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Nath D, Barbhuiya PA, Sen S, Pathak MP. A Review on in-vivo and in-vitro Models of Obesity and Obesity-Associated Co-Morbidities. Endocr Metab Immune Disord Drug Targets 2024; 25:EMIDDT-EPUB-142215. [PMID: 39136512 DOI: 10.2174/0118715303312932240801073903] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/26/2024] [Revised: 06/20/2024] [Accepted: 06/26/2024] [Indexed: 01/04/2025]
Abstract
BACKGROUND Obesity is becoming a global pandemic with pandemic proportions. According to the WHO estimates, there were over 1.9 billion overweight individuals and over 650 million obese adults in the globe in 2016. In recent years, scientists have encountered difficulties in choosing acceptable animal models, leading to a multitude of contradicting aspects and incorrect outcomes. This review comprehensively evaluates different screening models of obesity and obesity-associated comorbidities to reveal the advantages and disadvantages/limitations of each model while also mentioning the time duration each model requires to induce obesity. METHODOLOGY For this review, the authors have gone through a vast number of article sources from different scientific databases, such as Google Scholar, Web of Science, Medline, and PubMed. RESULTS In-vivo models used to represent a variety of obesity-inducing processes, such as diet-induced, drug-induced, surgical, chemical, stress-induced, and genetic models, are discussed. Animal cell models are examined with an emphasis on their use in understanding the molecular causes of obesity, for which we discussed in depth the important cell lines, including 3T3-L1, OP9, 3T3-F442A, and C3H10T1/2. Screening models of obesity-associated co-morbidities like diabetes, asthma, cardiovascular disorders, cancer, and polycystic ovarian syndrome (PCOS) were discussed, which provided light on the complex interactions between obesity and numerous health problems. CONCLUSION Mimicking obesity in an animal model reflects multifactorial aspects is a matter of challenge. Future studies could address the ethical issues surrounding the use of animals in obesity research as well as investigate newly developed models, such as non-mammalian models. In conclusion, improving our knowledge and management of obesity and related health problems will require ongoing assessment and improvement of study models.
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Affiliation(s)
- Digbijoy Nath
- Faculty of Pharmaceutical Science, Assam Down Town University, Sankar Madhab Path, Gandhi Nagar, Panikhaiti, Guwahati, Assam, 781026, India
- Centre for Research on Ethnomedicine, Assam Down Town University, Sankar Madhab Path, Gandhi Nagar, Panikhaiti, Guwahati, Assam, 781026, India
| | - Pervej Alom Barbhuiya
- Faculty of Pharmaceutical Science, Assam Down Town University, Sankar Madhab Path, Gandhi Nagar, Panikhaiti, Guwahati, Assam, 781026, India
- Centre for Research on Ethnomedicine, Assam Down Town University, Sankar Madhab Path, Gandhi Nagar, Panikhaiti, Guwahati, Assam, 781026, India
| | - Saikat Sen
- Faculty of Pharmaceutical Science, Assam Down Town University, Sankar Madhab Path, Gandhi Nagar, Panikhaiti, Guwahati, Assam, 781026, India
- Centre for Research on Ethnomedicine, Assam Down Town University, Sankar Madhab Path, Gandhi Nagar, Panikhaiti, Guwahati, Assam, 781026, India
| | - Manash Pratim Pathak
- Faculty of Pharmaceutical Science, Assam Down Town University, Sankar Madhab Path, Gandhi Nagar, Panikhaiti, Guwahati, Assam, 781026, India
- Centre for Research on Ethnomedicine, Assam Down Town University, Sankar Madhab Path, Gandhi Nagar, Panikhaiti, Guwahati, Assam, 781026, India
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Janapati YK, Junapudi S. Progress in experimental models to investigate the in vivo and in vitro antidiabetic activity of drugs. Animal Model Exp Med 2024; 7:297-309. [PMID: 38837635 PMCID: PMC11228097 DOI: 10.1002/ame2.12442] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2023] [Accepted: 04/01/2024] [Indexed: 06/07/2024] Open
Abstract
Diabetes mellitus is one of the world's most prevalent and complex metabolic disorders, and it is a rapidly growing global public health issue. It is characterized by hyperglycemia, a condition involving a high blood glucose level brought on by deficiencies in insulin secretion, decreased activity of insulin, or both. Prolonged effects of diabetes include cardiovascular problems, retinopathy, neuropathy, nephropathy, and vascular alterations in both macro- and micro-blood vessels. In vivo and in vitro models have always been important for investigating and characterizing disease pathogenesis, identifying targets, and reviewing novel treatment options and medications. Fully understanding these models is crucial for the researchers so this review summarizes the different experimental in vivo and in vitro model options used to study diabetes and its consequences. The most popular in vivo studies involves the small animal models, such as rodent models, chemically induced diabetogens like streptozotocin and alloxan, and the possibility of deleting or overexpressing a specific gene by knockout and transgenic technologies on these animals. Other models include virally induced models, diet/nutrition induced diabetic animals, surgically induced models or pancreatectomy models, and non-obese models. Large animals or non-rodent models like porcine (pig), canine (dog), nonhuman primate, and Zebrafish models are also outlined. The in vitro models discussed are murine and human beta-cell lines and pancreatic islets, human stem cells, and organoid cultures. The other enzymatic in vitro tests to assess diabetes include assay of amylase inhibition and inhibition of α-glucosidase activity.
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Affiliation(s)
- Yasodha Krishna Janapati
- School of Pharmacy & Health SciencesUnited States International University‐AFRICA (USIU‐A)NairobiKenya
| | - Sunil Junapudi
- Department of Pharmaceutical ChemistryGeethanjali College of PharmacyKeesaraIndia
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Vick LV, Canter RJ, Monjazeb AM, Murphy WJ. Multifaceted effects of obesity on cancer immunotherapies: Bridging preclinical models and clinical data. Semin Cancer Biol 2023; 95:88-102. [PMID: 37499846 PMCID: PMC10836337 DOI: 10.1016/j.semcancer.2023.07.004] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/01/2023] [Revised: 07/04/2023] [Accepted: 07/24/2023] [Indexed: 07/29/2023]
Abstract
Obesity, defined by excessive body fat, is a highly complex condition affecting numerous physiological processes, such as metabolism, proliferation, and cellular homeostasis. These multifaceted effects impact cells and tissues throughout the host, including immune cells as well as cancer biology. Because of the multifaceted nature of obesity, common parameters used to define it (such as body mass index in humans) can be problematic, and more nuanced methods are needed to characterize the pleiotropic metabolic effects of obesity. Obesity is well-accepted as an overall negative prognostic factor for cancer incidence, progression, and outcome. This is in part due to the meta-inflammatory and immunosuppressive effects of obesity. Immunotherapy is increasingly used in cancer therapy, and there are many different types of immunotherapy approaches. The effects of obesity on immunotherapy have only recently been studied with the demonstration of an "obesity paradox", in which some immune therapies have been demonstrated to result in greater efficacy in obese subjects despite the direct adverse effects of obesity and excess body fat acting on the cancer itself. The multifactorial characteristics that influence the effects of obesity (age, sex, lean muscle mass, underlying metabolic conditions and drugs) further confound interpretation of clinical data and necessitate the use of more relevant preclinical models mirroring these variables in the human scenario. Such models will allow for more nuanced mechanistic assessment of how obesity can impact, both positively and negatively, cancer biology, host metabolism, immune regulation, and how these intersecting processes impact the delivery and outcome of cancer immunotherapy.
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Affiliation(s)
- Logan V Vick
- Department of Dermatology, University of California Davis School of Medicine, Sacramento, CA, USA
| | - Robert J Canter
- Department of Surgery, Division of Surgical Oncology, University of California Davis Comprehensive Cancer Center, University of California Davis School of Medicine, Sacramento, CA, USA
| | - Arta M Monjazeb
- Department of Radiation Oncology, University of California Davis Comprehensive Cancer Center, University of California School of Medicine, Sacramento, CA, USA
| | - William J Murphy
- Department of Dermatology, University of California Davis School of Medicine, Sacramento, CA, USA; Department of Internal Medicine, Division of Malignant Hematology, Cellular Therapy and Transplantation, University of California Davis School of Medicine, Sacramento, CA, USA.
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Cuciureanu M, Caratașu CC, Gabrielian L, Frăsinariu OE, Checheriță LE, Trandafir LM, Stanciu GD, Szilagyi A, Pogonea I, Bordeianu G, Soroceanu RP, Andrițoiu CV, Anghel MM, Munteanu D, Cernescu IT, Tamba BI. 360-Degree Perspectives on Obesity. MEDICINA (KAUNAS, LITHUANIA) 2023; 59:1119. [PMID: 37374323 PMCID: PMC10304508 DOI: 10.3390/medicina59061119] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/15/2023] [Revised: 05/29/2023] [Accepted: 06/02/2023] [Indexed: 06/29/2023]
Abstract
Alarming statistics show that the number of people affected by excessive weight has surpassed 2 billion, representing approximately 30% of the world's population. The aim of this review is to provide a comprehensive overview of one of the most serious public health problems, considering that obesity requires an integrative approach that takes into account its complex etiology, including genetic, environmental, and lifestyle factors. Only an understanding of the connections between the many contributors to obesity and the synergy between treatment interventions can ensure satisfactory outcomes in reducing obesity. Mechanisms such as oxidative stress, chronic inflammation, and dysbiosis play a crucial role in the pathogenesis of obesity and its associated complications. Compounding factors such as the deleterious effects of stress, the novel challenge posed by the obesogenic digital (food) environment, and the stigma associated with obesity should not be overlooked. Preclinical research in animal models has been instrumental in elucidating these mechanisms, and translation into clinical practice has provided promising therapeutic options, including epigenetic approaches, pharmacotherapy, and bariatric surgery. However, more studies are necessary to discover new compounds that target key metabolic pathways, innovative ways to deliver the drugs, the optimal combinations of lifestyle interventions with allopathic treatments, and, last but not least, emerging biological markers for effective monitoring. With each passing day, the obesity crisis tightens its grip, threatening not only individual lives but also burdening healthcare systems and societies at large. It is high time we took action as we confront the urgent imperative to address this escalating global health challenge head-on.
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Affiliation(s)
- Magdalena Cuciureanu
- Department of Pharmacology, “Grigore T. Popa” University of Medicine and Pharmacy, 700115 Iasi, Romania; (M.C.); (C.-C.C.); (I.T.C.); (B.I.T.)
| | - Cătălin-Cezar Caratașu
- Department of Pharmacology, “Grigore T. Popa” University of Medicine and Pharmacy, 700115 Iasi, Romania; (M.C.); (C.-C.C.); (I.T.C.); (B.I.T.)
- Center for Advanced Research and Development in Experimental Medicine (CEMEX), “Grigore T. Popa” University of Medicine and Pharmacy, 700115 Iasi, Romania; (G.D.S.); (A.S.)
| | - Levon Gabrielian
- Department of Anatomy and Pathology, The University of Adelaide, Adelaide 5000, Australia;
| | - Otilia Elena Frăsinariu
- Department of Mother and Child, “Grigore T. Popa” University of Medicine and Pharmacy, 700115 Iasi, Romania;
| | - Laura Elisabeta Checheriță
- 2nd Dental Medicine Department, “Grigore T. Popa” University of Medicine and Pharmacy, 700115 Iasi, Romania
| | - Laura Mihaela Trandafir
- Department of Mother and Child, “Grigore T. Popa” University of Medicine and Pharmacy, 700115 Iasi, Romania;
| | - Gabriela Dumitrița Stanciu
- Center for Advanced Research and Development in Experimental Medicine (CEMEX), “Grigore T. Popa” University of Medicine and Pharmacy, 700115 Iasi, Romania; (G.D.S.); (A.S.)
| | - Andrei Szilagyi
- Center for Advanced Research and Development in Experimental Medicine (CEMEX), “Grigore T. Popa” University of Medicine and Pharmacy, 700115 Iasi, Romania; (G.D.S.); (A.S.)
| | - Ina Pogonea
- Department of Pharmacology and Clinical Pharmacology, “Nicolae Testemiţanu” State University of Medicine and Pharmacy, 2004 Chisinau, Moldova; (I.P.); (M.M.A.)
| | - Gabriela Bordeianu
- Department of Biochemistry, “Grigore T. Popa” University of Medicine and Pharmacy, 700115 Iasi, Romania;
| | - Radu Petru Soroceanu
- Department of Surgery, “Grigore T. Popa” University of Medicine and Pharmacy, 700115 Iasi, Romania;
| | - Călin Vasile Andrițoiu
- Specialization of Nutrition and Dietetics, “Vasile Goldis” Western University of Arad, 310025 Arad, Romania
| | - Maria Mihalache Anghel
- Department of Pharmacology and Clinical Pharmacology, “Nicolae Testemiţanu” State University of Medicine and Pharmacy, 2004 Chisinau, Moldova; (I.P.); (M.M.A.)
| | - Diana Munteanu
- Institute of Mother and Child, “Nicolae Testemiţanu” State University of Medicine and Pharmacy, 2062 Chisinau, Moldova;
| | - Irina Teodora Cernescu
- Department of Pharmacology, “Grigore T. Popa” University of Medicine and Pharmacy, 700115 Iasi, Romania; (M.C.); (C.-C.C.); (I.T.C.); (B.I.T.)
| | - Bogdan Ionel Tamba
- Department of Pharmacology, “Grigore T. Popa” University of Medicine and Pharmacy, 700115 Iasi, Romania; (M.C.); (C.-C.C.); (I.T.C.); (B.I.T.)
- Center for Advanced Research and Development in Experimental Medicine (CEMEX), “Grigore T. Popa” University of Medicine and Pharmacy, 700115 Iasi, Romania; (G.D.S.); (A.S.)
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Shakya A, Chaudary SK, Garabadu D, Bhat HR, Kakoti BB, Ghosh SK. A Comprehensive Review on Preclinical Diabetic Models. Curr Diabetes Rev 2020; 16:104-116. [PMID: 31074371 DOI: 10.2174/1573399815666190510112035] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/30/2018] [Revised: 02/20/2019] [Accepted: 04/22/2019] [Indexed: 12/16/2022]
Abstract
BACKGROUND Preclinical experimental models historically play a critical role in the exploration and characterization of disease pathophysiology. Further, these in-vivo and in-vitro preclinical experiments help in target identification, evaluation of novel therapeutic agents and validation of treatments. INTRODUCTION Diabetes mellitus (DM) is a multifaceted metabolic disorder of multidimensional aetiologies with the cardinal feature of chronic hyperglycemia. To avoid or minimize late complications of diabetes and related costs, primary prevention and early treatment are therefore necessary. Due to its chronic manifestations, new treatment strategies need to be developed, because of the limited effectiveness of the current therapies. METHODS The study included electronic databases such as Pubmed, Web of Science and Scopus. The datasets were searched for entries of studies up to June, 2018. RESULTS A large number of in-vivo and in-vitro models have been presented for evaluating the mechanism of anti-hyperglycaemic effect of drugs in hormone-, chemically-, pathogen-induced animal models of diabetes mellitus. The advantages and limitations of each model have also been addressed in this review. CONCLUSION This review encompasses the wide pathophysiological and molecular mechanisms associated with diabetes, particularly focusing on the challenges associated with the evaluation and predictive validation of these models as ideal animal models for preclinical assessments and discovering new drugs and therapeutic agents for translational application in humans. This review may further contribute to discover a novel drug to treat diabetes more efficaciously with minimum or no side effects. Furthermore, it also highlights ongoing research and considers the future perspectives in the field of diabetes.
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Affiliation(s)
- Anshul Shakya
- Department of Pharmaceutical Sciences, School of Science and Engineering, Dibrugarh University, Dibrugarh - 786 004, Assam, India
| | - Sushil Kumar Chaudary
- Department of Pharmacology, University of the Free State, Bloemfontein 9300, South Africa
| | - Debapriya Garabadu
- Institute of Pharmaceutical Research, GLA University, Mathura - 281406, Uttar Pradesh, India
| | - Hans Raj Bhat
- Department of Pharmaceutical Sciences, School of Science and Engineering, Dibrugarh University, Dibrugarh - 786 004, Assam, India
| | - Bibhuti Bhusan Kakoti
- Department of Pharmaceutical Sciences, School of Science and Engineering, Dibrugarh University, Dibrugarh - 786 004, Assam, India
| | - Surajit Kumar Ghosh
- Department of Pharmaceutical Sciences, School of Science and Engineering, Dibrugarh University, Dibrugarh - 786 004, Assam, India
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Jones PH, Deng B, Winkler J, Zirnheld AL, Ehringer S, Shetty V, Cox M, Nguyen H, Shen WJ, Huang TT, Wang E. Over-expression of miR-34c leads to early-life visceral fat accumulation and insulin resistance. Sci Rep 2019; 9:13844. [PMID: 31554925 PMCID: PMC6761099 DOI: 10.1038/s41598-019-50191-3] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/01/2019] [Accepted: 08/15/2019] [Indexed: 12/13/2022] Open
Abstract
Overweight children and adolescents are at high risk for adult and late life obesity. This report investigates some underlying mechanisms contributing to obesity during early life in an animal model. We generated a strain of transgenic mice, cU2, overexpressing human microRNA 34c, a microRNA functionally implicated in adipogenesis. Male and female cU2 mice exhibit significant weight gain, accompanied by marked increase in abdominal fat mass and metabolic abnormalities, including reduction of both glucose clearance rate and insulin sensitivity, as early as two months of age. Adipogenesis derailment at this early age is suggested by decreased expression of adiponectin, the fat mass and obesity-associated gene, and the adiponectin receptor R1, coupled with a reduction of the brown fat biomarker PAT2 and the adipogenesis inhibitor SIRT1. Notably, adiponectin is an important adipokine and an essential regulator of glucose and fatty acid homeostasis. cU2 mice may provide a crucial animal model for investigating the role of miR-34c in early onset insulin resistance and visceral fat mass increase, contributing to accelerated body weight gain and metabolic disorders. Intervention in this dysregulation may open a new preventive strategy to control early-life weight gain and abnormal insulin resistance, and thus prevalent adult and late life obesity.
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Affiliation(s)
| | - Brian Deng
- Palo Alto Veterans Institute for Research, Palo Alto, CA, USA.,Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, CA, USA
| | | | | | | | | | - Matthew Cox
- Advanced Genomic Technology, LLC, Louisville, KY, USA
| | - Huy Nguyen
- Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, CA, USA
| | - Wen-Jun Shen
- Department of Endocrinology, Stanford University School of Medicine, Stanford, CA, USA.,Geriatric Research, Education, and Clinical Center, VA Palo Alto Health Care System, Palo Alto, CA, USA
| | - Ting-Ting Huang
- Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, CA, USA. .,Geriatric Research, Education, and Clinical Center, VA Palo Alto Health Care System, Palo Alto, CA, USA.
| | - Eugenia Wang
- Advanced Genomic Technology, LLC, Louisville, KY, USA
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Lankatillake C, Huynh T, Dias DA. Understanding glycaemic control and current approaches for screening antidiabetic natural products from evidence-based medicinal plants. PLANT METHODS 2019; 15:105. [PMID: 31516543 PMCID: PMC6731622 DOI: 10.1186/s13007-019-0487-8] [Citation(s) in RCA: 68] [Impact Index Per Article: 11.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/22/2019] [Accepted: 08/20/2019] [Indexed: 05/15/2023]
Abstract
Type 2 Diabetes Mellitus has reached epidemic proportions as a result of over-nutrition and increasingly sedentary lifestyles. Current therapies, although effective, are not without limitations. These limitations, the alarming increase in the prevalence of diabetes, and the soaring cost of managing diabetes and its complications underscores an urgent need for safer, more efficient and affordable alternative treatments. Over 1200 plant species are reported in ethnomedicine for treating diabetes and these represents an important and promising source for the identification of novel antidiabetic compounds. Evaluating medicinal plants for desirable bioactivity goes hand-in-hand with methods in analytical biochemistry for separating and identifying lead compounds. This review aims to provide a comprehensive summary of current methods used in antidiabetic plant research to form a useful resource for researchers beginning in the field. The review summarises the current understanding of blood glucose regulation and the general mechanisms of action of current antidiabetic medications, and combines knowledge on common experimental approaches for screening plant extracts for antidiabetic activity and currently available analytical methods and technologies for the separation and identification of bioactive natural products. Common in vivo animal models, in vitro models, in silico methods and biochemical assays used for testing the antidiabetic effects of plants are discussed with a particular emphasis on in vitro methods such as cell-based bioassays for screening insulin secretagogues and insulinomimetics. Enzyme inhibition assays and molecular docking are also highlighted. The role of metabolomics, metabolite profiling, and dereplication of data for the high-throughput discovery of novel antidiabetic agents is reviewed. Finally, this review also summarises sample preparation techniques such as liquid-liquid extraction, solid phase extraction, and supercritical fluid extraction, and the critical function of nuclear magnetic resonance and high resolution liquid chromatography-mass spectrometry for the dereplication, putative identification and structure elucidation of natural compounds from evidence-based medicinal plants.
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Affiliation(s)
- Chintha Lankatillake
- School of Health and Biomedical Sciences, Discipline of Laboratory Medicine, RMIT University, Bundoora, 3083 Australia
| | - Tien Huynh
- School of Science, RMIT University, Bundoora, VIC 3083 Australia
| | - Daniel A. Dias
- School of Health and Biomedical Sciences, Discipline of Laboratory Medicine, RMIT University, Bundoora, 3083 Australia
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8
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Scroyen I, Hemmeryckx B, Lijnen HR. From mice to men – mouse models in obesity research: What can we learn? Thromb Haemost 2017; 110:634-40. [DOI: 10.1160/th12-11-0873] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2012] [Accepted: 01/26/2013] [Indexed: 12/30/2022]
Abstract
summaryObesity has become a world-wide epidemic and is associated with diseases such as diabetes, dyslipidaemia, cardiovascular disease and certain types of cancers. Understanding the adipose tissue developmental process, involving adipogenesis, angiogenesis and extracellular matrix remodelling, is therefore crucial to reveal the pathobiology of obesity. Experimental mouse models are extensively used to gain new insights into these processes and to evaluate the role of new key players, in particular proteolytic system components, in adipose tissue development and obesity. In this paper, we will review available in vitro and in vivo murine models of obesity and discuss their value in understanding the mechanisms contributing to obesity.
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Asrafuzzaman M, Cao Y, Afroz R, Kamato D, Gray S, Little PJ. Animal models for assessing the impact of natural products on the aetiology and metabolic pathophysiology of Type 2 diabetes. Biomed Pharmacother 2017; 89:1242-1251. [PMID: 28320091 DOI: 10.1016/j.biopha.2017.03.010] [Citation(s) in RCA: 49] [Impact Index Per Article: 6.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2017] [Revised: 02/28/2017] [Accepted: 03/05/2017] [Indexed: 01/24/2023] Open
Abstract
Type 2 diabetes mellitus is a complex and heterogeneous disorder which in its most common manifestation arises from insulin resistance and later insulin insufficiency. Type 2 diabetes is characterised by impaired insulin sensitivity and diagnosed as hyperglycaemia. Because of its cardiovascular consequences, Type 2 diabetes represents one of the world's leading causes of mortality and morbidity. Drug discovery and development are required to produce better ways to prevent, treat and manage diabetes and its complications. Diabetes is a human, not an animal disease, so animals do not get Type 2 diabetes. However there are animal models which are variously suitable for the investigation of new agents for the treatment of Type 2 diabetes. In this Review we have examined the various models that are available for the study of natural products with a focus on models (genetic, nutritional and spontaneous) for the metabolic abnormities of diabetes. These models are also relevant to the investigation of Western medicines for the treatment of diabetes. A suitable experimental model plays an important role in drug discovery for translational studies leading to increased understanding of the molecular basis and management of diabetes.
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Affiliation(s)
- Md Asrafuzzaman
- Asian Network of Research on Antidiabetic Plants (ANRAP), Bangladesh University of Health Science, Mirpur, Dhaka 1216, Bangladesh
| | - Yingnan Cao
- Department of Pharmacy, Xinhua College of Sun Yat-sen University,Tianhe District, Guangzhou 510520, China
| | - Rizwana Afroz
- School of Pharmacy, Pharmacy Australia Centre of Excellence, The University of Queensland, Woolloongabba, Queensland 4102 Australia
| | - Danielle Kamato
- School of Pharmacy, Pharmacy Australia Centre of Excellence, The University of Queensland, Woolloongabba, Queensland 4102 Australia
| | - Susan Gray
- School of Pharmacy, Pharmacy Australia Centre of Excellence, The University of Queensland, Woolloongabba, Queensland 4102 Australia
| | - Peter J Little
- Department of Pharmacy, Xinhua College of Sun Yat-sen University,Tianhe District, Guangzhou 510520, China; School of Pharmacy, Pharmacy Australia Centre of Excellence, The University of Queensland, Woolloongabba, Queensland 4102 Australia.
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10
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Elsukova EI, Medvedev LN, Mizonova OV. Physiological Features of Perigonadal Adipose Tissue Containing Uncoupling Protein UCP1 in ICR Mice. Bull Exp Biol Med 2016; 161:347-50. [PMID: 27496031 DOI: 10.1007/s10517-016-3411-5] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2015] [Indexed: 11/24/2022]
Abstract
Immunoreactive uncoupling protein UCP1 was found in the perigonadal fat of only twothirds of 14-week-old male ICR mice. The presence of UCP1 had no effect on the rate of O2 consumption by the adipose tissue. The cellularity of perigonadal fat estimated by the DNA content was significantly higher in tissue containing UCP1 than in samples without this protein. This regularity was also observed after adaptation of mice to moderate cold (10oC) over 8 weeks.
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Affiliation(s)
- E I Elsukova
- Faculty of Biology, Chemistry, Geography, V. P. Astafiev Krasnoyarsk State Pedagogical University, Krasnoyarsk, Russia
| | - L N Medvedev
- Faculty of Biology, Chemistry, Geography, V. P. Astafiev Krasnoyarsk State Pedagogical University, Krasnoyarsk, Russia.,Institute of Fundamental Biology and Biotechnology, Siberian Federal University, Krasnoyarsk, Russia
| | - O V Mizonova
- Faculty of Biology, Chemistry, Geography, V. P. Astafiev Krasnoyarsk State Pedagogical University, Krasnoyarsk, Russia
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11
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Dhuria RS, Singh G, Kaur A, Kaur R, Kaur T. Current status and patent prospective of animal models in diabetic research. Adv Biomed Res 2015; 4:117. [PMID: 26261819 PMCID: PMC4513317 DOI: 10.4103/2277-9175.157847] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2013] [Accepted: 12/15/2014] [Indexed: 12/21/2022] Open
Abstract
Diabetes mellitus is a heterogeneous complex metabolic disorder with multiple etiology which characterized by chronic hyperglycemia resulting from defects in insulin secretion, insulin action or both. The widespread occurrence of diabetes throughout the world has increased dramatically over the past few years. For better understanding, appropriate animal models that closely mimic the changes in humans needed, as vital tool for understanding the etiology and pathogenesis of the disease at the cellular/molecular level and for preclinical testing of drugs. This review aims to describe the animal models of type-1 diabetes (T1Ds) and T2Ds to mimic the causes and progression of the disease in humans. And also we highlight patent applications published in the last few years related to animal models in diabetes as an important milestone for future therapies that are aim to treating diabetes with specific symptoms and complications.
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Affiliation(s)
- Radhey S. Dhuria
- Department of Pharmaceutical Sciences, Guru Nanak Dev University, Amritsar, Punjab, India
| | - Gurpreet Singh
- Department of Pharmaceutical Sciences, Guru Nanak Dev University, Amritsar, Punjab, India
| | - Anudeep Kaur
- School of Pharmaceutical Sciences, Lovely Professional University, Phagwara, Punjab, India
| | - Ramandeep Kaur
- Department of Pharmaceutical Sciences, Guru Nanak Dev University, Amritsar, Punjab, India
| | - Tanurajvir Kaur
- Department of Pharmaceutical Sciences, Guru Nanak Dev University, Amritsar, Punjab, India
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Yazdi FT, Clee SM, Meyre D. Obesity genetics in mouse and human: back and forth, and back again. PeerJ 2015; 3:e856. [PMID: 25825681 PMCID: PMC4375971 DOI: 10.7717/peerj.856] [Citation(s) in RCA: 112] [Impact Index Per Article: 11.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/28/2014] [Accepted: 03/05/2015] [Indexed: 12/19/2022] Open
Abstract
Obesity is a major public health concern. This condition results from a constant and complex interplay between predisposing genes and environmental stimuli. Current attempts to manage obesity have been moderately effective and a better understanding of the etiology of obesity is required for the development of more successful and personalized prevention and treatment options. To that effect, mouse models have been an essential tool in expanding our understanding of obesity, due to the availability of their complete genome sequence, genetically identified and defined strains, various tools for genetic manipulation and the accessibility of target tissues for obesity that are not easily attainable from humans. Our knowledge of monogenic obesity in humans greatly benefited from the mouse obesity genetics field. Genes underlying highly penetrant forms of monogenic obesity are part of the leptin-melanocortin pathway in the hypothalamus. Recently, hypothesis-generating genome-wide association studies for polygenic obesity traits in humans have led to the identification of 119 common gene variants with modest effect, most of them having an unknown function. These discoveries have led to novel animal models and have illuminated new biologic pathways. Integrated mouse-human genetic approaches have firmly established new obesity candidate genes. Innovative strategies recently developed by scientists are described in this review to accelerate the identification of causal genes and deepen our understanding of obesity etiology. An exhaustive dissection of the molecular roots of obesity may ultimately help to tackle the growing obesity epidemic worldwide.
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Affiliation(s)
- Fereshteh T. Yazdi
- Department of Clinical Epidemiology and Biostatistics, McMaster University, Hamilton, ON, Canada
| | - Susanne M. Clee
- Department of Cellular and Physiological Sciences, Life Sciences Institute, University of British Columbia, Vancouver, BC, Canada
| | - David Meyre
- Department of Clinical Epidemiology and Biostatistics, McMaster University, Hamilton, ON, Canada
- Department of Pathology and Molecular Medicine, McMaster University, Hamilton, ON, Canada
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13
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El Gammal AT, Dupree A, Wolter S, Aberle J, Izbicki JR, Güngör C, Mann O. Obesity research: Status quo and future outlooks. World J Transl Med 2014; 3:119-132. [DOI: 10.5528/wjtm.v3.i3.119] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/28/2014] [Revised: 08/27/2014] [Accepted: 10/16/2014] [Indexed: 02/05/2023] Open
Abstract
Obesity is a multifactorial disease showing a pandemic increase within the last decades in developing, and developed countries. It is associated with several severe comorbidities such as type II diabetes, hypertension, sleep apnea, non-alcoholic steatosis hepatis and cancer. Due to the increasing number of overweight individuals worldwide, research in the field of obesity has become more vital than ever. Currently, great efforts are spend to understand this complex disease from a biological, psychological and sociological angle. Further insights of obesity research come from bariatric surgery that provides new information regarding hormonal changes during weight loss. The initiation of programs for obesity treatment, both interventional and pharmaceutical, are being pursued with the fullest intensity. Currently, bariatric surgery is the most effective therapy for weight loss and resolution of comorbidities in morbid obese patients. Reasons for weight loss and remission of comorbidities following Roux-en-Y-Gastric Bypass, Sleeve Gastrectomy, and other bariatric procedures are therefore under intense investigation. In this review, however, we will focus on obesity treatment, highlighting new insights and future trends of gut hormone research, the relation of obesity and cancer development via the obesity induced chronic state of inflammation, and new potential concepts of interventional and conservative obesity treatment.
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14
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Fajardo RJ, Karim L, Calley VI, Bouxsein ML. A review of rodent models of type 2 diabetic skeletal fragility. J Bone Miner Res 2014; 29:1025-40. [PMID: 24585709 PMCID: PMC5315418 DOI: 10.1002/jbmr.2210] [Citation(s) in RCA: 124] [Impact Index Per Article: 11.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/16/2013] [Revised: 02/21/2014] [Accepted: 02/25/2014] [Indexed: 12/21/2022]
Abstract
Evidence indicating that adult type 2 diabetes (T2D) is associated with increased fracture risk continues to mount. Unlike osteoporosis, diabetic fractures are associated with obesity and normal to high bone mineral density, two factors that are typically associated with reduced fracture risk. Animal models will likely play a critical role in efforts to identify the underlying mechanisms of skeletal fragility in T2D and to develop preventative treatments. In this review we critically examine the ability of current rodent models of T2D to mimic the skeletal characteristics of human T2D. We report that although there are numerous rodent models of T2D, few have undergone thorough assessments of bone metabolism and strength. Further, we find that many of the available rodent models of T2D have limitations for studies of skeletal fragility in T2D because the onset of diabetes is often prior to skeletal maturation and bone mass is low, in contrast to what is seen in adult humans. There is an urgent need to characterize the skeletal phenotype of existing models of T2D, and to develop new models that more closely mimic the skeletal effects seen in adult-onset T2D in humans.
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Affiliation(s)
- Roberto J. Fajardo
- Department of Orthopaedics, University of Texas Health Science Center at San Antonio
| | - Lamya Karim
- Center for Advanced Orthopaedic Studies, Beth Israel Deaconess Medical Center and Harvard Medical School
| | - Virginia I. Calley
- Department of Orthopaedics, University of Texas Health Science Center at San Antonio
| | - Mary L. Bouxsein
- Center for Advanced Orthopaedic Studies, Beth Israel Deaconess Medical Center and Harvard Medical School
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15
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Renne U, Langhammer M, Brenmoehl J, Walz C, Zeissler A, Tuchscherer A, Piechotta M, Wiesner RJ, Bielohuby M, Hoeflich A. Lifelong obesity in a polygenic mouse model prevents age- and diet-induced glucose intolerance- obesity is no road to late-onset diabetes in mice. PLoS One 2013; 8:e79788. [PMID: 24236159 PMCID: PMC3827443 DOI: 10.1371/journal.pone.0079788] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2012] [Accepted: 09/25/2013] [Indexed: 01/04/2023] Open
Abstract
Aims/Hypothesis Visceral obesity holds a central position in the concept of the metabolic syndrome characterized by glucose intolerance in humans. However, until now it is unclear if obesity by itself is responsible for the development of glucose intolerance. Methods We have used a novel polygenic mouse model characterized by genetically fixed obesity (DU6) and addressed age- and high fat diet-dependent glucose tolerance. Results Phenotype selection over 146 generations increased body weight by about 2.7-fold in male 12-week DU6 mice (P<0.0001) if compared to unselected controls (Fzt:DU). Absolute epididymal fat mass was particularly responsive to weight selection and increased by more than 5-fold (P<0.0001) in male DU6 mice. At an age of 6 weeks DU6 mice consumed about twice as much food if compared to unselected controls (P<0.001). Absolute food consumption was higher at all time points measured in DU6 mice than in Fzt:DU mice. Between 6 and 12 weeks of age, absolute food intake was reduced by 15% in DU6 mice (P<0.001) but not in Fzt:DU mice. In both mouse lines feeding of the high fat diet elevated body mass if compared to the control diet (P<0.05). In contrast to controls, DU6 mice did not display high fat diet-induced increases of epididymal and renal fat. Control mice progressively developed glucose intolerance with advancing age and even more in response to the high fat diet. In contrast, obese DU6 mice did neither develop a glucose intolerant phenotype with progressive age nor when challenged with a high fat diet. Conclusions/Interpretation Our results from a polygenic mouse model demonstrate that genetically pre-determined and life-long obesity is no precondition of glucose intolerance later in life.
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Affiliation(s)
- Ulla Renne
- Laboratory for Mouse Genetics, Leibniz Institute for Farm Animal Biology, Dummerstorf, Germany
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16
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Wang YW, Sun GD, Sun J, Liu SJ, Wang J, Xu XH, Miao LN. Spontaneous type 2 diabetic rodent models. J Diabetes Res 2013; 2013:401723. [PMID: 23671868 PMCID: PMC3647580 DOI: 10.1155/2013/401723] [Citation(s) in RCA: 37] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/22/2012] [Revised: 01/08/2013] [Accepted: 01/22/2013] [Indexed: 12/11/2022] Open
Abstract
Diabetes mellitus, especially type 2 diabetes (T2DM), is one of the most common chronic diseases and continues to increase in numbers with large proportion of health care budget being used. Many animal models have been established in order to investigate the mechanisms and pathophysiologic progress of T2DM and find effective treatments for its complications. On the basis of their strains, features, advantages, and disadvantages, various types of animal models of T2DM can be divided into spontaneously diabetic models, artificially induced diabetic models, and transgenic/knockout diabetic models. Among these models, the spontaneous rodent models are used more frequently because many of them can closely describe the characteristic features of T2DM, especially obesity and insulin resistance. In this paper, we aim to investigate the current available spontaneous rodent models for T2DM with regard to their characteristic features, advantages, and disadvantages, and especially to describe appropriate selection and usefulness of different spontaneous rodent models in testing of various new antidiabetic drugs for the treatment of type 2 diabetes.
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Affiliation(s)
- Yang-wei Wang
- Department of Nephrology, Second Hospital of Jilin University, Changchun 130041, China
| | - Guang-dong Sun
- Department of Nephrology, Second Hospital of Jilin University, Changchun 130041, China
| | - Jing Sun
- Department of Nephrology, Second Hospital of Jilin University, Changchun 130041, China
| | - Shu-jun Liu
- Department of Nephrology, Second Hospital of Jilin University, Changchun 130041, China
| | - Ji Wang
- Department of Nephrology, Second Hospital of Jilin University, Changchun 130041, China
| | - Xiao-hong Xu
- Department of Nephrology, Second Hospital of Jilin University, Changchun 130041, China
| | - Li-ning Miao
- Department of Nephrology, Second Hospital of Jilin University, Changchun 130041, China
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17
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Affiliation(s)
- David M. Ansell
- The Healing Foundation Centre; Faculty of Life Sciences; The University of Manchester; Manchester; UK
| | | | - Matthew J. Hardman
- The Healing Foundation Centre; Faculty of Life Sciences; The University of Manchester; Manchester; UK
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18
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Leamy LJ, Gordon RR, Pomp D. Epistatic Control of Mammary Cancer Susceptibility in Mice may Depend on the Dietary Environment. HEREDITARY GENETICS : CURRENT RESEARCH 2012; 1:108. [PMID: 24558641 PMCID: PMC3927415 DOI: 10.4172/2161-1041.1000108] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
Abstract
Recent studies have linked a high fat diet to the development of breast cancer, but any genetic basis for this association is poorly understood. We investigated this association with an epistatic analysis of seven cancer traits in a segregating population of mice with metastatic mammary cancer that were fed either a control or a high-fat diet. We used an interval mapping approach with single nucleotide polymorphisms to scan all 19 autosomes, and discovered a number of diet-independent epistatic interactions of quantitative trait loci (QTLs) affecting these traits. More importantly, we also discovered significant epistatic by diet interactions affecting some of the traits that suggested these epistatic effects varied depending on the dietary environment. An analysis of these interactions showed some were due to epistasis that occurred in mice fed only the control diet or only the high-fat diet whereas other interactions were generated by differential effects of epistasis in the two dietary environments. Some of the epistatic QTLs appeared to colocalize with cancer QTLs mapped in other mouse populations and with candidate genes identified from eQTLs previously mapped in this population, but others represented novel modifying loci affecting these cancer traits. It was concluded that these diet-dependent epistatic QTLs contribute to a genetic susceptibility of dietary effects on breast cancer, and their identification may eventually lead to a better understanding that will be needed for the design of more effective treatments for this disease.
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Affiliation(s)
- Larry J. Leamy
- Department of Biology, University of North Carolina at Charlotte, Charlotte, North Carolina, 28223
| | - Ryan R. Gordon
- Department of Nutrition, University of North Carolina, Chapel Hill, North Carolina 27599
| | - Daniel Pomp
- Department of Biology, Nutrition, and Cell and Molecular Physiology, University of North Carolina, Chapel Hill North Carolina, 27599
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19
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Leamy LJ, Gordon RR, Pomp D. Sex-, diet-, and cancer-dependent epistatic effects on complex traits in mice. Front Genet 2011; 2:71. [PMID: 22303366 PMCID: PMC3268624 DOI: 10.3389/fgene.2011.00071] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2011] [Accepted: 09/29/2011] [Indexed: 01/23/2023] Open
Abstract
The genetic basis of quantitative traits such as body weight and obesity is complex, with several hundred quantitative trait loci (QTLs) known to affect these and related traits in humans and mice. It also has become increasingly evident that the single-locus effects of these QTLs vary considerably depending on factors such as the sex of the individuals and their dietary environment, and we were interested to know whether this context-dependency also applies to two-locus epistatic effects of QTLs as well. We therefore conducted a genome scan to search for epistatic effects on 13 different weight and adiposity traits in an F2 population of mice (created from an original intercross of the FVB strain with M16i, a polygenic obesity model) that were fed either a control or a high-fat diet and half of which harbored a transgene (PyMT) that caused the development of metastatic mammary cancer. We used a conventional interval mapping approach with SNPs to scan all 19 autosomes, and found extensive epistasis affecting all of these traits. More importantly, we also discovered that the majority of these epistatic effects exhibited significant interactions with sex, diet, and/or presence of PyMT. Analysis of these interactions showed that many of them appeared to involve QTLs previously identified as affecting these traits, but whose single-locus effects were variously modified by two-locus epistatic effects of other QTLs depending on the sex, diet, or PyMT environment. It was concluded that this context-dependency of epistatic effects is an important component of the genetic architecture of complex traits such as those contributing to weight and obesity.
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Affiliation(s)
- Larry J Leamy
- Department of Biology, University of North Carolina at Charlotte Charlotte, NC, USA
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20
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Li XJ, Yang H, Li GX, Zhang GH, Cheng J, Guan H, Yang GS. Transcriptome profile analysis of porcine adipose tissue by high-throughput sequencing. Anim Genet 2011; 43:144-52. [DOI: 10.1111/j.1365-2052.2011.02240.x] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/22/2023]
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21
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Kanasaki K, Koya D. Biology of obesity: lessons from animal models of obesity. J Biomed Biotechnol 2011; 2011:197636. [PMID: 21274264 PMCID: PMC3022217 DOI: 10.1155/2011/197636] [Citation(s) in RCA: 103] [Impact Index Per Article: 7.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2010] [Accepted: 12/13/2010] [Indexed: 12/17/2022] Open
Abstract
Obesity is an epidemic problem in the world and is associated with several health problems, including diabetes, cardiovascular disease, respiratory failure, muscle weakness, and cancer. The precise molecular mechanisms by which obesity induces these health problems are not yet clear. To better understand the pathomechanisms of human disease, good animal models are essential. In this paper, we will analyze animal models of obesity and their use in the research of obesity-associated human health conditions and diseases such as diabetes, cancer, and obstructive sleep apnea syndrome.
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Affiliation(s)
- Keizo Kanasaki
- Division of Diabetes & Endocrinology, Kanazawa Medical University, Uchinada, Ishikawa 920-0293, Japan
| | - Daisuke Koya
- Division of Diabetes & Endocrinology, Kanazawa Medical University, Uchinada, Ishikawa 920-0293, Japan
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22
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Hantschel C, Wagener A, Neuschl C, Teupser D, Brockmann GA. Features of the metabolic syndrome in the Berlin Fat Mouse as a model for human obesity. Obes Facts 2011; 4:270-7. [PMID: 21921649 PMCID: PMC6444685 DOI: 10.1159/000330819] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND The Berlin Fat Mouse BFMI860 is a polygenic obesity mouse model which harbors a natural major gene defect resulting in early onset of obesity. To elucidate adult bodily responses in BFMI860 mice that develop juvenile obesity, we studied features of the metabolic syndrome at 20 weeks. METHODS We examined fat deposition patterns, adipokines, lipid profiles in serum, glucose homeostasis, and insulin sensitivity in mice that were fed either a standard maintenance (SMD) or a high-fat diet (HFD). RESULTS Like many obese humans, BFMI860 mice showed hyperleptinemia accompanied by hypoadiponectinemia already at SMD that was further unbalanced as a result of HFD. Furthermore, BFMI860 mice had high triglyceride concentrations. However, triglyceride clearance after an oral oil gavage was impaired on SMD but improved on HFD. The oral and intraperitoneal glucose as well as the insulin tolerance tests provided evidence for reduced insulin sensitivity under SMD and insulin resistance on HFD. BFMI860 mice can maintain normal glucose clearance over a wide range of feeding conditions according to an adaptation via increasing the insulin concentrations. CONCLUSIONS BFMI860 mice show obesity, dyslipidemia, and insulin resistance as three major components of the metabolic syndrome. As these mice develop the described phenotype as a result of a major gene defect, they are a unique model for the investigation of genetic and pathophysiological mechanisms underlying the observed features of the metabolic syndrome and to search for potential strategies to revert the adverse effects under controlled conditions.
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Affiliation(s)
- Claudia Hantschel
- Department for Crop and Animal Sciences, Humboldt-Universität zu Berlin
| | - Asja Wagener
- Department for Crop and Animal Sciences, Humboldt-Universität zu Berlin
| | - Christina Neuschl
- Department for Crop and Animal Sciences, Humboldt-Universität zu Berlin
| | - Daniel Teupser
- Institute of Laboratory Medicine, Clinical Chemistry and Molecular Diagnostics, University Hospital Leipzig, Germany
| | - Gudrun A. Brockmann
- Department for Crop and Animal Sciences, Humboldt-Universität zu Berlin
- * Breeding Biology and Molecular Genetics, Department for Crop and Animal Sciences, Humboldt-Universität zu Berlin, Invalidenstraße 42, 10115 Berlin, Germany, Tel. +49 30 2093-6449/6089, Fax -6397,
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Dietary fat-dependent transcriptional architecture and copy number alterations associated with modifiers of mammary cancer metastasis. Clin Exp Metastasis 2010; 27:279-93. [PMID: 20354763 DOI: 10.1007/s10585-010-9326-z] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2010] [Accepted: 03/17/2010] [Indexed: 01/01/2023]
Abstract
Breast cancer is a complex disease resulting from a combination of genetic and environmental factors. Among environmental factors, body composition and intake of specific dietary components like total fat are associated with increased incidence of breast cancer and metastasis. We previously showed that mice fed a high-fat diet have shorter mammary cancer latency, increased tumor growth and more pulmonary metastases than mice fed a standard diet. Subsequent genetic analysis identified several modifiers of metastatic mammary cancer along with widespread interactions between cancer modifiers and dietary fat. To elucidate diet-dependent genetic modifiers of mammary cancer and metastasis risk, global gene expression profiles and copy number alterations from mammary cancers were measured and expression quantitative trait loci (eQTL) identified. Functional candidate genes that colocalized with previously detected metastasis modifiers were identified. Additional analyses, such as eQTL by dietary fat interaction analysis, causality and database evaluations, helped to further refine the candidate loci to produce an enriched list of genes potentially involved in the pathogenesis of metastatic mammary cancer.
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24
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Dopaminergic dysregulation in mice selectively bred for excessive exercise or obesity. Behav Brain Res 2010; 210:155-63. [PMID: 20156488 DOI: 10.1016/j.bbr.2010.02.016] [Citation(s) in RCA: 78] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2009] [Revised: 02/04/2010] [Accepted: 02/07/2010] [Indexed: 11/24/2022]
Abstract
Dysregulation of the dopamine system is linked to various aberrant behaviors, including addiction, compulsive exercise, and hyperphagia leading to obesity. The goal of the present experiments was to determine how dopamine contributes to the expression of opposing phenotypes, excessive exercise and obesity. We hypothesized that similar alterations in dopamine and dopamine-related gene expression may underly obesity and excessive exercise, as competing traits for central reward pathways. Moreover, we hypothesized that selective breeding for high levels of exercise or obesity may have influenced genetic variation controlling these pathways, manifesting as opposing complex traits. Dopamine, dopamine-related peptide concentrations, and gene expression were evaluated in dorsal striatum (DS) and nucleus accumbens (NA) of mice from lines selectively bred for high rates of wheel running (HR) or obesity (M16), and the non-selected ICR strain from which these lines were derived. HPLC analysis showed significantly greater neurotransmitter concentrations in DS and NA of HR mice compared to M16 and ICR. Microarray analysis showed significant gene expression differences between HR and M16 compared to ICR in both brain areas, with changes revealed throughout the dopamine pathway including D1 and D2 receptors, associated G-proteins (e.g., Golf), and adenylate cyclase (e.g., Adcy5). The results suggest that similar modifications within the dopamine system may contribute to the expression of opposite phenotypes in mice, demonstrating that alterations within central reward pathways can contribute to both obesity and excessive exercise.
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25
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Nehrenberg DL, Hua K, Estrada-Smith D, Garland T, Pomp D. Voluntary exercise and its effects on body composition depend on genetic selection history. Obesity (Silver Spring) 2009; 17:1402-9. [PMID: 19282822 DOI: 10.1038/oby.2009.51] [Citation(s) in RCA: 41] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
Abstract
Little is known about how genetic variation affects the capacity for exercise to change body composition. We examined the extent to which voluntary exercise alters body composition in several lines of selectively bred mice compared to controls. Lines studied included high runner (HR) (selected for high wheel running), M16 (selected for rapid weight gain), Institute of Cancer Research (ICR) (randomly bred as control for M16), M16i (an inbred line derived from M16), HE (selected for high percentage of body fat while holding body weight constant), LF (selected for low percentage of body fat), C57BL/6J (common inbred line), and the F1 between HR and C57BL/6J. Body weight and body fat were recorded before and after 6 days of free access to running wheels in males and females that were individually caged. Total food intake was measured during this 6-day period. All pre- and postexercise measures showed significant strain effects. While HR mice predictably exercised at higher levels, all other selection lines had decreased levels of wheel running relative to ICR. The HR x B6 F1 ran at similar levels to HR demonstrating complete dominance for voluntary exercise. Also, all strains lost body fat after exercise, but the relationships between exercise and changes in percent body were not uniform across genotypes. These results indicate that there is significant genetic variation for voluntary exercise and its effects on body composition. It is important to carefully consider genetic background and/or selection history when using mice to model effects of exercise on body composition, and perhaps, other complex traits as well.
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Affiliation(s)
- Derrick L Nehrenberg
- Department of Nutrition, University of North Carolina, Chapel Hill, North Carolina, USA
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26
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Multi-tissue coexpression networks reveal unexpected subnetworks associated with disease. Genome Biol 2009; 10:R55. [PMID: 19463160 PMCID: PMC2718521 DOI: 10.1186/gb-2009-10-5-r55] [Citation(s) in RCA: 129] [Impact Index Per Article: 8.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/26/2008] [Revised: 02/12/2009] [Accepted: 05/22/2009] [Indexed: 11/15/2022] Open
Abstract
Tissue-to-tissue coexpression networks between genes in hypothalamus, liver or adipose tissue enable identification of obesity-specific genes. Background Obesity is a particularly complex disease that at least partially involves genetic and environmental perturbations to gene-networks connecting the hypothalamus and several metabolic tissues, resulting in an energy imbalance at the systems level. Results To provide an inter-tissue view of obesity with respect to molecular states that are associated with physiological states, we developed a framework for constructing tissue-to-tissue coexpression networks between genes in the hypothalamus, liver or adipose tissue. These networks have a scale-free architecture and are strikingly independent of gene-gene coexpression networks that are constructed from more standard analyses of single tissues. This is the first systematic effort to study inter-tissue relationships and highlights genes in the hypothalamus that act as information relays in the control of peripheral tissues in obese mice. The subnetworks identified as specific to tissue-to-tissue interactions are enriched in genes that have obesity-relevant biological functions such as circadian rhythm, energy balance, stress response, or immune response. Conclusions Tissue-to-tissue networks enable the identification of disease-specific genes that respond to changes induced by different tissues and they also provide unique details regarding candidate genes for obesity that are identified in genome-wide association studies. Identifying such genes from single tissue analyses would be difficult or impossible.
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27
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Hunter KW, Crawford NPS. The future of mouse QTL mapping to diagnose disease in mice in the age of whole-genome association studies. Annu Rev Genet 2009; 42:131-41. [PMID: 18759635 DOI: 10.1146/annurev.genet.42.110807.091659] [Citation(s) in RCA: 60] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
Abstract
Genome-wide association analysis is emerging as a powerful tool to define novel genes and molecular pathways involved in susceptibility to human complex disorders. However, in spite of recent successes, this approach is not without its limitations, the most notable of which is inconsistent phenotype penetrance due to varied environmental exposures. Mouse models do, however, circumvent some of these drawbacks by allowing for a much higher degree of control over genetic variation and environmental exposure, and although their application to human complex genetics is not always straightforward, they do serve as a powerful means of complementing observations in human populations. Mouse quantitative trait locus mapping has proven a successful, yet technically demanding method for defining trait susceptibility. In this review, we focus upon recent advances that are both reducing the technical burden traditionally associated with quantitative trait locus mapping, and enhancing the applicability of these approaches to human disease.
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Affiliation(s)
- Kent W Hunter
- Laboratory of Cancer Biology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.
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28
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Gordon RR, Hunter KW, Sørensen P, Pomp D. Genotype X diet interactions in mice predisposed to mammary cancer. I. Body weight and fat. Mamm Genome 2008; 19:163-78. [PMID: 18286334 DOI: 10.1007/s00335-008-9095-z] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2007] [Accepted: 12/19/2007] [Indexed: 12/01/2022]
Abstract
High dietary fat intake and obesity may increase susceptibility to certain forms of cancer. To study the interactions of dietary fat, obesity, and metastatic mammary cancer, we created a population of F(2) mice cosegregating obesity QTL and the MMTV-PyMT transgene. We fed the F(2) mice either a very-high-fat or a matched-control-fat diet and measured growth, body composition, age at mammary tumor onset, tumor number and severity, and formation of pulmonary metastases. SNP genotyping across the genome facilitated analyses of QTL and QTL x diet interaction effects. Here we describe development of the F(2) population (n = 615) which resulted from a cross between the polygenic obesity model M16i and FVB/NJ-TgN (MMTV-PyMT)(634Mul), effects of diet on growth and body composition, and QTL and QTL x diet and/or gender interaction effects for growth and obesity-related phenotypes. We identified 38 QTL for body composition traits that were significant at the genome-wide 0.05 level, likely representing nine distinct loci after accounting for pleiotropic effects. QTL x diet and/or gender interactions were present at 15 of these QTL, indicating that such interactions play a significant role in defining the genetic architecture of complex traits such as body weight and obesity.
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Affiliation(s)
- Ryan R Gordon
- Department of Nutrition, University of North Carolina, Chapel Hill, NC 27599, USA
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Are the available experimental models of type 2 diabetes appropriate for a gender perspective? Pharmacol Res 2007; 57:6-18. [PMID: 18221886 DOI: 10.1016/j.phrs.2007.11.007] [Citation(s) in RCA: 63] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/09/2007] [Revised: 11/20/2007] [Accepted: 11/21/2007] [Indexed: 01/01/2023]
Abstract
Several experimental models have so far been developed to improve our knowledge of the pathogenetic mechanisms of type 2 diabetes mellitus (T2D), to determine the possible pharmacological targets of this disease and to better evaluate diabetes-associated complications, e.g. the cardiovascular disease. In particular, the study of T2D gained the attention of several groups working with different animal species: rodents, cats or pigs, as well as other non-human primate species. Each of these species provided useful and different clues. However, T2D has to be considered as a gender-associated disease: sex differences play in fact a key role in the onset as well as in the progression of the disease and a higher mortality for cardiovascular diseases is detected in diabetic women with respect to men. The results obtained from all the available animal models appear to only partially address this issue so that the search for more precise information in this respect appears to be mandatory. In this review we summarize these concepts and literature in the field and propose a reappraisal of the various animal models for a study of T2D that would take into consideration a gender perspective.
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Abstract
Inbred mouse strains provide genetic diversity comparable to that of the human population. Like humans, mice have a wide range of diabetes-related phenotypes. The inbred mouse strains differ in the response of their critical physiological functions, such as insulin sensitivity, insulin secretion, beta-cell proliferation and survival, and fuel partitioning, to diet and obesity. Most of the critical genes underlying these differences have not been identified, although many loci have been mapped. The dramatic improvements in genomic and bioinformatics resources are accelerating the pace of gene discovery. This review describes how mouse genetics can be used to discover diabetes-related genes, summarizes how the mouse strains differ in their diabetes-related phenotypes, and describes several examples of how loci identified in the mouse may directly relate to human diabetes.
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Affiliation(s)
- Susanne M Clee
- Department of Biochemistry, University of Wisconsin-Madison, 433 Babcock Drive, Madison, Wisconsin 53706-1544, USA
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Phenotypic characterisation of extreme growth-selected mouse lines: An important prerequisite for future QTL analysis. Open Life Sci 2006. [DOI: 10.2478/s11535-006-0026-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022] Open
Abstract
AbstractA unique set of seven mouse lines, long-term selected for high growth, from different laboratories around the world has been comprehensively compared to evaluate these resources for future QTL and gene mapping for growth traits. The heaviest line (DUH) was 40% (males) to 44% (females) heavier than the smallest line (ROH) at birth, and 105% (males) to 114% (females) heavier at 98 d. Body conformation (body length and width, body areas), body composition (dry matter, fat, fatty acid composition, organ weights), and skeletal muscle cellularity also differed substantially. DUH was more than 20% longer (12.3 cm) compared to the shortest line ROH (9.7 cm). DAH (22.5%) had the highest percentage of gonadal fat and the leanest was BEH (7.7%). Line BEH (0.49 g) showed the highest weight for the left M. rectus femoris, which was 2.1 times higher, compared to ROH (0.23 g). These results suggest that different alleles, and possibly different physiological pathways, have contributed to the selection response in the different lines. Therefore these selection lines are an important tool with which to identify the genetic and physiological basis of growth as they may contain many, if not all, growth promoting alleles.
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Wagener A, Schmitt AO, Aksu S, Schlote W, Neuschl C, Brockmann GA. Genetic, sex, and diet effects on body weight and obesity in the Berlin Fat Mouse Inbred lines. Physiol Genomics 2006; 27:264-70. [PMID: 16912068 DOI: 10.1152/physiolgenomics.00225.2005] [Citation(s) in RCA: 28] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022] Open
Abstract
Mouse lines long-term selected for high fatness offer the possibility to identify individual genes involved in the development of obesity. The Berlin Fat Mouse (BFM) line has been selected for low protein content and afterward for high fatness. Three Berlin Fat Mouse Inbred (BFMI) lines, which are derivates of the selection line BFM and an unselected control line (C57BL/6; B6) were systematically phenotyped between 3 and 20 wk. The body weights and body compositions were measured on a weekly basis. We demonstrated that the BFMI lines dispose of more body weight, body fat mass, and body lean mass than the control line B6 because of a better feed efficiency in these lines. In contrast to other growth-selected mouse lines, the BFMI lines exhibited a general increase in body fat mass but only a marginal increase in body lean mass. The three BFMI lines also showed line- and sex-specific patterns and varied in their response to high-fat diet. The phenotypic differences between the BFMI lines can be traced back to different sets of fixed alleles contributing to fat accumulation and diet-induced obesity. Our results demonstrate that the genetically related BFMI lines are novel models to study the genetic as well as the nutritional aspects of obesity.
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Affiliation(s)
- Asja Wagener
- Institute of Animal Sciences, Humboldt-Universität zu Berlin, Berlin, Germany
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Yi N, Zinniel DK, Kim K, Eisen EJ, Bartolucci A, Allison DB, Pomp D. Bayesian analyses of multiple epistatic QTL models for body weight and body composition in mice. Genet Res (Camb) 2006; 87:45-60. [PMID: 16545150 PMCID: PMC5002393 DOI: 10.1017/s0016672306007944] [Citation(s) in RCA: 33] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/18/2005] [Revised: 11/29/2005] [Indexed: 11/07/2022] Open
Abstract
To comprehensively investigate the genetic architecture of growth and obesity, we performed Bayesian analyses of multiple epistatic quantitative trait locus (QTL) models for body weights at five ages (12 days, 3, 6, 9 and 12 weeks) and body composition traits (weights of two fat pads and five organs) in mice produced from a cross of the F1 between M16i (selected for rapid growth rate) and CAST/Ei (wild-derived strain of small and lean mice) back to M16i. Bayesian model selection revealed a temporally regulated network of multiple QTL for body weight, involving both strong main effects and epistatic effects. No QTL had strong support for both early and late growth, although overlapping combinations of main and epistatic effects were observed at adjacent ages. Most main effects and epistatic interactions had an opposite effect on early and late growth. The contribution of epistasis was more pronounced for body weights at older ages. Body composition traits were also influenced by an interacting network of multiple QTLs. Several main and epistatic effects were shared by the body composition and body weight traits, suggesting that pleiotropy plays an important role in growth and obesity.
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Affiliation(s)
- Nengjun Yi
- Department of Biostatistics, Section on Statistical Genetics, University of Alabama, Birmingham, AL 35294
- Clinical Nutrition Research Center, University of Alabama, Birmingham, AL 35294
| | - Denise K. Zinniel
- Department of Veterinary and Biomedical Sciences, University of Nebraska, Lincoln, NE 68583
| | - Kyoungmi Kim
- Department of Biostatistics, Section on Statistical Genetics, University of Alabama, Birmingham, AL 35294
| | - Eugene J. Eisen
- Department of Animal Science, North Carolina State University, Raleigh, NC 27695
| | - Alfred Bartolucci
- Department of Biostatistics, Section on Statistical Genetics, University of Alabama, Birmingham, AL 35294
| | - David B. Allison
- Department of Biostatistics, Section on Statistical Genetics, University of Alabama, Birmingham, AL 35294
- Clinical Nutrition Research Center, University of Alabama, Birmingham, AL 35294
| | - Daniel Pomp
- Departments of Nutrition, Cell and Molecular Physiology, University of North Carolina, Chapel Hill, NC 27599
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Allan MF, Eisen EJ, Pomp D. Genomic mapping of direct and correlated responses to long-term selection for rapid growth rate in mice. Genetics 2005; 170:1863-77. [PMID: 15944354 PMCID: PMC1449794 DOI: 10.1534/genetics.105.041319] [Citation(s) in RCA: 39] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2005] [Accepted: 05/02/2005] [Indexed: 01/07/2023] Open
Abstract
Understanding the genetic architecture of traits such as growth, body composition, and energy balance has become a primary focus for biomedical and agricultural research. The objective of this study was to map QTL in a large F(2) (n = 1181) population resulting from an intercross between the M16 and ICR lines of mice. The M16 line, developed by long-term selection for 3- to 6-week weight gain, is larger, heavier, fatter, hyperphagic, and diabetic relative to its randomly selected control line of ICR origin. The F(2) population was phenotyped for growth and energy intake at weekly intervals from 4 to 8 weeks of age and for body composition and plasma levels of insulin, leptin, TNFalpha, IL6, and glucose at 8 weeks and was genotyped for 80 microsatellite markers. Since the F(2) was a cross between a selection line and its unselected control, the QTL identified likely represent genes that contributed to direct and correlated responses to long-term selection for rapid growth rate. Across all traits measured, 95 QTL were identified, likely representing 19 unique regions on 13 chromosomes. Four chromosomes (2, 6, 11, and 17) harbored loci contributing disproportionately to selection response. Several QTL demonstrating differential regulation of regional adipose deposition and age-dependent regulation of growth and energy consumption were identified.
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Affiliation(s)
- Mark F Allan
- Department of Animal Science, University of Nebraska, Lincoln, Nebraska 68583, USA
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Jerez-Timaure NC, Eisen EJ, Pomp D. Fine mapping of a QTL region with large effects on growth and fatness on mouse chromosome 2. Physiol Genomics 2005; 21:411-22. [PMID: 15769905 DOI: 10.1152/physiolgenomics.00256.2004] [Citation(s) in RCA: 31] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022] Open
Abstract
We combined the use of a congenic line and recombinant progeny testing (RPT) to characterize and fine map a previously identified region of distal mouse chromosome 2 (MMU2) harboring quantitative trait loci (QTL) with large effects on growth and fatness. The congenic line [M16i.B6-(D2Mit306-D2Mit52); MB2] was created using an inbred line (M16i) derived from a line that had undergone long-term selection for rapid weight gain (M16) as the recipient for an approximately 38-cM region on MMU2 from the inbred line C57BL/6J. A large F2 cohort (1,200 mice) originating from a cross between MB2 and M16i was created, and 40 F2 males with defined recombinations within the QTL region were used to produce 665 segregating progeny. Linkage analysis of the F2 population detected QTL with very large effects on body weight, body fat, lean tissue mass, bone mineral density, and liver weight. Confidence intervals of the QTL were narrowed to regions of 1.5-4.5 cM. Analysis of progeny of the recombinant F2 males confirmed the existence of the QTL and further contributed to localization of their map positions. These efforts confirmed the presence of QTL with major effect on MMU2, narrowed the estimated region harboring the QTL from 38 to 12 cM, and further characterized phenotypic effects of the QTL, effectively culminating in a significantly decreased pool of positional candidate genes potentially representing these genes controlling predisposition to growth and fatness.
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Affiliation(s)
- Nancy C Jerez-Timaure
- Department of Animal Science, University of Nebraska, Lincoln, Nebraska 68583-0908, USA
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Jerez-Timaure NC, Kearney F, Simpson EB, Eisen EJ, Pomp D. Characterization of QTL with major effects on fatness and growth on mouse chromosome 2. ACTA ACUST UNITED AC 2005; 12:1408-20. [PMID: 15483205 DOI: 10.1038/oby.2004.177] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/08/2022]
Abstract
OBJECTIVE To isolate and characterize a region on mouse chromosome 2 harboring quantitative trait loci with large influences on growth and fatness. RESEARCH METHODS AND PROCEDURES A congenic line [M16i.B6-(D2Mit306-D2Mit52); MB2] was created using the polygenic obese M16i selection line as the recipient for an approximately 38-centimorgan region from C57BL/6J. Males and females from M16i and MB2 were compared for body weight, body composition, feed consumption, and additional traits at 6, 15, and 24 weeks. Interactions of genotype and environment (low and high dietary fat) were investigated. Males (8 weeks) were evaluated for fatty acid profiles in liver and for transcriptional profiles in liver and adipose. RESULTS Consequences of replacing M16i alleles with C57BL/6J alleles in MB2 were maximized at 15 weeks. MB2 mice were up to 15% lighter than M16i at this age, with no differences in feed consumption. As a percentage of body weight, MB2 had dramatically less epididymal (males) or perimetrial (females) fat (1.17% vs. 2.79% pooled across sex) and lower total lipids (16.1% vs. 23.3%) than M16i. Decreased adiposity in MB2 was not dependent on gender or diet. MB2 mice also had significant decreases in levels of leptin, insulin, and glucose, decreased de novo synthesis of hepatic fatty acid, and transcriptional changes for many genes both within, and external to, the congenic region. DISCUSSION Results confirm the presence and large effects of mouse chromosome 2 quantitative trait loci and further define their phenotypic consequences related to energy balance. The MB2 congenic line is a powerful resource for eventual identification of pathways and mutations within genes regulating predisposition to growth and obesity.
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