department of Research Support Platform, Graduate School of Medicine, Osaka City University, Osaka, Japan
| | - Norihiro Nishimura
- Graduate School of Regional Innovation Studies, Mie University, Tsu, Japan.,Mie University Zebrafish Drug Screening Center, Tsu, Japan
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19
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Elvira-Torales LI, García-Alonso J, Periago-Castón MJ. Nutritional Importance of Carotenoids and Their Effect on Liver Health: A Review. Antioxidants (Basel) 2019; 8:antiox8070229. [PMID: 31330977 PMCID: PMC6681007 DOI: 10.3390/antiox8070229] [Citation(s) in RCA: 95] [Impact Index Per Article: 15.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2019] [Revised: 07/15/2019] [Accepted: 07/18/2019] [Indexed: 12/11/2022] Open
Abstract
The consumption of carotenoids has beneficial effects on health, reducing the risk of certain forms of cancer, cardiovascular diseases, and macular degeneration, among others. The mechanism of action of carotenoids has not been clearly identified; however, it has been associated with the antioxidant capacity of carotenoids, which acts against reactive oxygen species and inactivating free radicals, although it has also been shown that carotenoids modulate gene expression. Dietary carotenoids are absorbed and accumulated in the liver and other organs, where they exert their beneficial effects. In recent years, it has been described that the intake of carotenoids can significantly reduce the risk of suffering from liver diseases, such as non-alcoholic fatty liver disease (NAFLD). This disease is characterized by an imbalance in lipid metabolism producing the accumulation of fat in the hepatocyte, leading to lipoperoxidation, followed by oxidative stress and inflammation. In the first phases, the main treatment of NAFLD is to change the lifestyle, including dietary habits. In this sense, carotenoids have been shown to have a hepatoprotective effect due to their ability to reduce oxidative stress and regulate the lipid metabolism of hepatocytes by modulating certain genes. The objective of this review was to provide a description of the effects of dietary carotenoids from fruits and vegetables on liver health.
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Affiliation(s)
- Laura Inés Elvira-Torales
- Department of Food Technology, Food Science and Nutrition, Faculty of Veterinary Sciences, Regional Campus of International Excellence "Campus Mare Nostrum", Biomedical Research Institute of Murcia (IMIB-Arrixaca-UMU), University Clinical Hospital "Virgen de la Arrixaca", University of Murcia, Espinardo, 30071 Murcia, Spain.
- Department of Food Engineering, Tierra Blanca Superior Technological Institute, Tierra Blanca 95180, Mexico.
| | - Javier García-Alonso
- Department of Food Technology, Food Science and Nutrition, Faculty of Veterinary Sciences, Regional Campus of International Excellence "Campus Mare Nostrum", Biomedical Research Institute of Murcia (IMIB-Arrixaca-UMU), University Clinical Hospital "Virgen de la Arrixaca", University of Murcia, Espinardo, 30071 Murcia, Spain
| | - María Jesús Periago-Castón
- Department of Food Technology, Food Science and Nutrition, Faculty of Veterinary Sciences, Regional Campus of International Excellence "Campus Mare Nostrum", Biomedical Research Institute of Murcia (IMIB-Arrixaca-UMU), University Clinical Hospital "Virgen de la Arrixaca", University of Murcia, Espinardo, 30071 Murcia, Spain.
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20
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Elvira-Torales LI, Martín-Pozuelo G, González-Barrio R, Navarro-González I, Pallarés FJ, Santaella M, García-Alonso J, Sevilla Á, Periago-Castón MJ. Ameliorative Effect of Spinach on Non-Alcoholic Fatty Liver Disease Induced in Rats by a High-Fat Diet. Int J Mol Sci 2019; 20:ijms20071662. [PMID: 30987167 PMCID: PMC6479744 DOI: 10.3390/ijms20071662] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/19/2019] [Revised: 03/22/2019] [Accepted: 04/01/2019] [Indexed: 12/24/2022] Open
Abstract
The purpose of this work was to evaluate the effect of dietary carotenoids from spinach on the inflammation and oxidative stress biomarkers, liver lipid profile, and liver transcriptomic and metabolomics profiles in Sprague–Dawley rats with steatosis induced by a high-fat diet. Two concentrations of spinach powder (2.5 and 5%) were used in two types of diet: high-fat (H) and standard (N). Although rats fed diet H showed an accumulation of fat in hepatocytes, they did not show differences in the values of adiponectin, tumor necrosis factor alpha (TNF-α), and oxygen radical absorption (ORAC) in plasma or of isoprostanes in urine compared with animals fed diet N. The consumption of spinach and the accumulation of α and β carotenes and lutein in the liver was inversely correlated with serum total cholesterol and glucose and the content of hepatic cholesterol, increasing monounsaturated fatty acids (MUFA), polyunsaturated fatty acids (PUFA) and reducing cholesterol in the livers of rats fed diet H and spinach. In addition, changes in the expression of genes related to the fatty liver condition occurred, and the expression of genes involved in the metabolism of fatty acids and cholesterol increased, mainly through the overexpression of peroxisome proliferator activated receptors (PPARs). Related to liver metabolites, animals fed with diet H showed hypoaminoacidemia, mainly for the glucogenic aminoacids. Although no changes were observed in inflammation and oxidative stress biomarkers, the consumption of spinach modulated the lipid metabolism in liver, which must be taken into consideration during the dietary treatment of steatosis.
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Affiliation(s)
- Laura Inés Elvira-Torales
- Department of Food Technology, Food Science and Nutrition, Faculty of Veterinary Sciences, Regional Campus of International Excellence "Campus Mare Nostrum", Biomedical Research Institute of Murcia (IMIB-Arrixaca-UMU), University Clinical Hospital "Virgen de la Arrixaca", University of Murcia, Espinardo, 30071 Murcia, Spain.
- Department of Food Engineering, Tierra Blanca Superior Technological Institute, 95180 Tierra Blanca, Veracruz, Mexico.
| | - Gala Martín-Pozuelo
- Department of Food Technology, Food Science and Nutrition, Faculty of Veterinary Sciences, Regional Campus of International Excellence "Campus Mare Nostrum", Biomedical Research Institute of Murcia (IMIB-Arrixaca-UMU), University Clinical Hospital "Virgen de la Arrixaca", University of Murcia, Espinardo, 30071 Murcia, Spain.
| | - Rocío González-Barrio
- Department of Food Technology, Food Science and Nutrition, Faculty of Veterinary Sciences, Regional Campus of International Excellence "Campus Mare Nostrum", Biomedical Research Institute of Murcia (IMIB-Arrixaca-UMU), University Clinical Hospital "Virgen de la Arrixaca", University of Murcia, Espinardo, 30071 Murcia, Spain.
| | - Inmaculada Navarro-González
- Department of Food Technology, Food Science and Nutrition, Faculty of Veterinary Sciences, Regional Campus of International Excellence "Campus Mare Nostrum", Biomedical Research Institute of Murcia (IMIB-Arrixaca-UMU), University Clinical Hospital "Virgen de la Arrixaca", University of Murcia, Espinardo, 30071 Murcia, Spain.
| | - Francisco-José Pallarés
- Department of Anatomy and Comparative Pathological Anatomy, Faculty of Veterinary Sciences, Regional Campus of International Excellence "Campus Mare Nostrum", University of Murcia, Espinardo, 30071 Murcia, Spain.
| | - Marina Santaella
- Department of Food Technology, Food Science and Nutrition, Faculty of Veterinary Sciences, Regional Campus of International Excellence "Campus Mare Nostrum", Biomedical Research Institute of Murcia (IMIB-Arrixaca-UMU), University Clinical Hospital "Virgen de la Arrixaca", University of Murcia, Espinardo, 30071 Murcia, Spain.
| | - Javier García-Alonso
- Department of Food Technology, Food Science and Nutrition, Faculty of Veterinary Sciences, Regional Campus of International Excellence "Campus Mare Nostrum", Biomedical Research Institute of Murcia (IMIB-Arrixaca-UMU), University Clinical Hospital "Virgen de la Arrixaca", University of Murcia, Espinardo, 30071 Murcia, Spain.
| | - Ángel Sevilla
- Anchormen, Pedro de Medinalaan 11, 1086 XK Amsterdam, The Netherlands.
| | - María Jesús Periago-Castón
- Department of Food Technology, Food Science and Nutrition, Faculty of Veterinary Sciences, Regional Campus of International Excellence "Campus Mare Nostrum", Biomedical Research Institute of Murcia (IMIB-Arrixaca-UMU), University Clinical Hospital "Virgen de la Arrixaca", University of Murcia, Espinardo, 30071 Murcia, Spain.
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21
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Tran VC, Cho SY, Kwon J, Kim D. Alginate oligosaccharide (AOS) improves immuno-metabolic systems by inhibiting STOML2 overexpression in high-fat-diet-induced obese zebrafish. Food Funct 2019; 10:4636-4648. [DOI: 10.1039/c9fo00982e] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
AOS improves immuno-metabolism systems in high-fat-died-induced obese zebrafish by regulating STOML2.
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Affiliation(s)
- Van Cuong Tran
- Department of Food Science and Technology
- Chonnam National University
- Gwangju
- Republic of Korea
- Department of Food Science and Post-harvest Technology
| | - Se-Young Cho
- Biological Disaster Analysis Group
- Korea Basic Science Institute
- Daejeon
- Republic of Korea
| | - Joseph Kwon
- Biological Disaster Analysis Group
- Korea Basic Science Institute
- Daejeon
- Republic of Korea
| | - Duwoon Kim
- Department of Food Science and Technology
- Chonnam National University
- Gwangju
- Republic of Korea
- Foodborne Virus Research Center
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Xiao Y, Wu Y, Zhong K, Gao H. Comprehensive evaluation of the composition of Mingshan Laochuancha green tea and demonstration of hypolipidemic activity in a zebrafish obesity model. RSC Adv 2019; 9:41269-41279. [PMID: 35540089 PMCID: PMC9076403 DOI: 10.1039/c9ra07655g] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2019] [Accepted: 11/28/2019] [Indexed: 11/21/2022] Open
Abstract
Laochuancha is an ancient tea plant originating from the Mingshan district of Ya'an city, Sichuan province, China, which is used to produce tea products with excellent quality. Mingshan Laochuancha green tea (MLGT) is a type of green tea manufactured from Laochuancha tea leaves. Currently, not much is known regarding the chemical compositions of MLGT and its bioactivity. Herein, the present study explores, for the first time, the chemical compositions and hypolipidemic activity of MLGT. It was observed that K was the most abundant element of 26.58 mg g−1, and contents of toxic As, Cd, Cr and Pb elements were all below concentration limits. Alcohols (55.65%) were the main volatiles, and numerous volatiles with chestnut-like aroma were detected. Total content of 21 amino acids was 28.61 mg g−1, and amino acids with velvety-like and umami taste totally accounted for 65.39%. The high content of amino acids and low ratio of polyphenols to total amino acids were attributed to strong umami and mellow taste of MLGT. Moreover, catechins and alkaloids were abundant in MLGT, where EGCG (85.82 mg g−1) and caffeine (33.78 mg g−1) were at highest content. Analyses of chemical compositions revealed excellent quality of MLGT. Correspondingly, MLGT showed potent hypolipidemic activity, and water extract of MLGT at 200 μg mL−1 significantly reduced lipid level to 43.06% of high-fat zebrafish. Results firstly revealed the quality characteristics of MLGT and provided further insights into bioactivity of Laochuancha. MLGT was investigated for the first time, and results revealed excellent quality and potent hypolipidemic activity of MLGT.![]()
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Affiliation(s)
- Yue Xiao
- College of Biomass Science and Engineering
- Healthy Food Evaluation Research Center
- Sichuan University
- Chengdu 610065
- China
| | - Yanping Wu
- College of Biomass Science and Engineering
- Healthy Food Evaluation Research Center
- Sichuan University
- Chengdu 610065
- China
| | - Kai Zhong
- College of Biomass Science and Engineering
- Healthy Food Evaluation Research Center
- Sichuan University
- Chengdu 610065
- China
| | - Hong Gao
- College of Biomass Science and Engineering
- Healthy Food Evaluation Research Center
- Sichuan University
- Chengdu 610065
- China
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23
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Faillaci F, Milosa F, Critelli RM, Turola E, Schepis F, Villa E. Obese zebrafish: A small fish for a major human health condition. Animal Model Exp Med 2018; 1:255-265. [PMID: 30891575 PMCID: PMC6388073 DOI: 10.1002/ame2.12042] [Citation(s) in RCA: 29] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2018] [Revised: 10/11/2018] [Accepted: 10/18/2018] [Indexed: 12/14/2022] Open
Abstract
Obesity is becoming a silent worldwide epidemic, with a steady increase in both adults and children. To date, even though several drugs have been licensed for long-term obesity treatment, none of them are yet used in routine clinical practice. So far the only successful intervention has been behavioral therapy. A suitable and economic experimental model mimicking the human condition would therefore be extremely useful to evaluate preventive measures and novel treatments. Zebrafish are emerging as an important model system to study obesity and related metabolic disease. Remarkable similarities have been reported in lipid metabolism and the adipogenic pathway between zebrafish and mammals. Moreover, the zebrafish possesses a number of features-the relative inexpensiveness of animal husbandry, its optical transparency and the ability to produce a large number of offspring at low cost-that make it ideal for large-scale screening and for testing drugs and intervention. In this review, we summarize recent progress in using zebrafish as a model system to study obesity and obesity-related metabolic disorders. We describe several zebrafish models (in both larvae and adult animals) that develop obesity and non-alcoholic fatty liver disease (NAFLD) using different approaches, including gene manipulation, diet manipulation and modification of microbiota composition. For these models, we have outlined the specific aspects related to obesity and its development and we have summarized their advantages and limitations.
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Affiliation(s)
- Francesca Faillaci
- Department of Internal MedicineGastroenterology UnitUniversity of Modena and Reggio EmiliaModenaItaly
- Women in Hepatology GroupModenaItaly
| | - Fabiola Milosa
- Women in Hepatology GroupModenaItaly
- National Institute of Gastroenterology“S. de Bellis” Research HospitalCastellana GrotteItaly
| | - Rosina Maria Critelli
- Department of Internal MedicineGastroenterology UnitUniversity of Modena and Reggio EmiliaModenaItaly
- Women in Hepatology GroupModenaItaly
| | - Elena Turola
- Department of Internal MedicineEndocrinology UnitAOU of ParmaParmaItaly
| | - Filippo Schepis
- Department of Internal MedicineGastroenterology UnitUniversity of Modena and Reggio EmiliaModenaItaly
| | - Erica Villa
- Department of Internal MedicineGastroenterology UnitUniversity of Modena and Reggio EmiliaModenaItaly
- Women in Hepatology GroupModenaItaly
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24
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Nakayama H, Shimada Y, Zang L, Terasawa M, Nishiura K, Matsuda K, Toombs C, Langdon C, Nishimura N. Novel Anti-Obesity Properties of Palmaria mollis in Zebrafish and Mouse Models. Nutrients 2018; 10:nu10101401. [PMID: 30279329 PMCID: PMC6213011 DOI: 10.3390/nu10101401] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/27/2018] [Revised: 09/26/2018] [Accepted: 09/28/2018] [Indexed: 12/14/2022] Open
Abstract
(1) Background: The red seaweed Palmaria mollis (PM), which has a bacon-like taste, is increasingly being included in Western diets. In this study, we evaluate anti-obesity effects of PM using diet-induced obese (DIO) zebrafish and mice models. (2) Methods: We fed PM-containing feed to DIO-zebrafish and mice, and evaluated the anti-obesity effects We also analyzed gene expression changes in their liver and visceral adipose tissues (VAT). (3) Results: PM ameliorated several anti-obesity traits in both animals, including dyslipidaemia, hepatic steatosis, and visceral adiposity. In liver tissues of DIO-zebrafish and mice, PM upregulated gene expressions involved in peroxisome proliferator-activated receptor alpha (PPARA) pathways, and downregulated peroxisome proliferator-activated receptor gamma (PPARG) pathways, suggesting that the lipid-lowering effect of PM might be caused by activation of beta-oxidation and inhibition of lipogenesis. In VAT, PM downregulated genes involved in early and late adipocyte differentiation in zebrafish, but not in mice. (4) Conclusions: We have demonstrated that PM can prevent hepatic steatosis and visceral adiposity for the first time. Dietary supplementation of PM as a functional food may be suitable for obesity prevention and reduction in the prevalence of obesity-related diseases.
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Affiliation(s)
- Hiroko Nakayama
- Graduate School of Regional Innovation Studies, Mie University, Tsu, Mie 514-8507, Japan.
| | - Yasuhito Shimada
- Mie University Zebrafish Drug Screening Center, Tsu, Mie 514-8507, Japan.
- Department of Integrative Pharmacology, Mie University Graduate School of Medicine, Tsu, Mie 514-8507, Japan.
- Department of Bioinformatics, Mie University Advanced Science Research Promotion Center, Tsu, Mie 514-8507, Japan.
| | - Liqing Zang
- Graduate School of Regional Innovation Studies, Mie University, Tsu, Mie 514-8507, Japan.
| | - Masahiro Terasawa
- Konan Chemical Manufacturing Co., Ltd., Yokkaichi, Mie 510-0103, Japan.
| | - Kaoru Nishiura
- Konan Chemical Manufacturing Co., Ltd., Yokkaichi, Mie 510-0103, Japan.
| | - Koichi Matsuda
- Konan Chemical Manufacturing Co., Ltd., Yokkaichi, Mie 510-0103, Japan.
| | - Charles Toombs
- College of Business, Oregon State University, Corvallis, OR 97331, USA.
| | - Chris Langdon
- Coastal Oregon Marine Experiment Station and Department of Fisheries and Wildlife, Hatfield Marine Science Center, College of Agricultural Sciences, Oregon State University, Corvallis, OR 97331, USA.
| | - Norihiro Nishimura
- Graduate School of Regional Innovation Studies, Mie University, Tsu, Mie 514-8507, Japan.
- Mie University Zebrafish Drug Screening Center, Tsu, Mie 514-8507, Japan.
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25
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Tomato Juice Supplementation Influences the Gene Expression Related to Steatosis in Rats. Nutrients 2018; 10:nu10091215. [PMID: 30200543 PMCID: PMC6165399 DOI: 10.3390/nu10091215] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2018] [Revised: 08/25/2018] [Accepted: 08/31/2018] [Indexed: 12/12/2022] Open
Abstract
The objective of this work was to identify the effect of tomato juice on the expression of genes and levels of metabolites related to steatosis in rats. Male Sprague Dawley rats (8 weeks-old) were grouped (6 rats/group) in four experimental groups: NA (normal diet and water), NL (normal diet and tomato juice), HA (high-fat diet and water), and HL (high-fat diet and tomato juice). After an intervention period of 5 weeks, rats were sacrificed and biochemical parameters, biomarkers of oxidative stress, liver metabolites, and gene expression were determined. Although the H diet provoked dislipemia related to steatosis, no changes in isoprostanes or liver malondialdehyde (MDA) were observed. Changes in the gene expression of the HA group were produced by the high consumption of fat, whereas the consumption of tomato juice had different effects, depending on the diet. In the NL group, the genes involved in β-oxidation were upregulated, and in groups NL and HL upregulation of CD36 and downregulation of APOB and LPL were observed. In addition, in the HL group the accumulation of lycopene upregulated the genes FXR and HNF4A, which have been suggested as preventive factors in relation to steatosis. Regarding the metabolomics study, intake of tomato juice stimulated the biosynthesis of glutathione and amino acids of the transulfurization pathway, increasing the levels of metabolites related to the antioxidant response.
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26
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Zang L, Maddison LA, Chen W. Zebrafish as a Model for Obesity and Diabetes. Front Cell Dev Biol 2018; 6:91. [PMID: 30177968 PMCID: PMC6110173 DOI: 10.3389/fcell.2018.00091] [Citation(s) in RCA: 165] [Impact Index Per Article: 23.6] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2018] [Accepted: 07/25/2018] [Indexed: 12/13/2022] Open
Abstract
Obesity and diabetes now considered global epidemics. The prevalence rates of diabetes are increasing in parallel with the rates of obesity and the strong connection between these two diseases has been coined as “diabesity.” The health risks of overweight or obesity include Type 2 diabetes mellitus (T2DM), coronary heart disease and cancer of numerous organs. Both obesity and diabetes are complex diseases that involve the interaction of genetics and environmental factors. The underlying pathogenesis of obesity and diabetes are not well understood and further research is needed for pharmacological and surgical management. Consequently, the use of animal models of obesity and/or diabetes is important for both improving the understanding of these diseases and to identify and develop effective treatments. Zebrafish is an attractive model system for studying metabolic diseases because of the functional conservation in lipid metabolism, adipose biology, pancreas structure, and glucose homeostasis. It is also suited for identification of novel targets associated with the risk and treatment of obesity and diabetes in humans. In this review, we highlight studies using zebrafish to model metabolic diseases, and discuss the advantages and disadvantages of studying pathologies associated with obesity and diabetes in zebrafish.
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Affiliation(s)
- Liqing Zang
- Department of Molecular Physiology and Biophysics, Vanderbilt University School of Medicine, Nashville, TN, United States.,Graduate School of Regional Innovation Studies, Mie University, Tsu, Japan
| | - Lisette A Maddison
- Center for Reproductive Biology, Washington State University, Pullman, WA, United States
| | - Wenbiao Chen
- Department of Molecular Physiology and Biophysics, Vanderbilt University School of Medicine, Nashville, TN, United States
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27
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Du J, Jia R, Cao LP, Ding W, Xu P, Yin G. Effects of Rhizoma Alismatis extract on biochemical indices and adipose gene expression in oleic acid-induced hepatocyte injury in Jian carp (Cyprinus carpio var. Jian). FISH PHYSIOLOGY AND BIOCHEMISTRY 2018; 44:747-768. [PMID: 29603076 DOI: 10.1007/s10695-017-0428-2] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/01/2016] [Accepted: 09/21/2017] [Indexed: 05/09/2023]
Abstract
Fatty liver is an increasingly serious disease of fish in aquaculture. However, the mechanisms responsible for the occurrence of fatty liver remain unclear, and no effective methods for the prevention and treatment of this disease have yet been found. In the present study, we aimed to develop an in vitro model of hepatocyte injury using oleic acid as hepatotoxicant and evaluate the protective effects of Rhizoma Alismatis extract (RAE) in Jian carp using this model. Primary hepatocytes from Jian carp were isolated and purified and cultured in vitro. The result indicated that 0.4 mmol L-1 oleic acid and 48 h could be the optimal conditions to induce hepatocyte injury model in cultured hepatocytes. Hepatocytes were exposed to oleic acid, followed by the addition of RAE at 0, 1, 5, 10, 20, or 50 μg mL-1. The hepatocytes and supernatant were then analyzed. RAE suppressed oleic acid-induced elevations in aspartate aminotransferase, alanine aminotransferase, triglycerides, total cholesterol, lactate dehydrogenase, alkaline phosphatase, cholinesterase, malondialdehyde, γ-glutamyl transferase, cytochrome P450 1A, cytochrome P450 2E1, liver-type fatty acid binding protein, free fatty acid, fatty acid synthetase, and tumor necrosis factor-α (P < 0.01 or P < 0.05); reduced protein levels of cytochrome P450 1A, nuclear factor (NF)-κB p65, and NF-κB c-Rel; and inhibited cytochrome P4503A, NF-κB c-Rel, nuclear factor erythroid-related factor 2, peroxisome proliferator-activated receptor-α, and cytochrome P4501A mRNA levels. In conclusion, RAE exhibited a protective effect against hepatocyte injury in Jian carp. Further in vivo studies are needed to provide more evidence for the use of RAE as a hepatoprotective agent for the treatment of hepatocyte injury.
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Affiliation(s)
- Jinliang Du
- Key Laboratory of Freshwater Fisheries and Germplasm Resources Utilization, Ministry of Agriculture, Freshwater Fisheries Research Center, Chinese Academy of Fishery Sciences, Wuxi, 214081, China
- International Joint Research Laboratory for Fish Immunopharmacology, Freshwater Fisheries Research Center, Chinese Academy of Fishery Sciences, Wuxi, 214081, China
| | - Rui Jia
- Key Laboratory of Freshwater Fisheries and Germplasm Resources Utilization, Ministry of Agriculture, Freshwater Fisheries Research Center, Chinese Academy of Fishery Sciences, Wuxi, 214081, China
- International Joint Research Laboratory for Fish Immunopharmacology, Freshwater Fisheries Research Center, Chinese Academy of Fishery Sciences, Wuxi, 214081, China
| | - Li-Ping Cao
- Key Laboratory of Freshwater Fisheries and Germplasm Resources Utilization, Ministry of Agriculture, Freshwater Fisheries Research Center, Chinese Academy of Fishery Sciences, Wuxi, 214081, China
- International Joint Research Laboratory for Fish Immunopharmacology, Freshwater Fisheries Research Center, Chinese Academy of Fishery Sciences, Wuxi, 214081, China
| | - Weidong Ding
- Key Laboratory of Freshwater Fisheries and Germplasm Resources Utilization, Ministry of Agriculture, Freshwater Fisheries Research Center, Chinese Academy of Fishery Sciences, Wuxi, 214081, China
- International Joint Research Laboratory for Fish Immunopharmacology, Freshwater Fisheries Research Center, Chinese Academy of Fishery Sciences, Wuxi, 214081, China
| | - Pao Xu
- Key Laboratory of Freshwater Fisheries and Germplasm Resources Utilization, Ministry of Agriculture, Freshwater Fisheries Research Center, Chinese Academy of Fishery Sciences, Wuxi, 214081, China.
- International Joint Research Laboratory for Fish Immunopharmacology, Freshwater Fisheries Research Center, Chinese Academy of Fishery Sciences, Wuxi, 214081, China.
- Wuxi Fisheries College, Nanjing Agricultural University, Wuxi, 214081, China.
| | - Guojun Yin
- Key Laboratory of Freshwater Fisheries and Germplasm Resources Utilization, Ministry of Agriculture, Freshwater Fisheries Research Center, Chinese Academy of Fishery Sciences, Wuxi, 214081, China.
- International Joint Research Laboratory for Fish Immunopharmacology, Freshwater Fisheries Research Center, Chinese Academy of Fishery Sciences, Wuxi, 214081, China.
- Wuxi Fisheries College, Nanjing Agricultural University, Wuxi, 214081, China.
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28
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Dietary cholesterol-induced transcriptome differences in the intestine, hepatopancreas, and muscle of Oriental River prawn Macrobrachium nipponense. COMPARATIVE BIOCHEMISTRY AND PHYSIOLOGY D-GENOMICS & PROTEOMICS 2017; 23:39-48. [DOI: 10.1016/j.cbd.2017.06.001] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/15/2017] [Revised: 05/10/2017] [Accepted: 06/11/2017] [Indexed: 11/18/2022]
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29
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Ran G, Ying L, Li L, Yan Q, Yi W, Ying C, Wu H, Ye X. Resveratrol ameliorates diet-induced dysregulation of lipid metabolism in zebrafish (Danio rerio). PLoS One 2017; 12:e0180865. [PMID: 28686680 PMCID: PMC5501612 DOI: 10.1371/journal.pone.0180865] [Citation(s) in RCA: 42] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2016] [Accepted: 06/22/2017] [Indexed: 11/23/2022] Open
Abstract
Defective lipid metabolism is associated with increased risk of various chronic diseases, such as obesity, cardiovascular diseases, and diabetes. Resveratrol (RSV), a natural polyphenol, has been shown the potential of ameliorating disregulations of lipid metabolism. The objective of this study was to investigate the effects of feed intake and RSV on lipid metabolism in zebrafish (Danio rerio). The adult males were randomly allocated to 6 groups: control (Con, 8 mg cysts/fish/day), control with 20 μmol/L RSV (Con+RSV), calorie restriction (CR, 5 mg cysts/fish/day), calorie restriction with RSV (CR+RSV), overfeed (OF, 60 mg cysts/fish/day), and overfeed with RSV (OF+RSV) groups. The treatment period was 8 weeks. Results showed that CR reduced body length, body weight, and condition factor of zebrafish. CR reduced levels of plasma triglyceride (TG) and induced protein expression of phosphorylated AMP-activated protein kinase-α (pAMPKα), silent information regulator 2 homolog 1 (Sirt1), and peroxisome proliferator activated receptor gamma coactivator-1α (PGC1α). RSV attenuated CR-induced pAMPKα/AMPKαincreases. RSV increased levels of Sirt1 protein in the OF zebrafish, and decreased OF-induced increase in peroxisome proliferator-activated receptor-γ (PPARγ) protein level. Additionally, RSV down-regulated caveolin-1 and up-regulated microtubule-associated protein 1 light chain 3 -II (LC3-II) protein levels in OF zebrafish. In conclusion, these results suggest that 1) CR reduces plasma TG level through activation of the AMPKα-Sirt1- PGC1α pathway; 2) under different dietary stress conditions RSV might regulate AMPK phosphorylation bi-directionally; 3) RSV might regulate lipid metabolism through the AMPKα-Sirt1-PPARγ pathway in OF zebrafish.
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Affiliation(s)
- Gai Ran
- Department of Preventive Medicine, School of Public Health and Management, Wenzhou Medical University, Wenzhou, China
| | - Li Ying
- School of Stomatology, Wenzhou Medical University, Wenzhou, China
| | - Lin Li
- Department of Preventive Medicine, School of Public Health and Management, Wenzhou Medical University, Wenzhou, China
| | - Qiaoqiao Yan
- Department of Preventive Medicine, School of Public Health and Management, Wenzhou Medical University, Wenzhou, China
| | - Weijie Yi
- Department of Nutrition and Food Hygiene, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Chenjiang Ying
- Department of Nutrition and Food Hygiene, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Hongmei Wu
- Department of Preventive Medicine, School of Public Health and Management, Wenzhou Medical University, Wenzhou, China
- * E-mail: (XY); (HW)
| | - Xiaolei Ye
- Department of Preventive Medicine, School of Public Health and Management, Wenzhou Medical University, Wenzhou, China
- * E-mail: (XY); (HW)
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30
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Pham DH, Zhang C, Yin C. Using zebrafish to model liver diseases-Where do we stand? CURRENT PATHOBIOLOGY REPORTS 2017; 5:207-221. [PMID: 29098121 DOI: 10.1007/s40139-017-0141-y] [Citation(s) in RCA: 30] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
Purpose of Review The liver is the largest internal organ and performs both exocrine and endocrine function that is necessary for survival. Liver failure is among the leading causes of death and represents a major global health burden. Liver transplantation is the only effective treatment for end-stage liver diseases. Animal models advance our understanding of liver disease etiology and hold promise for the development of alternative therapies. Zebrafish has become an increasingly popular system for modeling liver diseases and complements the rodent models. Recent Findings The zebrafish liver contains main cell types that are found in mammalian liver and exhibits similar pathogenic responses to environmental insults and genetic mutations. Zebrafish have been used to model neonatal cholestasis, cholangiopathies, such as polycystic liver disease, alcoholic liver disease, and non-alcoholic fatty liver disease. It also provides a unique opportunity to study the plasticity of liver parenchymal cells during regeneration. Summary In this review, we summarize the recent work of building zebrafish models of liver diseases. We highlight how these studies have brought new knowledge of disease mechanisms. We also discuss the advantages and challenges of using zebrafish to model liver diseases.
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Affiliation(s)
- Duc-Hung Pham
- Division of Gastroenterology, Hepatology and Nutrition, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, 45229, USA
| | - Changwen Zhang
- Division of Gastroenterology, Hepatology and Nutrition, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, 45229, USA
| | - Chunyue Yin
- Division of Gastroenterology, Hepatology and Nutrition, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, 45229, USA.,Division of Developmental Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, 45229, USA
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31
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Landgraf K, Schuster S, Meusel A, Garten A, Riemer T, Schleinitz D, Kiess W, Körner A. Short-term overfeeding of zebrafish with normal or high-fat diet as a model for the development of metabolically healthy versus unhealthy obesity. BMC PHYSIOLOGY 2017; 17:4. [PMID: 28327129 PMCID: PMC5361797 DOI: 10.1186/s12899-017-0031-x] [Citation(s) in RCA: 116] [Impact Index Per Article: 14.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/03/2016] [Accepted: 03/14/2017] [Indexed: 12/13/2022]
Abstract
BACKGROUND Obese individuals differ in their risk of developing metabolic and cardiovascular complications depending on fat distribution (subcutaneous versus visceral) and adipose tissue (AT) phenotype (hyperplasic versus hypertrophic). However, the exact mechanisms which determine whether an obese individual is metabolically healthy or unhealthy are not clear, and analyses of the underlying pathomechanisms are limited by the lack of suitable in vivo models in which metabolically healthy versus metabolically unhealthy AT accumulation can be specifically induced. In the current study, we aimed to establish a protocol for the use of zebrafish as a model for obesity-related metabolically healthy versus metabolically unhealthy AT accumulation. METHODS We overfed adult male zebrafish of the AB strain with normal fat diet (NFD) or high fat diet (HFD) for 8 weeks and compared parameters related to obesity, i.e. body weight, body mass index, condition index and body fat percentage, to control zebrafish fed under physiological conditions. In addition, we investigated the presence of early obesity-related metabolic alterations by quantifying blood glucose levels, plasma triglyceride and cholesterol levels, and by assessing ectopic lipid accumulation in the liver of zebrafish. Finally, we determined gene expression levels of marker genes related to lipid metabolism, inflammation and fibrosis in visceral AT and liver. RESULTS We show that 8-weeks overfeeding with either NFD or HFD leads to a significant increase in body weight and AT mass compared to controls. In contrast to NFD-overfed zebrafish, HFD-overfed zebrafish additionally present metabolic alterations, e.g. hyperglycemia and ectopic lipid accumulation in the liver, and a metabolically unhealthy AT phenotype with adipocyte hypertrophy especially in the visceral AT depot, which is accompanied by changes in the expression of marker genes for lipid metabolism, inflammation and fibrosis. CONCLUSIONS In summary, we have established a method for the specific induction of metabolically distinct obesity phenotypes in zebrafish. Our results indicate that zebrafish represents an attractive model to study regulatory mechanisms involved in the determination of AT phenotype during development of metabolically healthy versus metabolically unhealthy obesity.
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Affiliation(s)
- Kathrin Landgraf
- Center for Pediatric Research Leipzig (CPL), University Hospital for Children & Adolescents, University of Leipzig, Liebigstraße 21, 04103, Leipzig, Germany. .,Integrated Research and Treatment Center (IFB) Adiposity Diseases, University of Leipzig, Leipzig, Germany.
| | - Susanne Schuster
- Center for Pediatric Research Leipzig (CPL), University Hospital for Children & Adolescents, University of Leipzig, Liebigstraße 21, 04103, Leipzig, Germany
| | - Andrej Meusel
- Institute of Medical Physics and Biophysics, University of Leipzig, Leipzig, Germany
| | - Antje Garten
- Center for Pediatric Research Leipzig (CPL), University Hospital for Children & Adolescents, University of Leipzig, Liebigstraße 21, 04103, Leipzig, Germany
| | - Thomas Riemer
- Institute of Medical Physics and Biophysics, University of Leipzig, Leipzig, Germany
| | - Dorit Schleinitz
- Integrated Research and Treatment Center (IFB) Adiposity Diseases, University of Leipzig, Leipzig, Germany
| | - Wieland Kiess
- Center for Pediatric Research Leipzig (CPL), University Hospital for Children & Adolescents, University of Leipzig, Liebigstraße 21, 04103, Leipzig, Germany
| | - Antje Körner
- Center for Pediatric Research Leipzig (CPL), University Hospital for Children & Adolescents, University of Leipzig, Liebigstraße 21, 04103, Leipzig, Germany.,Integrated Research and Treatment Center (IFB) Adiposity Diseases, University of Leipzig, Leipzig, Germany
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32
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Newman T, Jhinku N, Meier M, Horsfield J. Dietary Intake Influences Adult Fertility and Offspring Fitness in Zebrafish. PLoS One 2016; 11:e0166394. [PMID: 27870856 PMCID: PMC5117665 DOI: 10.1371/journal.pone.0166394] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2016] [Accepted: 10/27/2016] [Indexed: 01/30/2023] Open
Abstract
The burden of malnutrition, including both over- and undernutrition, is a major public health concern. Here we used a zebrafish model of diet-induced obesity to analyze the impact of dietary intake on fertility and the phenotype of the next generation. Over an eight-week period, one group received 60 mg of food each day (60 mg arm), while another received 5 mg (5 mg arm). At the end of the diet, the body mass index of the 60 mg arm was 1.5 fold greater than the 5 mg arm. The intervention also had a marked impact on fertility; breeding success and egg production in the 60 mg arm were increased 2.1- and 6.2-fold compared to the 5 mg arm, respectively. Transcriptome analysis of eggs revealed that transcripts involved in metabolic biological processes differed according to dietary intake. The progeny from the differentially fed fish were more likely to survive when the parents had access to more food. An intergenerational crossover study revealed that while parental diet did not influence weight gain in the offspring, the progeny of well-fed parents had increased levels of physical activity when exposed again to high nutrient availability. We conclude that dietary intake has an important influence on fertility and the subsequent fitness of offspring, even prior to breeding.
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Affiliation(s)
- Trent Newman
- Department of Pathology, Dunedin School of Medicine, PO Box 913, University of Otago, Dunedin, 9054, New Zealand
| | - Noel Jhinku
- Department of Pathology, Dunedin School of Medicine, PO Box 913, University of Otago, Dunedin, 9054, New Zealand
| | - Michael Meier
- Department of Pathology, Dunedin School of Medicine, PO Box 913, University of Otago, Dunedin, 9054, New Zealand
- Gravida: National Centre for Growth and Development, University of Auckland, Auckland, New Zealand
| | - Julia Horsfield
- Department of Pathology, Dunedin School of Medicine, PO Box 913, University of Otago, Dunedin, 9054, New Zealand
- Gravida: National Centre for Growth and Development, University of Auckland, Auckland, New Zealand
- Maurice Wilkins Centre for Molecular Biodiscovery, University of Auckland, Auckland, New Zealand
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Morales Fénero CI, Colombo Flores AA, Câmara NOS. Inflammatory diseases modelling in zebrafish. World J Exp Med 2016; 6:9-20. [PMID: 26929916 PMCID: PMC4759353 DOI: 10.5493/wjem.v6.i1.9] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/29/2015] [Revised: 10/20/2015] [Accepted: 12/18/2015] [Indexed: 02/06/2023] Open
Abstract
The ingest of diets with high content of fats and carbohydrates, low or no physical exercise and a stressful routine are part of the everyday lifestyle of most people in the western world. These conditions are triggers for different diseases with complex interactions between the host genetics, the metabolism, the immune system and the microbiota, including inflammatory bowel diseases (IBD), obesity and diabetes. The incidence of these disorders is growing worldwide; therefore, new strategies for its study are needed. Nowadays, the majority of researches are in use of murine models for understand the genetics, physiopathology and interaction between cells and signaling pathways to find therapeutic solutions to these diseases. The zebrafish, a little tropical water fish, shares 70% of our genes and conserves anatomic and physiological characteristics, as well as metabolical pathways, with mammals, and is rising as a new complementary model for the study of metabolic and inflammatory diseases. Its high fecundity, fast development, transparency, versatility and low cost of maintenance makes the zebrafish an interesting option for new researches. In this review, we offer a discussion of the existing genetic and induced zebrafish models of two important Western diseases that have a strong inflammatory component, the IBD and the obesity.
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Caro M, Iturria I, Martinez-Santos M, Pardo MA, Rainieri S, Tueros I, Navarro V. Zebrafish dives into food research: effectiveness assessment of bioactive compounds. Food Funct 2016; 7:2615-23. [DOI: 10.1039/c6fo00046k] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
Zebrafish ease of use and characteristics reveal it to be an interesting and underused model in food and nutrition research.
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Affiliation(s)
- M. Caro
- AZTI, Food Research, Astondo Bidea 609
- 48160 Derio
- Spain
| | - I. Iturria
- AZTI, Food Research, Astondo Bidea 609
- 48160 Derio
- Spain
| | | | - M. A. Pardo
- AZTI, Food Research, Astondo Bidea 609
- 48160 Derio
- Spain
| | - S. Rainieri
- AZTI, Food Research, Astondo Bidea 609
- 48160 Derio
- Spain
| | - I. Tueros
- AZTI, Food Research, Astondo Bidea 609
- 48160 Derio
- Spain
| | - V. Navarro
- AZTI, Food Research, Astondo Bidea 609
- 48160 Derio
- Spain
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Montalbano G, Mania M, Guerrera MC, Abbate F, Laurà R, Navarra M, Vega JA, Ciriaco E, Germanà A. Morphological differences in adipose tissue and changes in BDNF/Trkb expression in brain and gut of a diet induced obese zebrafish model. Ann Anat 2015; 204:36-44. [PMID: 26617157 DOI: 10.1016/j.aanat.2015.11.003] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2015] [Revised: 10/14/2015] [Accepted: 11/04/2015] [Indexed: 12/15/2022]
Abstract
Obesity is a multifactorial disease generated by an alteration in balance between energy intake and expenditure, also dependent on genetic and non-genetic factors. Moreover, various nuclei of the hypothalamus receive and process peripheral stimuli from the gastrointestinal tract, controlling food intake and therefore energy balance. Among anorexigenic molecules, brain-derived neurotrophic factor (BDNF) acts through the tyrosine-kinase receptor TrkB. Numerous data demonstrate that the BDNF/TrkB system has a fundamental role in the control of food intake and body weight. Quantitative PCR and immunohistochemistry for both BDNF and TrkB were used to determine changes in levels in the brain and gastro-intestinal tract of an experimental zebrafish model of diet-induced obesity. Overfed animals showed increased weight and body mass index as well as accumulation of adipose tissue in the visceral, subcutaneous and hepatic areas. These changes were concomitant with decreased levels of BDNF mRNA in the gastro-intestinal tract and increased expression of TrkB mRNA in the brain. Overfeeding did not change the density of cells displaying immunoreactivity for BDNF or TrkB in the brain although both were significantly diminished in the gastro-intestinal tract. These results suggest an involvement of the BDNF/TrkB system in the regulation of food intake and energy balance in zebrafish, as in mammals.
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Affiliation(s)
- Giuseppe Montalbano
- Dipartimento di Scienze Veterinarie, 98168 Messina, Italy; Zebrafish Neuromorphology Lab, Università di Messina, Polo Universitario SS. Annunziata, 98168 Messina, Italy.
| | - Manuela Mania
- Dipartimento di Scienze Veterinarie, 98168 Messina, Italy; Zebrafish Neuromorphology Lab, Università di Messina, Polo Universitario SS. Annunziata, 98168 Messina, Italy
| | - Maria Cristina Guerrera
- Dipartimento di Scienze Veterinarie, 98168 Messina, Italy; Zebrafish Neuromorphology Lab, Università di Messina, Polo Universitario SS. Annunziata, 98168 Messina, Italy
| | - Francesco Abbate
- Dipartimento di Scienze Veterinarie, 98168 Messina, Italy; Zebrafish Neuromorphology Lab, Università di Messina, Polo Universitario SS. Annunziata, 98168 Messina, Italy
| | - Rosaria Laurà
- Dipartimento di Scienze Veterinarie, 98168 Messina, Italy; Zebrafish Neuromorphology Lab, Università di Messina, Polo Universitario SS. Annunziata, 98168 Messina, Italy
| | - Michele Navarra
- Dipartimento di Scienza del Farmaco e Prodotti per la Salute, Università di Messina, Polo Universitario SS. Annunziata, 98168 Messina, Italy
| | - Jose A Vega
- Departamento de Morfologia y Biologia Celular, Facultad de Medicina, Universidad de Oviedo, Av de Julián Clavería 6, 33006 Oviedo, España; Facultad de Ciencias de la Salud, Universidad Autónoma de Chile, 5 Poniente, 1670 Talca, Chile
| | - Emilia Ciriaco
- Dipartimento di Scienze Veterinarie, 98168 Messina, Italy; Zebrafish Neuromorphology Lab, Università di Messina, Polo Universitario SS. Annunziata, 98168 Messina, Italy
| | - Antonino Germanà
- Dipartimento di Scienze Veterinarie, 98168 Messina, Italy; Zebrafish Neuromorphology Lab, Università di Messina, Polo Universitario SS. Annunziata, 98168 Messina, Italy
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Zheng X, Dai W, Chen X, Wang K, Zhang W, Liu L, Hou J. Caffeine reduces hepatic lipid accumulation through regulation of lipogenesis and ER stress in zebrafish larvae. J Biomed Sci 2015; 22:105. [PMID: 26572131 PMCID: PMC4647812 DOI: 10.1186/s12929-015-0206-3] [Citation(s) in RCA: 54] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2015] [Accepted: 10/16/2015] [Indexed: 12/21/2022] Open
Abstract
BACKGROUND Caffeine, the main component of coffee, has showed its protective effect on non-alcoholic fatty liver disease (NAFLD) in many studies. However, the hepatoprotection of caffeine and its mechanisms in zebrafish were unexplored. Thus, this study's intentions are to establish a NAFLD model of zebrafish larvae and to examine the role of caffeine on fatty liver with the model. RESULTS Growth and the incidence of fatty liver of zebrafish larvae increased with the increased amount of feeding in a dose-dependent manner. The degree of hepatic steatosis of larvae also gradually aggravated with the increased quantity and duration of feeding. Triglyceride contents of zebrafish fed for 20 days significantly increased in model group (180 mg/d) compared with control group (30 mg/d) (P < 0.001). Significant decreases in body weight and hepatic steatosis rate were observed in 2.5, 5, 8 % caffeine treatment group compared with model group (P < 0.05). Hepatic lipid accumulation was also significantly reduced in caffeine treatment larvae. Moreover, caffeine treatment was associated with upregulation of lipid β-oxidation gene ACO and downregulation of lipogenesis-associated genes (SREBP1, ACC1, CD36 and UCP2), ER stress-associated genes (PERK, IRE1, ATF6 and BIP), the inflammatory cytokine genes (IL-1beta and TNF-alpha) and autophagy associated genes (ATG12 and Beclin-1). Protein expression of CHOP, BIP and IL-1beta remarkably reduced in caffeine treatment group compared with model group. CONCLUSIONS We induced hepatoteatosis in zebrafish by overfeeding regimen and demonstrated caffeine have a role in suppression of hepatosteatosis by downregulation of genes associated with lipogenesis, ER stress, inflammatory response and enhancement of lipid oxidation, indicating zebrafish model may be used to identify putative pharmacological targets and to test novel drugs for human NAFLD treatment.
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Affiliation(s)
- Xinchun Zheng
- State Key Laboratory of Organ Failure Research, Guangdong Provincial Key Laboratory of Viral Hepatitis Research, Department of Infectious Diseases, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, China.
| | - Wencong Dai
- State Key Laboratory of Organ Failure Research, Guangdong Provincial Key Laboratory of Viral Hepatitis Research, Department of Infectious Diseases, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, China.
| | - Xiaohui Chen
- Key Laboratory of Zebrafish Modeling and Drug Screening for Human Diseases of Guangdong Higher Education Institutes, Department of Cell Biology, Southern Medical University, Guangzhou, 510515, China.
| | - Kunyuan Wang
- State Key Laboratory of Organ Failure Research, Guangdong Provincial Key Laboratory of Viral Hepatitis Research, Department of Infectious Diseases, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, China.
| | - Wenqing Zhang
- Key Laboratory of Zebrafish Modeling and Drug Screening for Human Diseases of Guangdong Higher Education Institutes, Department of Cell Biology, Southern Medical University, Guangzhou, 510515, China.
| | - Li Liu
- State Key Laboratory of Organ Failure Research, Guangdong Provincial Key Laboratory of Viral Hepatitis Research, Department of Infectious Diseases, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, China.
| | - Jinlin Hou
- State Key Laboratory of Organ Failure Research, Guangdong Provincial Key Laboratory of Viral Hepatitis Research, Department of Infectious Diseases, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, China.
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Zang L, Shimada Y, Tanaka T, Nishimura N. Rhamnan sulphate from Monostroma nitidum attenuates hepatic steatosis by suppressing lipogenesis in a diet-induced obesity zebrafish model. J Funct Foods 2015. [DOI: 10.1016/j.jff.2015.05.041] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/10/2023] Open
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Yilmaz B, Sahin K, Bilen H, Bahcecioglu IH, Bilir B, Ashraf S, Halazun KJ, Kucuk O. Carotenoids and non-alcoholic fatty liver disease. Hepatobiliary Surg Nutr 2015; 4:161-71. [PMID: 26151056 DOI: 10.3978/j.issn.2304-3881.2015.01.11] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/01/2014] [Accepted: 01/08/2015] [Indexed: 12/16/2022]
Abstract
Non-alcoholic fatty liver disease (NAFLD) is a growing health problem around the world, especially in developed countries. NAFLD includes all cases of fatty liver disease from simple steatosis to cirrhosis, without excessive alcohol intake, use of steatogenic medication or hereditary disorders. Pathogenesis is associated with dietary high fat intake, decreased free fatty acid (FFA) oxidation, increased hepatic lipogenesis and lipolysis from the adipose tissue. These metabolic alterations contribute to the hepatic fat accumulation. Consequently, stimulated oxidative stress and inflammation play a major role in hepatocellular damage. Therefore, antioxidant and anti-inflammatory agents may have a role in the prevention of this disease. Carotenoids are potent antioxidant and anti-inflammatory micronutrients, which have been investigated in the prevention and treatment of NAFLD. The main sources of the carotenoids are fruits and vegetables. In this article we review the potential role and possible molecular mechanism of carotenoids in NAFLD.
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Affiliation(s)
- Bahiddin Yilmaz
- 1 Winship Cancer Institute, Emory University, Atlanta, GA, USA ; 2 Division of Animal Nutrition, Faculty of Veterinary Medicine, 3 Division of Gastroenterology, School of Medicine, Firat University, Elazig, Turkey ; 4 Department of Surgery, Emory University, Atlanta, GA, USA
| | - Kazim Sahin
- 1 Winship Cancer Institute, Emory University, Atlanta, GA, USA ; 2 Division of Animal Nutrition, Faculty of Veterinary Medicine, 3 Division of Gastroenterology, School of Medicine, Firat University, Elazig, Turkey ; 4 Department of Surgery, Emory University, Atlanta, GA, USA
| | - Hande Bilen
- 1 Winship Cancer Institute, Emory University, Atlanta, GA, USA ; 2 Division of Animal Nutrition, Faculty of Veterinary Medicine, 3 Division of Gastroenterology, School of Medicine, Firat University, Elazig, Turkey ; 4 Department of Surgery, Emory University, Atlanta, GA, USA
| | - Ibrahim H Bahcecioglu
- 1 Winship Cancer Institute, Emory University, Atlanta, GA, USA ; 2 Division of Animal Nutrition, Faculty of Veterinary Medicine, 3 Division of Gastroenterology, School of Medicine, Firat University, Elazig, Turkey ; 4 Department of Surgery, Emory University, Atlanta, GA, USA
| | - Birdal Bilir
- 1 Winship Cancer Institute, Emory University, Atlanta, GA, USA ; 2 Division of Animal Nutrition, Faculty of Veterinary Medicine, 3 Division of Gastroenterology, School of Medicine, Firat University, Elazig, Turkey ; 4 Department of Surgery, Emory University, Atlanta, GA, USA
| | - Sara Ashraf
- 1 Winship Cancer Institute, Emory University, Atlanta, GA, USA ; 2 Division of Animal Nutrition, Faculty of Veterinary Medicine, 3 Division of Gastroenterology, School of Medicine, Firat University, Elazig, Turkey ; 4 Department of Surgery, Emory University, Atlanta, GA, USA
| | - Karim J Halazun
- 1 Winship Cancer Institute, Emory University, Atlanta, GA, USA ; 2 Division of Animal Nutrition, Faculty of Veterinary Medicine, 3 Division of Gastroenterology, School of Medicine, Firat University, Elazig, Turkey ; 4 Department of Surgery, Emory University, Atlanta, GA, USA
| | - Omer Kucuk
- 1 Winship Cancer Institute, Emory University, Atlanta, GA, USA ; 2 Division of Animal Nutrition, Faculty of Veterinary Medicine, 3 Division of Gastroenterology, School of Medicine, Firat University, Elazig, Turkey ; 4 Department of Surgery, Emory University, Atlanta, GA, USA
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Willebrords J, Pereira IVA, Maes M, Crespo Yanguas S, Colle I, Van Den Bossche B, Da Silva TC, de Oliveira CPMS, Andraus W, Alves VA, Cogliati B, Vinken M. Strategies, models and biomarkers in experimental non-alcoholic fatty liver disease research. Prog Lipid Res 2015; 59:106-25. [PMID: 26073454 DOI: 10.1016/j.plipres.2015.05.002] [Citation(s) in RCA: 127] [Impact Index Per Article: 12.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2015] [Revised: 05/13/2015] [Accepted: 05/13/2015] [Indexed: 12/12/2022]
Abstract
Non-alcoholic fatty liver disease encompasses a spectrum of liver diseases, including simple steatosis, steatohepatitis, liver fibrosis and cirrhosis and hepatocellular carcinoma. Non-alcoholic fatty liver disease is currently the most dominant chronic liver disease in Western countries due to the fact that hepatic steatosis is associated with insulin resistance, type 2 diabetes mellitus, obesity, metabolic syndrome and drug-induced injury. A variety of chemicals, mainly drugs, and diets is known to cause hepatic steatosis in humans and rodents. Experimental non-alcoholic fatty liver disease models rely on the application of a diet or the administration of drugs to laboratory animals or the exposure of hepatic cell lines to these drugs. More recently, genetically modified rodents or zebrafish have been introduced as non-alcoholic fatty liver disease models. Considerable interest now lies in the discovery and development of novel non-invasive biomarkers of non-alcoholic fatty liver disease, with specific focus on hepatic steatosis. Experimental diagnostic biomarkers of non-alcoholic fatty liver disease, such as (epi)genetic parameters and '-omics'-based read-outs are still in their infancy, but show great promise. In this paper, the array of tools and models for the study of liver steatosis is discussed. Furthermore, the current state-of-art regarding experimental biomarkers such as epigenetic, genetic, transcriptomic, proteomic and metabonomic biomarkers will be reviewed.
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Affiliation(s)
- Joost Willebrords
- Department of In Vitro Toxicology and Dermato-Cosmetology, Faculty of Medicine and Pharmacy, Vrije Universiteit Brussel, Laarbeeklaan 103, 1090 Brussels, Belgium.
| | - Isabel Veloso Alves Pereira
- Department of Pathology, School of Veterinary Medicine and Animal Science, University of São Paulo, Av. Prof. Dr. Orlando Marques de Paiva, 87, São Paulo, Brazil.
| | - Michaël Maes
- Department of In Vitro Toxicology and Dermato-Cosmetology, Faculty of Medicine and Pharmacy, Vrije Universiteit Brussel, Laarbeeklaan 103, 1090 Brussels, Belgium.
| | - Sara Crespo Yanguas
- Department of In Vitro Toxicology and Dermato-Cosmetology, Faculty of Medicine and Pharmacy, Vrije Universiteit Brussel, Laarbeeklaan 103, 1090 Brussels, Belgium.
| | - Isabelle Colle
- Department of Hepatology and Gastroenterology, Algemeen Stedelijk Ziekenhuis Campus Aalst, Merestraat 80, 9300 Aalst, Belgium.
| | - Bert Van Den Bossche
- Department of Abdominal Surgery and Hepato-Pancreatico-Biliary Surgery, Algemeen Stedelijk Ziekenhuis Campus Aalst, Merestraat 80, 9300 Aalst, Belgium.
| | - Tereza Cristina Da Silva
- Department of Pathology, School of Veterinary Medicine and Animal Science, University of São Paulo, Av. Prof. Dr. Orlando Marques de Paiva, 87, São Paulo, Brazil.
| | | | - Wellington Andraus
- Department of Gastroenterology, University of São Paulo School of Medicine, Av. Dr. Arnaldo, 455, São Paulo, Brazil.
| | - Venâncio Avancini Alves
- Laboratory of Medical Investigation, Department of Pathology, University of São Paulo School of Medicine, Av. Dr. Arnaldo, 455, São Paulo, Brazil.
| | - Bruno Cogliati
- Department of Pathology, School of Veterinary Medicine and Animal Science, University of São Paulo, Av. Prof. Dr. Orlando Marques de Paiva, 87, São Paulo, Brazil.
| | - Mathieu Vinken
- Department of In Vitro Toxicology and Dermato-Cosmetology, Faculty of Medicine and Pharmacy, Vrije Universiteit Brussel, Laarbeeklaan 103, 1090 Brussels, Belgium.
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Shimada Y, Kuninaga S, Ariyoshi M, Zhang B, Shiina Y, Takahashi Y, Umemoto N, Nishimura Y, Enari H, Tanaka T. E2F8 promotes hepatic steatosis through FABP3 expression in diet-induced obesity in zebrafish. Nutr Metab (Lond) 2015; 12:17. [PMID: 26052340 PMCID: PMC4456805 DOI: 10.1186/s12986-015-0012-7] [Citation(s) in RCA: 41] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2014] [Accepted: 05/04/2015] [Indexed: 12/13/2022] Open
Abstract
Background Diet-induced hepatic steatosis is highly associated with nonalcoholic fatty liver disease, which is related to the development of metabolic syndrome. While advanced stage nonalcoholic hepatic steatosis and steatohepatitis (NASH) result ultimately in fibrosis and cirrhosis, the molecular basis for lipid droplet formation is poorly understood. Common pathways underlie the pathology of mammalian obesity and the zebrafish diet-induced obesity model (DIO-zebrafish) used in this study. Methods Our analysis involved a combination of transcriptome (DNA microarray) and proteome (two-dimensional electrophoresis) methods using liver tissue from DIO-zebrafish to find candidate genes involved in hepatic steatosis. We conducted intraperitoneal injection (i.p.) of morpholino antisense oligonucleotides (MOs) for each gene into DIO-zebrafish. We also conducted in vitro overexpression in human cells. Additionally, we examined gene expression during feeding experiments involving anti-obesity compounds, creatine and anserine. Results We found that fatty acid binding protein 3 (fabp3) and E2F transcription factors were upregulated in hepatic steatosis. E2f8 MO i.p. suppressed fabp3 expression in liver, and ameliorated hepatic steatosis. In human cells (HepG2), E2F8 overexpression promoted FABP3 expression. Additionally, co-administration of creatine and anserine suppressed obesity associated phenotypes including hepatic steatosis as indicated by e2f8 and fabp3 down regulation. Conclusion We discovered that the e2f8–fabp3 axis is important in the promotion of hepatic steatosis in DIO-zebrafish. The combination of transcriptome and proteome analyses using the disease model zebrafish allow identification of novel pathways involved in human diseases. Electronic supplementary material The online version of this article (doi:10.1186/s12986-015-0012-7) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Yasuhito Shimada
- Department of Molecular and Cellular Pharmacology, Pharmacogenomics and Pharmacoinformatics, Mie University Graduate School of Medicine, 2-174, Edobashi, Tsu, Mie Japan ; Department of Systems Pharmacology, Mie University Graduate School of Medicine, Mie, Japan ; Mie University Medical Zebrafish Research Center, Mie, Japan ; Department of Bioinformatics, Mie University Life Science Research Center, Mie, Japan ; Department of Omics Medicine, Mie University Industrial Technology Innovation, Mie, Japan
| | - Shisei Kuninaga
- Central Research Institute, Maruha Nichiro Corporation, Ibaraki, Japan
| | - Michiko Ariyoshi
- Department of Molecular and Cellular Pharmacology, Pharmacogenomics and Pharmacoinformatics, Mie University Graduate School of Medicine, 2-174, Edobashi, Tsu, Mie Japan
| | - Beibei Zhang
- Department of Molecular and Cellular Pharmacology, Pharmacogenomics and Pharmacoinformatics, Mie University Graduate School of Medicine, 2-174, Edobashi, Tsu, Mie Japan
| | - Yasuhiko Shiina
- Central Research Institute, Maruha Nichiro Corporation, Ibaraki, Japan
| | | | - Noriko Umemoto
- Department of Molecular and Cellular Pharmacology, Pharmacogenomics and Pharmacoinformatics, Mie University Graduate School of Medicine, 2-174, Edobashi, Tsu, Mie Japan ; Department of Systems Pharmacology, Mie University Graduate School of Medicine, Mie, Japan
| | - Yuhei Nishimura
- Department of Molecular and Cellular Pharmacology, Pharmacogenomics and Pharmacoinformatics, Mie University Graduate School of Medicine, 2-174, Edobashi, Tsu, Mie Japan ; Department of Systems Pharmacology, Mie University Graduate School of Medicine, Mie, Japan ; Mie University Medical Zebrafish Research Center, Mie, Japan ; Department of Bioinformatics, Mie University Life Science Research Center, Mie, Japan ; Department of Omics Medicine, Mie University Industrial Technology Innovation, Mie, Japan
| | - Hiroyuki Enari
- Central Research Institute, Maruha Nichiro Corporation, Ibaraki, Japan
| | - Toshio Tanaka
- Department of Molecular and Cellular Pharmacology, Pharmacogenomics and Pharmacoinformatics, Mie University Graduate School of Medicine, 2-174, Edobashi, Tsu, Mie Japan ; Department of Systems Pharmacology, Mie University Graduate School of Medicine, Mie, Japan ; Mie University Medical Zebrafish Research Center, Mie, Japan ; Department of Bioinformatics, Mie University Life Science Research Center, Mie, Japan ; Department of Omics Medicine, Mie University Industrial Technology Innovation, Mie, Japan
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Long-term hyperphagia and caloric restriction caused by low- or high-density husbandry have differential effects on zebrafish postembryonic development, somatic growth, fat accumulation and reproduction. PLoS One 2015; 10:e0120776. [PMID: 25799180 PMCID: PMC4370574 DOI: 10.1371/journal.pone.0120776] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2014] [Accepted: 01/29/2015] [Indexed: 12/19/2022] Open
Abstract
In recent years, the zebrafish (Danio rerio) has emerged as an alternative vertebrate model for energy homeostasis and metabolic diseases, including obesity and anorexia. It has been shown that diet-induced obesity (DIO) in zebrafish shares multiple pathophysiological features with obesity in mammals. However, a systematic and comprehensive analysis of the different pathways of energy expenditure in obese and starved fish had been missing thus far. Here, we carry out long-term ad libitum feeding (hyperphagia) and caloric restriction studies induced by low- or high-density husbandry, respectively, to investigate the impact of caloric intake on the timing of scale formation, a crucial step of postembryonic development and metamorphosis, and on somatic growth, body weight, fat storage and female reproduction. We show that all of them are positively affected by increased caloric intake, that middle-aged fish develop severe DIO, and that the body mass index (BMI) displays a strict linear correlation with whole-body triglyceride levels in adult zebrafish. Interestingly, juvenile fish are largely resistant to DIO, while BMI and triglyceride values drop in aged fish, pointing to aging-associated anorexic effects. Histological analyses further indicate that increased fat storage in white adipose tissue involves both hyperplasia and hypertrophy of adipocytes. Furthermore, in ovaries, caloric intake primarily affects the rate of oocyte growth, rather than total oocyte numbers. Finally, comparing the different pathways of energy expenditure with each other, we demonstrate that they are differentially affected by caloric restriction / high-density husbandry. In juvenile fish, scale formation is prioritized over somatic growth, while in sexually mature adults, female reproduction is prioritized over somatic growth, and somatic growth over fat storage. Our data will serve as a template for future functional studies to dissect the neuroendocrine regulators of energy homeostasis mediating differential energy allocation.
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Forn-Cuní G, Varela M, Fernández-Rodríguez CM, Figueras A, Novoa B. Liver immune responses to inflammatory stimuli in a diet-induced obesity model of zebrafish. J Endocrinol 2015; 224:159-70. [PMID: 25371540 DOI: 10.1530/joe-14-0398] [Citation(s) in RCA: 33] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
Obesity- and metabolic syndrome-related diseases are becoming important medical challenges for the western world. Non-alcoholic fatty liver disease (NAFLD) is a manifestation of these altered conditions in the liver, and inflammation appears to be a factor that is tightly connected to its evolution. In this study, we used a diet-induced obesity approach in zebrafish (Danio rerio) based on overfeeding to analyze liver transcriptomic modulation in the disease and to determine how obesity affects the immune response against an acute inflammatory stimulus such as lipopolysaccharide (LPS). Overfed zebrafish developed an obese phenotype, showed signs of liver steatosis, and its modulation profile resembled that observed in humans, with overexpression of tac4, col4a3, col4a5, lysyl oxidases, and genes involved in retinoid metabolism. In response to LPS, healthy fish exhibited a typical host defense reaction comparable to that which occurs in mammals, whereas there was no significant gene modulation when comparing expression in the liver of LPS-stimulated and non-stimulated obese zebrafish at the same statistical level. The stimulation of obese fish represents a double-hit to the already damaged liver and can help understand the evolution of the disease. Finally, a comparison of the differential gene activation between stimulated healthy and obese zebrafish revealed the expected difference in the metabolic state between healthy and diseased liver. The differentially modulated genes are currently being studied as putative new pathological markers in NAFLD-stimulated liver in humans.
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Affiliation(s)
- Gabriel Forn-Cuní
- Instituto de Investigaciones MarinasCSIC, Eduardo Cabello 6, 36208 Vigo, SpainHospital Universitario Fundación AlcorcónMadrid, Spain
| | - Monica Varela
- Instituto de Investigaciones MarinasCSIC, Eduardo Cabello 6, 36208 Vigo, SpainHospital Universitario Fundación AlcorcónMadrid, Spain
| | - Conrado M Fernández-Rodríguez
- Instituto de Investigaciones MarinasCSIC, Eduardo Cabello 6, 36208 Vigo, SpainHospital Universitario Fundación AlcorcónMadrid, Spain
| | - Antonio Figueras
- Instituto de Investigaciones MarinasCSIC, Eduardo Cabello 6, 36208 Vigo, SpainHospital Universitario Fundación AlcorcónMadrid, Spain
| | - Beatriz Novoa
- Instituto de Investigaciones MarinasCSIC, Eduardo Cabello 6, 36208 Vigo, SpainHospital Universitario Fundación AlcorcónMadrid, Spain
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Sapp V, Gaffney L, EauClaire SF, Matthews RP. Fructose leads to hepatic steatosis in zebrafish that is reversed by mechanistic target of rapamycin (mTOR) inhibition. Hepatology 2014; 60:1581-92. [PMID: 25043405 DOI: 10.1002/hep.27284] [Citation(s) in RCA: 94] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/24/2014] [Accepted: 06/27/2014] [Indexed: 12/14/2022]
Abstract
UNLABELLED Nonalcoholic fatty liver disease (NAFLD), the accumulation of lipid within hepatocytes, is increasing in prevalence. Increasing fructose consumption correlates with this increased prevalence, and rodent studies directly support fructose leading to NAFLD. The mechanisms of NAFLD and in particular fructose-induced lipid accumulation remain unclear, although there is evidence for a role for endoplasmic reticulum (ER) stress and oxidative stress. We have evidence that NAFLD models demonstrate activation of the target of rapamycin complex 1 (Torc1) pathway. We set out to assess the contribution of ER stress, oxidative stress, and Torc1 up-regulation in the development of steatohepatitis in fructose-treated larval zebrafish. Zebrafish were treated with fructose or glucose as a calorie-matched control. We also treated larvae with rapamycin, tunicamycin (ER stress), or valinomycin (oxidative stress). Fish were stained with oil red O to assess hepatic lipid accumulation, and we also performed quantitative polymerase chain reaction (qPCR)and western blot analysis. We performed immunostaining on samples from patients with NAFLD and nonalcoholic steatohepatitis (NASH). Treatment with fructose induced hepatic lipid accumulation, mitochondrial abnormalities, and ER defects. In addition, fructose-treated fish showed activation of inflammatory and lipogenic genes. Treatment with tunicamycin or valinomycin also induced hepatic lipid accumulation. Expression microarray studies of zebrafish NAFLD models showed an elevation of genes downstream of Torc1 signaling. Rapamycin treatment of fructose-treated fish prevented development of hepatic steatosis, as did treatment of tunicamycin- or valinomycin-treated fish. Examination of liver samples from patients with hepatic steatosis demonstrated activation of Torc1 signaling. CONCLUSION Fructose treatment of larval zebrafish induces hepatic lipid accumulation, inflammation, and oxidative stress. Our results indicate that Torc1 activation is required for hepatic lipid accumulation across models of NAFLD, and in patients.
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Affiliation(s)
- Valerie Sapp
- Division of Gastroenterology, Hepatology, and Nutrition, Children's Hospital of Philadelphia Research Institute, Philadelphia, PA
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Zang L, Shimada Y, Kawajiri J, Tanaka T, Nishimura N. Effects of Yuzu (Citrus junos Siebold ex Tanaka) peel on the diet-induced obesity in a zebrafish model. J Funct Foods 2014. [DOI: 10.1016/j.jff.2014.08.002] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/28/2022] Open
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Abstract
A notable advantage of zebrafish as a model organism is the ease of gene knockdown using morpholino antisense oligonucleotide (MO). However, zebrafish morphants injected with MO for a target protein often show heterogeneous phenotypes, despite controlling the injection volume of the MO solution in all embryos. We developed a method for estimating the quantity of MO injected into each living morphant, based on the co-injection of a control MO labeled with the fluorophore lissamine. By applying this method for knockdown of cardiac troponin T (tnnt2a) in zebrafish, we could efficiently select the partial tnnt2a-depleted zebrafish with a decreased heart rate and impairment of cardiac contraction. To investigate cardiac impairment of the tnnt2a morphant, we performed fluorescent cardiac imaging using Bodipy-ceramide. Cardiac image analysis showed moderate reduction of tnnt2a impaired diastolic distensibility and decreased contraction and relaxation velocities. To the best of our knowledge, this is the first report to analyze the role of tnnt2a in cardiac function in tnnt2a-depleted living animals. Our combinatorial approach can be applied for analyzing the molecular function of any protein associated with human cardiac diseases.
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Pardal D, Caro M, Tueros I, Barranco A, Navarro V. Resveratrol and Piceid Metabolites and Their Fat-Reduction Effects in Zebrafish Larvae. Zebrafish 2014; 11:32-40. [DOI: 10.1089/zeb.2013.0893] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022] Open
Affiliation(s)
- David Pardal
- Food Research Division, AZTI-Tecnalia, Derio, Spain
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Eriocitrin ameliorates diet-induced hepatic steatosis with activation of mitochondrial biogenesis. Sci Rep 2014; 4:3708. [PMID: 24424211 PMCID: PMC3892443 DOI: 10.1038/srep03708] [Citation(s) in RCA: 71] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2013] [Accepted: 12/10/2013] [Indexed: 02/06/2023] Open
Abstract
Lemon (Citrus limon) contains various bioactive flavonoids, and prevents obesity and obesity-associated metabolic diseases. We focused on eriocitrin (eriodictyol 7-rutinoside), a powerful antioxidative flavonoid in lemon with lipid-lowering effects in a rat model of high-fat diet. To investigate the mechanism of action of eriocitrin, we conducted feeding experiments on zebrafish with diet-induced obesity. Oral administration of eriocitrin (32 mg/kg/day for 28 days) improved dyslipidaemia and decreased lipid droplets in the liver. DNA microarray analysis revealed that eriocitrin increased mRNA of mitochondrial biogenesis genes, such as mitochondria transcription factor, nuclear respiratory factor 1, cytochrome c oxidase subunit 4, and ATP synthase. In HepG2 cells, eriocitrin also induced the corresponding orthologues, and reduced lipid accumulation under conditions of lipid loading. Eriocitrin increased mitochondrial size and mtDNA content, which resulted in ATP production in HepG2 cells and zebrafish. In summary, dietary eriocitrin ameliorates diet-induced hepatic steatosis with activation of mitochondrial biogenesis.
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Shimada Y, Kuroyanagi J, Zhang B, Ariyoshi M, Umemoto N, Nishimura Y, Tanaka T. Downregulation of Max dimerization protein 3 is involved in decreased visceral adipose tissue by inhibiting adipocyte differentiation in zebrafish and mice. Int J Obes (Lond) 2013; 38:1053-60. [PMID: 24254064 DOI: 10.1038/ijo.2013.217] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/10/2013] [Revised: 10/16/2013] [Accepted: 11/05/2013] [Indexed: 01/14/2023]
Abstract
BACKGROUND The diet-induced obesity model of zebrafish (DIO-zebrafish) share a common pathophysiological pathway with mammalian obesity. OBJECTIVES We aimed to investigate the role of Max dimerization protein 3 (MXD3) in visceral fat accumulation and adipocyte differentiation, by conducting knockdown experiments using zebrafish and mouse preadipocytes. METHODS To identify genes related to visceral adiposity, we conducted transcriptome analyses of human and zebrafish obese populations using the Gene Expression Omnibus and DNA microarray. We then intraperitoneally injected morpholino antisense oligonucleotides (MO-mxd3) to knockdown mxd3 gene expression in DIO-zebrafish and measured several parameters, which reflected human obesity and associated metabolic diseases. Finally, lentiviral Mxd3 shRNA knockdown in mouse 3T3-L1 preadipocytes was conducted. Quantitative PCR analyses of several differentiation markers were conducted during these gene knockdown experiments. RESULTS We found that MXD3 expression was increased in the obese population in humans and zebrafish. Intraperitoneal MO-mxd3 administration to DIO-zebrafish suppressed the increase in body weight, visceral fat accumulation and the size of mature adipocytes. Subsequently, dyslipidemia and liver steatosis were also ameliorated by MO-mxd3. In mouse adipocytes, Mxd3 expression was drastically increased in the early differentiation stage. Mxd3 shRNA inhibited preadipocyte proliferation and adipocyte maturation. Quantitative PCR analyses showed that the early differentiation marker, CCAAT/enhancer-binding protein delta (Cebpd) and late differentiation markers (CCAAT/enhancer-binding protein, alpha and peroxisome proliferator-activated receptor gamma) were downregulated by Mxd3 knockdown in 3T3-L1 cells and DIO-zebrafish. Subsequently, mature adipocyte markers (adiponectin and caveolin 1 for zebrafish, and fatty acid binding protein 4 and stearoyl-coenzyme A desaturase 1 for mouse adipocytes) were also decreased. CONCLUSION Mxd3 regulates preadipocyte proliferation and early adipocyte differentiation via Cebpd downregulation in vitro and in vivo. Integrated analysis of human and zebrafish transcriptomes allows identification of a novel therapeutic target against human obesity and further associated metabolic disease.
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Affiliation(s)
- Y Shimada
- 1] Department of Molecular and Cellular Pharmacology, Pharmacogenomics and Pharmacoinformatics, Mie University Graduate School of Medicine, Mie, Japan [2] Department of Systems Pharmacology, Mie University Graduate School of Medicine, Mie, Japan [3] Mie University Medical Zebrafish Research Center, Mie, Japan [4] Department of Bioinformatics, Mie University Life Science Research Center, Mie, Japan [5] Department of Omics Medicine, Mie University Industrial Technology Innovation, Mie, Japan
| | - J Kuroyanagi
- Department of Molecular and Cellular Pharmacology, Pharmacogenomics and Pharmacoinformatics, Mie University Graduate School of Medicine, Mie, Japan
| | - B Zhang
- Department of Molecular and Cellular Pharmacology, Pharmacogenomics and Pharmacoinformatics, Mie University Graduate School of Medicine, Mie, Japan
| | - M Ariyoshi
- 1] Department of Molecular and Cellular Pharmacology, Pharmacogenomics and Pharmacoinformatics, Mie University Graduate School of Medicine, Mie, Japan [2] Department of Systems Pharmacology, Mie University Graduate School of Medicine, Mie, Japan
| | - N Umemoto
- 1] Department of Molecular and Cellular Pharmacology, Pharmacogenomics and Pharmacoinformatics, Mie University Graduate School of Medicine, Mie, Japan [2] Department of Systems Pharmacology, Mie University Graduate School of Medicine, Mie, Japan
| | - Y Nishimura
- 1] Department of Molecular and Cellular Pharmacology, Pharmacogenomics and Pharmacoinformatics, Mie University Graduate School of Medicine, Mie, Japan [2] Department of Systems Pharmacology, Mie University Graduate School of Medicine, Mie, Japan [3] Mie University Medical Zebrafish Research Center, Mie, Japan [4] Department of Bioinformatics, Mie University Life Science Research Center, Mie, Japan [5] Department of Omics Medicine, Mie University Industrial Technology Innovation, Mie, Japan
| | - T Tanaka
- 1] Department of Molecular and Cellular Pharmacology, Pharmacogenomics and Pharmacoinformatics, Mie University Graduate School of Medicine, Mie, Japan [2] Department of Systems Pharmacology, Mie University Graduate School of Medicine, Mie, Japan [3] Mie University Medical Zebrafish Research Center, Mie, Japan [4] Department of Bioinformatics, Mie University Life Science Research Center, Mie, Japan [5] Department of Omics Medicine, Mie University Industrial Technology Innovation, Mie, Japan
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Abstract
The liver performs a large number of essential synthetic and regulatory functions that are acquired during fetal development and persist throughout life. Their disruption underlies a diverse group of heritable and acquired diseases that affect both pediatric and adult patients. Although experimental analyses used to study liver development and disease are typically performed in cell culture models or rodents, the zebrafish is increasingly used to complement discoveries made in these systems. Forward and reverse genetic analyses over the past two decades have shown that the molecular program for liver development is largely conserved between zebrafish and mammals, and that the zebrafish can be used to model heritable human liver disorders. Recent work has demonstrated that zebrafish can also be used to study the mechanistic basis of acquired liver diseases. Here, we provide a comprehensive summary of how the zebrafish has contributed to our understanding of human liver development and disease.
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Affiliation(s)
- Benjamin J Wilkins
- Department of Pathology and Laboratory Medicine, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA
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Nguyen M, Yang E, Neelkantan N, Mikhaylova A, Arnold R, Poudel MK, Stewart AM, Kalueff AV. Developing 'integrative' zebrafish models of behavioral and metabolic disorders. Behav Brain Res 2013; 256:172-87. [PMID: 23948218 DOI: 10.1016/j.bbr.2013.08.012] [Citation(s) in RCA: 41] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2013] [Revised: 07/31/2013] [Accepted: 08/03/2013] [Indexed: 02/09/2023]
Abstract
Recently, the pathophysiological overlap between metabolic and mental disorders has received increased recognition. Zebrafish (Danio rerio) are rapidly becoming a popular model organism for translational biomedical research due to their genetic tractability, low cost, quick reproductive cycle, and ease of behavioral, pharmacological or genetic manipulation. High homology to mammalian physiology and the availability of well-developed assays also make the zebrafish an attractive organism for studying human disorders. Zebrafish neurobehavioral and endocrine phenotypes show promise for the use of zebrafish in studies of stress, obesity and related behavioral and metabolic disorders. Here, we discuss the parallels between zebrafish and other model species in stress and obesity physiology, as well as outline the available zebrafish models of weight gain, metabolic deficits, feeding, stress, anxiety and related behavioral disorders. Overall, zebrafish demonstrate a strong potential for modeling human behavioral and metabolic disorders, and their comorbidity.
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Affiliation(s)
- Michael Nguyen
- Department of Biomedical Engineering, University of Virginia, 415 Lane Road, Charlottesville, VA 22908, USA; Thomas Jefferson High School for Science and Technology, 6560 Braddock Road, Alexandria, VA 22312, USA
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