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Vasilev V, Georgieva K, Arabadzhiyska D, Delchev S, Gerginska F, Komrakova M, Boeker KO, Schilling AF, Boaydjiev N. Ligandrol lowers endurance and negatively affects lipid and hormonal profile of male rats. NAUNYN-SCHMIEDEBERG'S ARCHIVES OF PHARMACOLOGY 2025:10.1007/s00210-025-04028-8. [PMID: 40087185 DOI: 10.1007/s00210-025-04028-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/23/2024] [Accepted: 03/06/2025] [Indexed: 03/17/2025]
Abstract
Selective androgen receptor modulators are currently not approved but are widely used in gyms. In the present study, the effects of ligandrol and its combination with endurance training on functional and clinically important parameters were studied in male healthy rats. Fourteen-week-old male rats were divided into four groups: two training (40 min, 5 times/week) and two non-training (5 min, 3 times/week). The velocity was 25 m/min at a track elevation of 5° for all groups. Ligandrol (0.4 mg/kg body weight, 5 times/week) was administered to one training and one non-training group and vehicle to the other groups (n = 10 per group) for 8 weeks. We conducted functional tests and examined morphometric, functional, hematological, hormonal, and clinical chemistry indicators in rats and histological and gene expression analyses in gastrocnemius muscle. Endurance training had a positive effect on all functional tests and increased vascular endothelial growth factor a (Vegf-a) gene expression. Ligandrol treatment reduced submaximal endurance, maximal oxygen consumption, concentrations of glucose, follicle-stimulating hormone, and testosterone. It increased grip strength, triglycerides, and total cholesterol concentrations and had no effect on maximal sprinting speed, maximal time to exhaustion, hematological and morphometric parameters, and gene expression of myostatin and insulin-like growth factor 1. The negative effects of ligandrol treatment outweighed its benefits in this study. Endurance training alone had favorable effects, and its combination with ligandrol did not seem to have an advantage. In the training group, ligandrol decreased Vegf-a gene expression and the size of muscle fibers type I and IIa.
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Affiliation(s)
- Veselin Vasilev
- Department of Physiology, Medical University Plovdiv, 15A V. Aprilov Blvd., Plovdiv, 4002, Bulgaria.
| | - Katerina Georgieva
- Department of Physiology, Medical University Plovdiv, 15A V. Aprilov Blvd., Plovdiv, 4002, Bulgaria
| | | | - Slavi Delchev
- Department of Anatomy, Histology, Embryology, Medical University Plovdiv, Plovdiv, Bulgaria
| | - Fanka Gerginska
- Department of Anatomy, Histology, Embryology, Medical University Plovdiv, Plovdiv, Bulgaria
| | - Marina Komrakova
- Department of Trauma Surgery, Orthopaedics and Plastic Surgery, University Medical Center Goettingen, Goettingen, Germany
| | - Kai O Boeker
- Department of Trauma Surgery, Orthopaedics and Plastic Surgery, University Medical Center Goettingen, Goettingen, Germany
| | - Arndt F Schilling
- Department of Trauma Surgery, Orthopaedics and Plastic Surgery, University Medical Center Goettingen, Goettingen, Germany
| | - Nikolay Boaydjiev
- Department of Physiology, Medical University Plovdiv, 15A V. Aprilov Blvd., Plovdiv, 4002, Bulgaria
- Research Institute, Medical University Plovdiv, Plovdiv, Bulgaria
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2
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Liu H, Wang S, Wang J, Guo X, Song Y, Fu K, Gao Z, Liu D, He W, Yang LL. Energy metabolism in health and diseases. Signal Transduct Target Ther 2025; 10:69. [PMID: 39966374 PMCID: PMC11836267 DOI: 10.1038/s41392-025-02141-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/12/2024] [Revised: 11/08/2024] [Accepted: 12/25/2024] [Indexed: 02/20/2025] Open
Abstract
Energy metabolism is indispensable for sustaining physiological functions in living organisms and assumes a pivotal role across physiological and pathological conditions. This review provides an extensive overview of advancements in energy metabolism research, elucidating critical pathways such as glycolysis, oxidative phosphorylation, fatty acid metabolism, and amino acid metabolism, along with their intricate regulatory mechanisms. The homeostatic balance of these processes is crucial; however, in pathological states such as neurodegenerative diseases, autoimmune disorders, and cancer, extensive metabolic reprogramming occurs, resulting in impaired glucose metabolism and mitochondrial dysfunction, which accelerate disease progression. Recent investigations into key regulatory pathways, including mechanistic target of rapamycin, sirtuins, and adenosine monophosphate-activated protein kinase, have considerably deepened our understanding of metabolic dysregulation and opened new avenues for therapeutic innovation. Emerging technologies, such as fluorescent probes, nano-biomaterials, and metabolomic analyses, promise substantial improvements in diagnostic precision. This review critically examines recent advancements and ongoing challenges in metabolism research, emphasizing its potential for precision diagnostics and personalized therapeutic interventions. Future studies should prioritize unraveling the regulatory mechanisms of energy metabolism and the dynamics of intercellular energy interactions. Integrating cutting-edge gene-editing technologies and multi-omics approaches, the development of multi-target pharmaceuticals in synergy with existing therapies such as immunotherapy and dietary interventions could enhance therapeutic efficacy. Personalized metabolic analysis is indispensable for crafting tailored treatment protocols, ultimately providing more accurate medical solutions for patients. This review aims to deepen the understanding and improve the application of energy metabolism to drive innovative diagnostic and therapeutic strategies.
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Affiliation(s)
- Hui Liu
- Department of Stomatology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Shuo Wang
- Department of Stomatology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Jianhua Wang
- Department of Stomatology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Xin Guo
- Department of Stomatology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Yujing Song
- Department of Stomatology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Kun Fu
- Department of Stomatology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Zhenjie Gao
- Department of Stomatology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Danfeng Liu
- Department of Stomatology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China.
| | - Wei He
- Department of Stomatology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China.
| | - Lei-Lei Yang
- Department of Stomatology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China.
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3
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Silaeva YY, Safonova PD, Popov DV, Filatov MA, Okulova YD, Shafei RA, Skobel OI, Vysotskii DE, Gubarev YD, Glazko VI, Glazko TT, Georgiev PG, Kosovsky GY, Shepelev MV. Generation of LEPR Knockout Rabbits with CRISPR/CAS9 System. DOKLADY BIOLOGICAL SCIENCES : PROCEEDINGS OF THE ACADEMY OF SCIENCES OF THE USSR, BIOLOGICAL SCIENCES SECTIONS 2024; 518:248-255. [PMID: 39212886 DOI: 10.1134/s0012496624600234] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/25/2024] [Revised: 06/25/2024] [Accepted: 06/30/2024] [Indexed: 09/04/2024]
Abstract
The LEPR gene encodes a leptin hormone receptor, and its mutations are associated with morbid obesity, dysregulation of lipid metabolism, and fertility defects in humans. Spontaneous Lepr mutations have been described in rodents, and Lepr knockout animals have been generated, in particular, using the CRISPR/Cas9 system. Lipid metabolism in rodents significantly differs from that in humans or rabbits, and rabbits are therefore considered as the most relevant model of morbid obesity and lipid metabolism dysregulation in humans. LEPR knockout rabbits have not been reported so far. In this work a LEPR knockout rabbit was generated by introducing a deletion of the region around LEPR exon 10 using the CRISPR/Cas9 system. The body weight of the knockout rabbit was significantly higher than the average body weight of the wild type rabbits. CRISPR/Cas9-mediated generation of LEPR knockout rabbits will allow the development of a model of morbid obesity and endocrine defects due to leptin receptor mutations in humans.
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Affiliation(s)
- Yu Yu Silaeva
- Center for Precision Genome Editing and Genetic Technologies for Biomedicine, Institute of Gene Biology, Russian Academy of Sciences, Moscow, Russia
| | - P D Safonova
- Institute of Gene Biology, Russian Academy of Sciences, Moscow, Russia
| | - D V Popov
- Afanas'ev Institute of Fur-bearing Animal Breeding and Rabbit Breeding, Rodniki, Moscow Region, Russia
| | - M A Filatov
- Center for Precision Genome Editing and Genetic Technologies for Biomedicine, Institute of Gene Biology, Russian Academy of Sciences, Moscow, Russia
| | - Yu D Okulova
- Center for Precision Genome Editing and Genetic Technologies for Biomedicine, Institute of Gene Biology, Russian Academy of Sciences, Moscow, Russia
| | | | - O I Skobel
- Afanas'ev Institute of Fur-bearing Animal Breeding and Rabbit Breeding, Rodniki, Moscow Region, Russia
| | - D E Vysotskii
- Afanas'ev Institute of Fur-bearing Animal Breeding and Rabbit Breeding, Rodniki, Moscow Region, Russia
| | - Yu D Gubarev
- Belgorod State National Research University, Belgorod, Russia
| | - V I Glazko
- Afanas'ev Institute of Fur-bearing Animal Breeding and Rabbit Breeding, Rodniki, Moscow Region, Russia
| | - T T Glazko
- Afanas'ev Institute of Fur-bearing Animal Breeding and Rabbit Breeding, Rodniki, Moscow Region, Russia
| | - P G Georgiev
- Institute of Gene Biology, Russian Academy of Sciences, Moscow, Russia
| | - G Yu Kosovsky
- Afanas'ev Institute of Fur-bearing Animal Breeding and Rabbit Breeding, Rodniki, Moscow Region, Russia
| | - M V Shepelev
- Center for Precision Genome Editing and Genetic Technologies for Biomedicine, Institute of Gene Biology, Russian Academy of Sciences, Moscow, Russia.
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Vasilev V, Boyadjiev N, Hrischev P, Gerginska F, Delchev S, Arabadzhiyska D, Komrakova M, Boeker KO, Schilling AF, Georgieva K. Ostarine blunts the effect of endurance training on submaximal endurance in rats. NAUNYN-SCHMIEDEBERG'S ARCHIVES OF PHARMACOLOGY 2024; 397:6523-6532. [PMID: 38451281 PMCID: PMC11422473 DOI: 10.1007/s00210-024-03030-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/27/2023] [Accepted: 02/27/2024] [Indexed: 03/08/2024]
Abstract
The purpose of this study is to study the effects of ostarine alone and in combination with endurance training in sexually mature, male Wistar rats. The rats were divided into a treadmill-trained group and a sedentary group. Half of each group received either ostarine or vehicle for 8 weeks (n = 10 each, in total n = 40). We examined some functional, hormonal, and anthropometric parameters and the myogenic gene expression of myostatin, insulin-like growth factor-1 (IGF-1), and vascular endothelial growth factor-A (VEGF-A) in m. gastrocnemius. Ostarine decreased submaximal endurance and increased myogenic gene expression of myostatin but had no effect on maximal time to exhaustion and grip strength. Training increased submaximal endurance, maximal time to exhaustion, and grip strength. Our results indicate that both exercise and ostarine treatment had no significant effects on serum levels of luteinizing hormone, follicle-stimulating hormone, and testosterone, or on the myogenic gene expression of IGF-1 and VEGF-A. Neither ostarine nor the training had a significant effect on the testis, liver, and heart weights. In conclusion, ostarine had no effect on anthropometric and hormonal parameters but increased the myostatin gene expression in muscle. The SARM treatment decreased submaximal endurance without affecting maximal time to exhaustion, and training increased both metrics.
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Affiliation(s)
- Veselin Vasilev
- Department of Physiology, Faculty of Medicine, Medical University of Plovdiv, 15-A "Vasil Aprilov" Blvd, Plovdiv, 4002, Bulgaria.
| | - Nikolay Boyadjiev
- Department of Physiology, Faculty of Medicine, Medical University of Plovdiv, 15-A "Vasil Aprilov" Blvd, Plovdiv, 4002, Bulgaria
| | - Petar Hrischev
- Department of Physiology, Faculty of Medicine, Medical University of Plovdiv, 15-A "Vasil Aprilov" Blvd, Plovdiv, 4002, Bulgaria
| | - Fanka Gerginska
- Department of Anatomy, Histology and Embryology, Faculty of Medicine, Medical University of Plovdiv, 15-A "Vasil Aprilov" Blvd, Plovdiv, 4002, Bulgaria
| | - Slavi Delchev
- Department of Anatomy, Histology and Embryology, Faculty of Medicine, Medical University of Plovdiv, 15-A "Vasil Aprilov" Blvd, Plovdiv, 4002, Bulgaria
| | - Desislava Arabadzhiyska
- Department of Clinical Laboratory, Faculty of Medicine, Medical University of Plovdiv, 15-A "Vasil Aprilov" Blvd, Plovdiv, 4002, Bulgaria
| | - Marina Komrakova
- Department of Trauma Surgery, Orthopaedics and Plastic Surgery, University Medical Center Goettingen, Robert-Koch-Str. 40, 37075, Goettingen, Germany
| | - Kai O Boeker
- Department of Trauma Surgery, Orthopaedics and Plastic Surgery, University Medical Center Goettingen, Robert-Koch-Str. 40, 37075, Goettingen, Germany
| | - Arndt F Schilling
- Department of Trauma Surgery, Orthopaedics and Plastic Surgery, University Medical Center Goettingen, Robert-Koch-Str. 40, 37075, Goettingen, Germany
| | - Katerina Georgieva
- Department of Physiology, Faculty of Medicine, Medical University of Plovdiv, 15-A "Vasil Aprilov" Blvd, Plovdiv, 4002, Bulgaria
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5
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Hemerich D, Svenstrup V, Obrero VD, Preuss M, Moscati A, Hirschhorn JN, Loos RJF. An integrative framework to prioritize genes in more than 500 loci associated with body mass index. Am J Hum Genet 2024; 111:1035-1046. [PMID: 38754426 PMCID: PMC11179420 DOI: 10.1016/j.ajhg.2024.04.016] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2024] [Revised: 04/20/2024] [Accepted: 04/22/2024] [Indexed: 05/18/2024] Open
Abstract
Obesity is a major risk factor for a myriad of diseases, affecting >600 million people worldwide. Genome-wide association studies (GWASs) have identified hundreds of genetic variants that influence body mass index (BMI), a commonly used metric to assess obesity risk. Most variants are non-coding and likely act through regulating genes nearby. Here, we apply multiple computational methods to prioritize the likely causal gene(s) within each of the 536 previously reported GWAS-identified BMI-associated loci. We performed summary-data-based Mendelian randomization (SMR), FINEMAP, DEPICT, MAGMA, transcriptome-wide association studies (TWASs), mutation significance cutoff (MSC), polygenic priority score (PoPS), and the nearest gene strategy. Results of each method were weighted based on their success in identifying genes known to be implicated in obesity, ranking all prioritized genes according to a confidence score (minimum: 0; max: 28). We identified 292 high-scoring genes (≥11) in 264 loci, including genes known to play a role in body weight regulation (e.g., DGKI, ANKRD26, MC4R, LEPR, BDNF, GIPR, AKT3, KAT8, MTOR) and genes related to comorbidities (e.g., FGFR1, ISL1, TFAP2B, PARK2, TCF7L2, GSK3B). For most of the high-scoring genes, however, we found limited or no evidence for a role in obesity, including the top-scoring gene BPTF. Many of the top-scoring genes seem to act through a neuronal regulation of body weight, whereas others affect peripheral pathways, including circadian rhythm, insulin secretion, and glucose and carbohydrate homeostasis. The characterization of these likely causal genes can increase our understanding of the underlying biology and offer avenues to develop therapeutics for weight loss.
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Affiliation(s)
- Daiane Hemerich
- The Charles Bronfman Institute for Personalized Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA; Bristol Myers Squibb, Summit, NJ, USA
| | - Victor Svenstrup
- Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen, Copenhagen, Denmark; Novo Nordisk Foundation Center for Genomic Mechanisms of Disease, Broad Institute of MIT and Harvard, Cambridge, MA, USA
| | - Virginia Diez Obrero
- Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen, Copenhagen, Denmark; Novo Nordisk Foundation Center for Genomic Mechanisms of Disease, Broad Institute of MIT and Harvard, Cambridge, MA, USA
| | - Michael Preuss
- The Charles Bronfman Institute for Personalized Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Arden Moscati
- The Charles Bronfman Institute for Personalized Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA; Regeneron Genetics Center, Tarrytown, NY, USA
| | - Joel N Hirschhorn
- Department of Genetics, Harvard Medical School, Boston, MA 02115, USA; Program in Medical and Population Genetics, Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA; Division of Endocrinology and Center for Basic and Translational Obesity Research, Boston Children's Hospital, Boston, MA 02115, USA
| | - Ruth J F Loos
- The Charles Bronfman Institute for Personalized Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA; Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen, Copenhagen, Denmark; Novo Nordisk Foundation Center for Genomic Mechanisms of Disease, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
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6
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Lutz TA. Mammalian models of diabetes mellitus, with a focus on type 2 diabetes mellitus. Nat Rev Endocrinol 2023; 19:350-360. [PMID: 36941447 DOI: 10.1038/s41574-023-00818-3] [Citation(s) in RCA: 27] [Impact Index Per Article: 13.5] [Reference Citation Analysis] [Abstract] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 02/21/2023] [Indexed: 03/23/2023]
Abstract
Although no single animal model replicates all aspects of diabetes mellitus in humans, animal models are essential for the study of energy balance and metabolism control as well as to investigate the reasons for their imbalance that could eventually lead to overt metabolic diseases such as type 2 diabetes mellitus. The most frequently used animal models in diabetes mellitus research are small rodents that harbour spontaneous genetic mutations or that can be manipulated genetically or by other means to influence their nutrient metabolism and nutrient handling. Non-rodent species, including pigs, cats and dogs, are also useful models in diabetes mellitus research. This Review will outline the advantages and disadvantages of selected animal models of diabetes mellitus to build a basis for their most appropriate use in biomedical research.
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Affiliation(s)
- Thomas A Lutz
- Institute of Veterinary Physiology, Vetsuisse Faculty University of Zurich, Zurich, Switzerland.
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7
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Abstract
Leptin for over 25 years has been a central theme in the study of appetite, obesity, and starvation. As the major site of leptin production is peripheral, and the site of action of greatest interest is the hypothalamus, how leptin accesses the central nervous system (CNS) and crosses the blood-brain barrier (BBB) has been of great interest. We review here the ongoing research that addresses fundamental questions such as the sites of leptin resistances in obesity and other conditions, the causes of resistances and their relations to one another, the three barrier sites of entry into the CNS, why recent studies using suprapharmacological doses cannot address these questions but give insight into nonsaturable entry of leptin into the CNS, and how that might be useful in using leptin therapeutically. The current status of the controversy of whether the short form of the leptin receptor acts as the BBB leptin transporter and how obesity may transform leptin transport is reviewed. Review of these and other topics summarizes in a new appreciation of what leptin may have actually evolved to do and what physiological role leptin resistance may play. © 2021 American Physiological Society. Compr Physiol 11:1-19, 2021.
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Affiliation(s)
- William A Banks
- Geriatric Research Education and Clinical Center, Veterans Affairs Puget Sound Health Care System, Seattle, Washington, USA.,Division of Gerontology and Geriatric Medicine, Department of Medicine, University of Washington School of Medicine, Seattle, Washington, USA
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8
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Szpirer C. Rat models of human diseases and related phenotypes: a systematic inventory of the causative genes. J Biomed Sci 2020; 27:84. [PMID: 32741357 PMCID: PMC7395987 DOI: 10.1186/s12929-020-00673-8] [Citation(s) in RCA: 40] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2020] [Accepted: 07/09/2020] [Indexed: 12/13/2022] Open
Abstract
The laboratory rat has been used for a long time as the model of choice in several biomedical disciplines. Numerous inbred strains have been isolated, displaying a wide range of phenotypes and providing many models of human traits and diseases. Rat genome mapping and genomics was considerably developed in the last decades. The availability of these resources has stimulated numerous studies aimed at discovering causal disease genes by positional identification. Numerous rat genes have now been identified that underlie monogenic or complex diseases and remarkably, these results have been translated to the human in a significant proportion of cases, leading to the identification of novel human disease susceptibility genes, helping in studying the mechanisms underlying the pathological abnormalities and also suggesting new therapeutic approaches. In addition, reverse genetic tools have been developed. Several genome-editing methods were introduced to generate targeted mutations in genes the function of which could be clarified in this manner [generally these are knockout mutations]. Furthermore, even when the human gene causing a disease had been identified without resorting to a rat model, mutated rat strains (in particular KO strains) were created to analyze the gene function and the disease pathogenesis. Today, over 350 rat genes have been identified as underlying diseases or playing a key role in critical biological processes that are altered in diseases, thereby providing a rich resource of disease models. This article is an update of the progress made in this research and provides the reader with an inventory of these disease genes, a significant number of which have similar effects in rat and humans.
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Affiliation(s)
- Claude Szpirer
- Université Libre de Bruxelles, B-6041, Gosselies, Belgium.
- , Waterloo, Belgium.
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9
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Abstract
Many animal models that are currently used in appetite and obesity research share at least some main features of human obesity and its comorbidities. Hence, even though no animal model replicates all aspects of "common" human obesity, animal models are imperative in studying the control of energy balance and reasons for its imbalance that may eventually lead to overt obesity. The most frequently used animal models are small rodents that may be based on mutations or manipulations of individual or several genes and on the exposure to obesogenic diets or other manipulations that predispose the animals to gaining or maintaining excessive weight. Characteristics include hyperphagia or changes in energy metabolism and at least in some models the frequent comorbidities of obesity, like hyperglycemia, insulin resistance, or diabetes-like syndromes. Some of the most frequently used animal models of obesity research involve animals with monogenic mutations of the leptin pathway which in fact are useful to study specific mechanistic aspects of eating controls, but typically do not recapitulate "common" obesity in the human population. Hence, this review will mention advantages and disadvantages of respective animal models in order to build a basis for the most appropriate use in biomedical research.
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Affiliation(s)
- Thomas A Lutz
- Institute of Veterinary Physiology, Vetsuisse Faculty University of Zurich, Zurich, Switzerland.
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10
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Alhadeff AL, Conway SM, Ong ZY, Wald HS, Roitman MF, Grill HJ. Central leptin signaling transmits positive valence. Brain Res 2019; 1724:146441. [PMID: 31513793 DOI: 10.1016/j.brainres.2019.146441] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/11/2019] [Revised: 09/04/2019] [Accepted: 09/06/2019] [Indexed: 01/06/2023]
Abstract
Hunger resulting from food deprivation is associated with negative affect. This is supported by recent evidence showing that hunger-sensitive neurons drive feeding through a negative valence teaching signal. However, the complementary hypothesis that hormonal signals of energy surfeit counteract this negative valence, or even transmit positive valence, has received less attention. The adipose-derived hormone leptin signals in proportion to fat mass, is an indicator of energy surplus, and reduces food intake. Here, we showed that centrally-delivered leptin reduced food intake and conditioned a place preference in food-restricted as well as ad libitum fed rats. In contrast, leptin did not reduce food intake nor condition a place preference in obese rats, likely due to leptin resistance. Despite a well-known role for hindbrain leptin receptor signaling in energy balance control, hindbrain leptin delivery did not condition a place preference in food-restricted rats, suggesting that leptin acting in midbrain or forebrain sites mediates place preference conditioning. Supporting the hypothesis that leptin signaling induces a positive affective state, leptin also decreased the threshold for ventral tegmental area brain stimulation reward. Together, these data suggest that leptin signaling is intrinsically preferred, and support the view that signals of energy surfeit are associated with positive affect. Harnessing the positive valence of signals such as leptin may attenuate the negative affect associated with hunger, providing a compelling new approach for weight loss maintenance.
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Affiliation(s)
- Amber L Alhadeff
- Department of Biology, University of Pennsylvania, Philadelphia, PA, United States; Department of Psychology, University of Pennsylvania, Philadelphia, PA, United States.
| | - Sineadh M Conway
- Department of Psychology, University of Illinois at Chicago, Chicago, IL, United States
| | - Zhi Yi Ong
- Department of Psychology, University of Pennsylvania, Philadelphia, PA, United States
| | - Hallie S Wald
- Department of Psychology, University of Pennsylvania, Philadelphia, PA, United States
| | - Mitchell F Roitman
- Department of Psychology, University of Illinois at Chicago, Chicago, IL, United States
| | - Harvey J Grill
- Department of Psychology, University of Pennsylvania, Philadelphia, PA, United States
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11
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Zhang N, Yang L, Guo L, Bi S. Activation of Dorsomedial Hypothalamic Neurons Promotes Physical Activity and Decreases Food Intake and Body Weight in Zucker Fatty Rats. Front Mol Neurosci 2018; 11:179. [PMID: 29896090 PMCID: PMC5987017 DOI: 10.3389/fnmol.2018.00179] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2018] [Accepted: 05/09/2018] [Indexed: 02/05/2023] Open
Abstract
Previous reports have shown that running wheel activity or voluntary exercise prevents hyperphagia and obesity in various animal models of obesity, but such effects seem only minimal in obese animals lacking leptin or leptin receptors. The mechanisms underlying this ineffectiveness remain unclear. Here, we identified the action of neuronal activation in the dorsomedial hypothalamus (DMH) in modulating physical activity, food intake and body weight using leptin receptor mutant obese Zucker (Lepr(fa), ZF) and Koletsky (Lepr(fak), SHROB) rats. Ad lib-fed SHROB rats with locked running wheels became hyperphagic and gained body weight rapidly. These alterations were not ameliorated in ad lib-fed SHROB rats with voluntary access to running wheels, but the body weight of SHROB rats with running wheel access was significantly decreased when they were pair-fed to the amounts consumed by lean controls. Determinations of hypothalamic gene expression revealed that sedentary ad lib-fed SHROB rats had increased expression of neuropeptide Y (Npy) and decreased expression of pro-opiomelanocortin (Pomc) in the arcuate nucleus (ARC). Both ARC Npy and Pomc expression were further altered under running and pair-fed conditions, indicating that both genes are appropriately regulated in response to increased energy demands or alterations caused by running activity and food restriction. Strikingly, c-Fos immunohistochemistry revealed that while voluntary running activity elevated the number of c-Fos positive cells in the DMH (particularly in the ventral and caudal subregions) of intact rats, such activation was not observed in ZF rats. Using adeno-associated virus (AAV)-mediated expression of the designer receptors hM3D(Gq) in the ventral and caudal DMH of ZF rats, we found that chemogenetic stimulation of neurons in these DMH subregions via injection of the designer drug clozapine N-oxide (CNO) significantly increased their running activity and reduced their food intake and body weight. Together, these results demonstrate that activation of ventral and caudal DMH neurons promotes physical activity and decreases food intake and body weight and suggest that intact DMH neural signaling is likely crucial for exercise-induced reductions of food intake and body weight in obese rats lacking leptin receptors.
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Affiliation(s)
- Ni Zhang
- Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, MD, United States.,Department of Psychiatry, West China Hospital, Sichuan University, Chengdu, China
| | - Liang Yang
- Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, MD, United States
| | - Lanting Guo
- Department of Psychiatry, West China Hospital, Sichuan University, Chengdu, China
| | - Sheng Bi
- Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, MD, United States
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12
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Kleinert M, Clemmensen C, Hofmann SM, Moore MC, Renner S, Woods SC, Huypens P, Beckers J, de Angelis MH, Schürmann A, Bakhti M, Klingenspor M, Heiman M, Cherrington AD, Ristow M, Lickert H, Wolf E, Havel PJ, Müller TD, Tschöp MH. Animal models of obesity and diabetes mellitus. Nat Rev Endocrinol 2018; 14:140-162. [PMID: 29348476 DOI: 10.1038/nrendo.2017.161] [Citation(s) in RCA: 568] [Impact Index Per Article: 81.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
More than one-third of the worldwide population is overweight or obese and therefore at risk of developing type 2 diabetes mellitus. In order to mitigate this pandemic, safer and more potent therapeutics are urgently required. This necessitates the continued use of animal models to discover, validate and optimize novel therapeutics for their safe use in humans. In order to improve the transition from bench to bedside, researchers must not only carefully select the appropriate model but also draw the right conclusions. In this Review, we consolidate the key information on the currently available animal models of obesity and diabetes and highlight the advantages, limitations and important caveats of each of these models.
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Affiliation(s)
- Maximilian Kleinert
- Institute for Diabetes and Obesity, Helmholtz Diabetes Center at Helmholtz Zentrum München, German Research Center for Environmental Health (GmbH), Ingolstädter Landstr. 1, D-85764 Neuherberg, Germany
- Division of Metabolic Diseases, Department of Medicine, Technische Universität München, D-80333 Munich, Germany
- German Center for Diabetes Research (DZD), Ingolstädter Landstr. 1, D-85764 Neuherberg, Germany
- Section of Molecular Physiology, Department of Nutrition, Exercise and Sports, Faculty of Science, University of Copenhagen, DK-2200 Copenhagen, Denmark
| | - Christoffer Clemmensen
- Institute for Diabetes and Obesity, Helmholtz Diabetes Center at Helmholtz Zentrum München, German Research Center for Environmental Health (GmbH), Ingolstädter Landstr. 1, D-85764 Neuherberg, Germany
- Division of Metabolic Diseases, Department of Medicine, Technische Universität München, D-80333 Munich, Germany
- German Center for Diabetes Research (DZD), Ingolstädter Landstr. 1, D-85764 Neuherberg, Germany
| | - Susanna M Hofmann
- German Center for Diabetes Research (DZD), Ingolstädter Landstr. 1, D-85764 Neuherberg, Germany
- Institute for Diabetes and Regeneration Research, Helmholtz Zentrum München, German Research Center for Environmental Health (GmbH), Ingolstädter Landstr. 1, D-85764 Neuherberg, Germany
- Medizinische Klinik und Poliklinik IV, Klinikum der Ludwig-Maximilians-Universität München, Ziemssenstr. 1, D-80336 Munich, Germany
| | - Mary C Moore
- Department of Molecular Physiology and Biophysics, Vanderbilt University School of Medicine, Nashville, Tennessee 37212, USA
| | - Simone Renner
- German Center for Diabetes Research (DZD), Ingolstädter Landstr. 1, D-85764 Neuherberg, Germany
- Chair for Molecular Animal Breeding and Biotechnology, Gene Center, Ludwig-Maximilan University München, Feodor-Lynen-Str. 25, D-81377 Munich, Germany
| | - Stephen C Woods
- University of Cincinnati College of Medicine, Department of Psychiatry and Behavioral Neuroscience, Metabolic Diseases Institute, 2170 East Galbraith Road, Cincinnati, Ohio 45237, USA
| | - Peter Huypens
- German Center for Diabetes Research (DZD), Ingolstädter Landstr. 1, D-85764 Neuherberg, Germany
- Institute of Experimental Genetics, Helmholtz Zentrum München, German Research Center for Environmental Health (GmbH), Ingolstädter Landstr. 1, D-85764 Neuherberg, Germany
| | - Johannes Beckers
- German Center for Diabetes Research (DZD), Ingolstädter Landstr. 1, D-85764 Neuherberg, Germany
- Institute of Experimental Genetics, Helmholtz Zentrum München, German Research Center for Environmental Health (GmbH), Ingolstädter Landstr. 1, D-85764 Neuherberg, Germany
- Technische Universität München, Chair of Experimental Genetics, D-85354 Freising, Germany
| | - Martin Hrabe de Angelis
- German Center for Diabetes Research (DZD), Ingolstädter Landstr. 1, D-85764 Neuherberg, Germany
- Institute of Experimental Genetics, Helmholtz Zentrum München, German Research Center for Environmental Health (GmbH), Ingolstädter Landstr. 1, D-85764 Neuherberg, Germany
- Technische Universität München, Chair of Experimental Genetics, D-85354 Freising, Germany
| | - Annette Schürmann
- German Center for Diabetes Research (DZD), Ingolstädter Landstr. 1, D-85764 Neuherberg, Germany
- Department of Experimental Diabetology, German Institute of Human Nutrition (DIfE), Arthur-Scheunert-Allee 114-116, D-14558 Nuthetal, Germany
| | - Mostafa Bakhti
- German Center for Diabetes Research (DZD), Ingolstädter Landstr. 1, D-85764 Neuherberg, Germany
- Institute for Diabetes and Regeneration Research, Helmholtz Zentrum München, German Research Center for Environmental Health (GmbH), Ingolstädter Landstr. 1, D-85764 Neuherberg, Germany
- Institute of Stem Cell Research, Helmholtz Zentrum München, German Research Center for Environmental Health (GmbH), Ingolstädter Landstr. 1, D-85764 Neuherberg, Germany
| | - Martin Klingenspor
- Chair of Molecular Nutritional Medicine, Technische Universität München, TUM School of Life Sciences Weihenstephan, Gregor-Mendel-Str. 2, D-85354 Freising, Germany
- Else Kröner-Fresenius Center for Nutritional Medicine, Technische Universität München, D-85354 Freising, Germany
- Institute for Food & Health, Technische Universität München, D-85354 Freising, Germany
| | - Mark Heiman
- MicroBiome Therapeutics, 1316 Jefferson Ave, New Orleans, Louisiana 70115, USA
| | - Alan D Cherrington
- Department of Molecular Physiology and Biophysics, Vanderbilt University School of Medicine, Nashville, Tennessee 37212, USA
| | - Michael Ristow
- Energy Metabolism Laboratory, Institute of Translational Medicine, Swiss Federal Institute of Technology (ETH) Zurich, CH-8603 Zurich-Schwerzenbach, Switzerland
| | - Heiko Lickert
- German Center for Diabetes Research (DZD), Ingolstädter Landstr. 1, D-85764 Neuherberg, Germany
- Institute for Diabetes and Regeneration Research, Helmholtz Zentrum München, German Research Center for Environmental Health (GmbH), Ingolstädter Landstr. 1, D-85764 Neuherberg, Germany
- Institute of Stem Cell Research, Helmholtz Zentrum München, German Research Center for Environmental Health (GmbH), Ingolstädter Landstr. 1, D-85764 Neuherberg, Germany
| | - Eckhard Wolf
- German Center for Diabetes Research (DZD), Ingolstädter Landstr. 1, D-85764 Neuherberg, Germany
- Chair for Molecular Animal Breeding and Biotechnology, Gene Center, Ludwig-Maximilan University München, Feodor-Lynen-Str. 25, D-81377 Munich, Germany
| | - Peter J Havel
- Department of Molecular Biosciences, School of Veterinary Medicine and Department of Nutrition, 3135 Meyer Hall, University of California, Davis, California 95616-5270, USA
| | - Timo D Müller
- Institute for Diabetes and Obesity, Helmholtz Diabetes Center at Helmholtz Zentrum München, German Research Center for Environmental Health (GmbH), Ingolstädter Landstr. 1, D-85764 Neuherberg, Germany
- Division of Metabolic Diseases, Department of Medicine, Technische Universität München, D-80333 Munich, Germany
- German Center for Diabetes Research (DZD), Ingolstädter Landstr. 1, D-85764 Neuherberg, Germany
| | - Matthias H Tschöp
- Institute for Diabetes and Obesity, Helmholtz Diabetes Center at Helmholtz Zentrum München, German Research Center for Environmental Health (GmbH), Ingolstädter Landstr. 1, D-85764 Neuherberg, Germany
- Division of Metabolic Diseases, Department of Medicine, Technische Universität München, D-80333 Munich, Germany
- German Center for Diabetes Research (DZD), Ingolstädter Landstr. 1, D-85764 Neuherberg, Germany
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14
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Yuan D, Yi X, Zhao Y, Poon CD, Bullock KM, Hansen KM, Salameh TS, Farr SA, Banks WA, Kabanov AV. Intranasal delivery of N-terminal modified leptin-pluronic conjugate for treatment of obesity. J Control Release 2017; 263:172-184. [PMID: 28344017 DOI: 10.1016/j.jconrel.2017.03.029] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2016] [Revised: 03/07/2017] [Accepted: 03/17/2017] [Indexed: 10/19/2022]
Abstract
Leptin is an adipocyte-secreted hormone that is delivered via a specific transport system across the blood-brain barrier (BBB) to the brain where it acts on the hypothalamus receptors to control appetite and thermogenesis. Peripheral resistance to leptin due to its impaired brain delivery prevents therapeutic use of leptin in overweight and moderately obese patients. To address this problem, we modified the N-terminal amine of leptin with Pluronic P85 (LepNP85) and administered this conjugate intranasally using the nose-to-brain (INB) route to bypass the BBB. We compared this conjugate with the native leptin, the N-terminal leptin conjugate with poly(ethylene glycol) (LepNPEG5K), and two conjugates of leptin with Pluronic P85 attached randomly to the lysine amino groups of the hormone. Compared to the random conjugates of leptin with P85, LepNP85 has shown higher affinity upon binding with the leptin receptor, and similarly to native hormone activated hypothalamus receptors after direct injection into brain. After INB delivery, LepNP85 conjugate was transported to the brain and accumulated in the hypothalamus and hippocampus to a greater extent than the native leptin and LepNPEG5K and activated leptin receptors in hypothalamus at lower dose than native leptin. Our work suggests that LepNP85 can access the brain directly after INB delivery and confirms our hypothesis that the improvement in brain accumulation of this conjugate is due to its enhanced brain absorption. In conclusion, the LepNP85 with optimized conjugation chemistry is a promising candidate for treatment of obesity.
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Affiliation(s)
- Dongfen Yuan
- Center for Nanotechnology in Drug Delivery, Division of Pharmacoengineering and Molecular Pharmaceutics, Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, NC 27599, USA
| | - Xiang Yi
- Center for Nanotechnology in Drug Delivery, Division of Pharmacoengineering and Molecular Pharmaceutics, Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, NC 27599, USA
| | - Yuling Zhao
- Center for Nanotechnology in Drug Delivery, Division of Pharmacoengineering and Molecular Pharmaceutics, Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, NC 27599, USA
| | - Chi-Duen Poon
- Research Computer Center, University of North Carolina at Chapel Hill, NC 27599, USA
| | - Kristin M Bullock
- Research and Development, Veterans Affairs Puget Sound Health Care System, Seattle, WA, USA
| | - Kim M Hansen
- Geriatric Research Education and Clinical Center, Veterans Affairs Puget Sound Health Care System, Seattle, WA 98108, USA; Division of Gerontology and Geriatric Medicine, Department of Medicine, University of Washington School of Medicine, Seattle, WA 98104, USA
| | - Therese S Salameh
- Geriatric Research Education and Clinical Center, Veterans Affairs Puget Sound Health Care System, Seattle, WA 98108, USA; Division of Gerontology and Geriatric Medicine, Department of Medicine, University of Washington School of Medicine, Seattle, WA 98104, USA
| | - Susan A Farr
- Research and Development, VA Medical Center and Division of Geriatrics, School of Medicine, St. Louis University, St. Louis, MO 63110, USA
| | - William A Banks
- Geriatric Research Education and Clinical Center, Veterans Affairs Puget Sound Health Care System, Seattle, WA 98108, USA; Division of Gerontology and Geriatric Medicine, Department of Medicine, University of Washington School of Medicine, Seattle, WA 98104, USA
| | - Alexander V Kabanov
- Center for Nanotechnology in Drug Delivery, Division of Pharmacoengineering and Molecular Pharmaceutics, Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, NC 27599, USA; Laboratory of Chemical Design of Bionanomaterials, Faculty of Chemistry, M.V. Lomonosov Moscow State University, Moscow 119992, Russia.
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15
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Heinrich G, Muturi HT, Rezaei K, Al-Share QY, DeAngelis AM, Bowman TA, Ghadieh HE, Ghanem SS, Zhang D, Garofalo RS, Yin L, Najjar SM. Reduced Hepatic Carcinoembryonic Antigen-Related Cell Adhesion Molecule 1 Level in Obesity. Front Endocrinol (Lausanne) 2017; 8:54. [PMID: 28396653 PMCID: PMC5366977 DOI: 10.3389/fendo.2017.00054] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/04/2016] [Accepted: 03/03/2017] [Indexed: 12/12/2022] Open
Abstract
Impairment of insulin clearance is being increasingly recognized as a critical step in the development of insulin resistance and metabolic disease. The carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1) promotes insulin clearance. Null deletion or liver-specific inactivation of Ceacam1 in mice causes a defect in insulin clearance, insulin resistance, steatohepatitis, and visceral obesity. Immunohistological analysis revealed reduction of hepatic CEACAM1 in obese subjects with fatty liver disease. Thus, we aimed to determine whether this occurs at the hepatocyte level in response to systemic extrahepatic factors and whether this holds across species. Northern and Western blot analyses demonstrate that CEACAM1 mRNA and protein levels are reduced in liver tissues of obese individuals compared to their lean age-matched counterparts. Furthermore, Western analysis reveals a comparable reduction of CEACAM1 protein in primary hepatocytes derived from the same obese subjects. Similar to humans, Ceacam1 mRNA level, assessed by quantitative RT-PCR analysis, is significantly reduced in the livers of obese Zucker (fa/fa, ZDF) and Koletsky (f/f) rats relative to their age-matched lean counterparts. These studies demonstrate that the reduction of hepatic CEACAM1 in obesity occurs at the level of hepatocytes and identify the reduction of hepatic CEACAM1 as a common denominator of obesity across multiple species.
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Affiliation(s)
- Garrett Heinrich
- Department of Biomedical Sciences, Heritage College of Osteopathic Medicine, Ohio University, Athens, OH, USA
- Diabetes Institute, Heritage College of Osteopathic Medicine, Ohio University, Athens, OH, USA
| | - Harrison T. Muturi
- Department of Biomedical Sciences, Heritage College of Osteopathic Medicine, Ohio University, Athens, OH, USA
| | - Khadijeh Rezaei
- Center for Diabetes and Endocrine Research (CeDER), College of Medicine and Life Sciences, University of Toledo, Toledo, OH, USA
| | - Qusai Y. Al-Share
- Center for Diabetes and Endocrine Research (CeDER), College of Medicine and Life Sciences, University of Toledo, Toledo, OH, USA
| | - Anthony M. DeAngelis
- Center for Diabetes and Endocrine Research (CeDER), College of Medicine and Life Sciences, University of Toledo, Toledo, OH, USA
| | - Thomas A. Bowman
- Center for Diabetes and Endocrine Research (CeDER), College of Medicine and Life Sciences, University of Toledo, Toledo, OH, USA
| | - Hilda E. Ghadieh
- Center for Diabetes and Endocrine Research (CeDER), College of Medicine and Life Sciences, University of Toledo, Toledo, OH, USA
| | - Simona S. Ghanem
- Center for Diabetes and Endocrine Research (CeDER), College of Medicine and Life Sciences, University of Toledo, Toledo, OH, USA
| | - Deqiang Zhang
- Department of Molecular and Integrative Physiology, University of Michigan Medical School, Ann Arbor, MI, USA
| | | | - Lei Yin
- Department of Molecular and Integrative Physiology, University of Michigan Medical School, Ann Arbor, MI, USA
| | - Sonia M. Najjar
- Department of Biomedical Sciences, Heritage College of Osteopathic Medicine, Ohio University, Athens, OH, USA
- Diabetes Institute, Heritage College of Osteopathic Medicine, Ohio University, Athens, OH, USA
- Center for Diabetes and Endocrine Research (CeDER), College of Medicine and Life Sciences, University of Toledo, Toledo, OH, USA
- *Correspondence: Sonia M. Najjar,
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16
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Diane A, Borthwick F, Wu S, Lee J, Brown PN, Dickinson TA, Croft KD, Vine DF, Proctor SD. Hypolipidemic and cardioprotective benefits of a novel fireberry hawthorn fruit extract in the JCR:LA-cp rodent model of dyslipidemia and cardiac dysfunction. Food Funct 2016; 7:3943-52. [PMID: 27538786 DOI: 10.1039/c6fo01023g] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022]
Abstract
Hawthorn is a widely used herbal alternative medicine for the treatment of various cardiovascular diseases. However, the attributed health benefits, purported to be due to the presence of phenolic compounds, may depend on both the specific species and plant part. Studies to date investigating effects of hawthorn on heart disease(s) have used well-described European and/or Asian species, while little is known regarding the bioactivity of species native to North America. Six weeks of supplementation of both fireberry hawthorn berry (native Crataegus chrysocarpa) and English hawthorn leaf (C. monogyna, naturalized in North America) in the JCR:LA-cp rat, resulted in a significant reduction in heart weight, fasting LDL-C and improved heart function (p < 0.05). Fasting triglyceride and myocardial fibrosis were also reduced, but only by the berry extract. We demonstrate that both of the Canadian-sourced hawthorn extracts (introduced leaf and native berry) have cardioprotective benefits, likely via increased availability of nitric oxide.
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Affiliation(s)
- Abdoulaye Diane
- Metabolic and Cardiovascular Diseases Laboratory, Molecular Cell Biology of Lipids Group, Alberta Diabetes and Mazankowski Heart Institutes, University of Alberta, Edmonton, Alberta, Canada.
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17
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Generation of obese rat model by transcription activator-like effector nucleases targeting the leptin receptor gene. SCIENCE CHINA-LIFE SCIENCES 2016; 60:152-157. [DOI: 10.1007/s11427-016-5049-y] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/12/2015] [Accepted: 11/06/2015] [Indexed: 12/20/2022]
Abstract
Abstract
The laboratory rat is a valuable mammalian model organism for basic research and drug discovery. Here we demonstrate an efficient methodology by applying transcription activator-like effector nucleases (TALENs) technology to generate Leptin receptor (Lepr) knockout rats on the Sprague Dawley (SD) genetic background. Through direct injection of in vitro transcribed mRNA of TALEN pairs into SD rat zygotes, somatic mutations were induced in two of three resulting pups. One of the founders carrying bi-allelic mutation exhibited early onset of obesity and infertility. The other founder carried a chimeric mutation which was efficiently transmitted to the progenies. Through phenotyping of the resulting three lines of rats bearing distinct mutations in the Lepr locus, we found that the strains with a frame-shifted or premature stop codon mutation led to obesity and metabolic disorders. However, no obvious defect was observed in a strain with an in-frame 57 bp deletion in the extracellular domain of Lepr. This suggests the deleted amino acids do not significantly affect Lepr structure and function. This is the first report of generating the Lepr mutant obese rat model in SD strain through a reverse genetic approach. This suggests that TALEN is an efficient and powerful gene editing technology for the generation of disease models.
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Abstract
Recent studies indicate that dietary interventions have the potential to prevent and even treat cardiovascular disease, which is the leading cause of death. Many of these studies have focused on various animal models that are able to recreate one or more conditions or elevate risk factors that characterize the disease. Here, we highlight macronutrient-focused interventions in both mammalian model organisms and humans with emphasis on some of the most relevant and well-established diets known to be associated with cardiovascular disease prevention and treatment. We also discuss more recent dietary interventions in rodents, monkeys, and humans, which affect atherosclerosis and cardiovascular diseases with focus on those that also delay aging.
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Beef Fat Enriched with Polyunsaturated Fatty Acid Biohydrogenation Products Improves Insulin Sensitivity Without Altering Dyslipidemia in Insulin Resistant JCR:LA-cp Rats. Lipids 2016; 51:821-31. [PMID: 27072368 DOI: 10.1007/s11745-016-4148-7] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2015] [Accepted: 03/28/2016] [Indexed: 12/27/2022]
Abstract
The main dietary sources of trans fatty acids are partially hydrogenated vegetable oils (PHVO), and products derived from polyunsaturated fatty acid biohydrogenation (PUFA-BHP) in ruminants. Trans fatty acid intake has historically been associated with negative effects on health, generating an anti-trans fat campaign to reduce their consumption. The profiles and effects on health of PHVO and PUFA-BHP can, however, be quite different. Dairy products naturally enriched with vaccenic and rumenic acids have many purported health benefits, but the putative benefits of beef fat naturally enriched with PUFA-BHP have not been investigated. The objective of the present experiment was to determine the effects of beef peri-renal fat (PRF) with differing enrichments of PUFA-BHP on lipid and insulin metabolism in a rodent model of dyslipidemia and insulin resistance (JCR:LA-cp rat). The results showed that 6 weeks of diet supplementation with beef PRF naturally enriched due to flaxseed (FS-PRF) or sunflower-seed (SS-PRF) feeding to cattle significantly improved plasma fasting insulin levels and insulin sensitivity, postprandial insulin levels (only in the FS-PRF) without altering dyslipidemia. Moreover, FS-PRF but not SS-PRF attenuated adipose tissue accumulation. Therefore, enhancing levels of PUFA-BHP in beef PRF with FS feeding may be a useful approach to maximize the health-conferring value of beef-derived fats.
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20
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Ryan MJ, Coleman TT, Sasser JM, Pittman KM, Hankins MW, Stec DE. Vascular smooth muscle-specific deletion of the leptin receptor attenuates leptin-induced alterations in vascular relaxation. Am J Physiol Regul Integr Comp Physiol 2016; 310:R960-7. [PMID: 26936780 DOI: 10.1152/ajpregu.00336.2015] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2015] [Accepted: 02/23/2016] [Indexed: 01/09/2023]
Abstract
Obesity is a risk factor for cardiovascular disease and is associated with increased plasma levels of the adipose-derived hormone leptin. Vascular smooth muscle cells (VSMC) express leptin receptors (LepR); however, their physiological role is unclear. We hypothesized that leptin, at levels to mimic morbid obesity, impairs vascular relaxation. To test this, we used control and VSM-LepR knockout mice (VSM-LepR KO) created with a tamoxifen-inducible specific Cre recombinase to delete the LepR gene in VSMC. Control (10-12 wk old) and VSM-LepR KO (10-12 wk old) mice were fed a diet containing tamoxifen (50 mg/kg) for 6 wk, after which vascular reactivity was studied in isolated carotid arteries using an organ chamber bath. Vessels were incubated with leptin (100 ng/ml) or vehicle (0.1 mM Tris·HCl) for 30 min. Leptin treatment resulted in significant impairment of vessel relaxation to the endothelial-specific agonist acetylcholine (ACh). When these experiments were repeated in the presence of the superoxide scavenger tempol, relaxation responses to ACh were restored. VSM-LepR deletion resulted in a significant attenuation of leptin-mediated impaired ACh-induced relaxation. These data show that leptin directly impairs vascular relaxation via a VSM-LepR-mediated mechanism, suggesting a potential pathogenic role for leptin to increase cardiovascular risk during obesity.
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Affiliation(s)
- Michael J Ryan
- Department of Physiology and Biophysics, Mississippi Center for Obesity Research, Cardiovascular-Renal Research Center, Jackson, Mississippi; and
| | - T Taylor Coleman
- Department of Physiology and Biophysics, Mississippi Center for Obesity Research, Cardiovascular-Renal Research Center, Jackson, Mississippi; and
| | - Jennifer M Sasser
- Department of Pharmacology and Toxicology, University of Mississippi Medical Center, Jackson, Mississippi
| | - Katarina M Pittman
- Department of Physiology and Biophysics, Mississippi Center for Obesity Research, Cardiovascular-Renal Research Center, Jackson, Mississippi; and
| | - Michael W Hankins
- Department of Physiology and Biophysics, Mississippi Center for Obesity Research, Cardiovascular-Renal Research Center, Jackson, Mississippi; and
| | - David E Stec
- Department of Physiology and Biophysics, Mississippi Center for Obesity Research, Cardiovascular-Renal Research Center, Jackson, Mississippi; and
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21
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Huang-Doran I, Franks S. Genetic Rodent Models of Obesity-Associated Ovarian Dysfunction and Subfertility: Insights into Polycystic Ovary Syndrome. Front Endocrinol (Lausanne) 2016; 7:53. [PMID: 27375552 PMCID: PMC4894870 DOI: 10.3389/fendo.2016.00053] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/01/2016] [Accepted: 05/17/2016] [Indexed: 01/26/2023] Open
Abstract
Polycystic ovary syndrome (PCOS) is the most common endocrinopathy affecting women and a leading cause of female infertility worldwide. Defined clinically by the presence of hyperandrogenemia and oligomenorrhoea, PCOS represents a state of hormonal dysregulation, disrupted ovarian follicle dynamics, and subsequent oligo- or anovulation. The syndrome's prevalence is attributed, at least partly, to a well-established association with obesity and insulin resistance (IR). Indeed, the presence of severe PCOS in human genetic obesity and IR syndromes supports a causal role for IR in the pathogenesis of PCOS. However, the molecular mechanisms underlying this causality, as well as the important role of hyperandrogenemia, remain poorly elucidated. As such, treatment of PCOS is necessarily empirical, focusing on symptom alleviation. The generation of knockout and transgenic rodent models of obesity and IR offers a promising platform in which to address mechanistic questions about reproductive dysfunction in the context of metabolic disease. Similarly, the impact of primary perturbations in rodent gonadotrophin or androgen signaling has been interrogated. However, the insights gained from such models have been limited by the relatively poor fidelity of rodent models to human PCOS. In this mini review, we evaluate the ovarian phenotypes associated with rodent models of obesity and IR, including the extent of endocrine disturbance, ovarian dysmorphology, and subfertility. We compare them to both human PCOS and other animal models of the syndrome (genetic and hormonal), explore reasons for their discordance, and consider the new opportunities that are emerging to better understand and treat this important condition.
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Affiliation(s)
- Isabel Huang-Doran
- Institute of Reproductive and Developmental Biology, Department of Surgery and Cancer, Imperial College London, Hammersmith Hospital, London, UK
- *Correspondence: Isabel Huang-Doran,
| | - Stephen Franks
- Institute of Reproductive and Developmental Biology, Department of Surgery and Cancer, Imperial College London, Hammersmith Hospital, London, UK
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22
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Preliminary Characterization of a Leptin Receptor Knockout Rat Created by CRISPR/Cas9 System. Sci Rep 2015; 5:15942. [PMID: 26537785 PMCID: PMC4633582 DOI: 10.1038/srep15942] [Citation(s) in RCA: 33] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2015] [Accepted: 09/29/2015] [Indexed: 12/28/2022] Open
Abstract
Leptin receptor, which is encoded by the diabetes (db) gene and is highly expressed in the choroid plexus, regulatesenergy homeostasis, the balance between food intake and energy expenditure, fertility and bone mass. Here, using CRISPR/Cas9 technology, we created the leptin receptor knockout rat. Homozygous leptin receptor null rats are characterized by obesity, hyperphagia, hyperglycemia, glucose intolerance, hyperinsulinemia and dyslipidemia. Due to long-term poor glycemic control, the leptin receptor knockout rats also develop some diabetic complications such as pancreatic, hepatic and renal lesions. In addition, the leptin receptor knockout rats show a significant decrease in bone volume and bone mineral density of the femur compared with their wild-type littermates. Our model has rescued some deficiency of the existing rodent models, such as the transient hyperglycemia of db/db mice in the C57BL/6J genetic background and the delayed onset of glucose intolerance in the Zucker rats, and it is proven to be a useful animal model for biomedical and pharmacological research on obesity and diabetes.
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23
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Hall ME, Harmancey R, Stec DE. Lean heart: Role of leptin in cardiac hypertrophy and metabolism. World J Cardiol 2015; 7:511-524. [PMID: 26413228 PMCID: PMC4577678 DOI: 10.4330/wjc.v7.i9.511] [Citation(s) in RCA: 69] [Impact Index Per Article: 6.9] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/02/2015] [Revised: 06/16/2015] [Accepted: 07/23/2015] [Indexed: 02/06/2023] Open
Abstract
Leptin is an adipokine that has been linked with the cardiovascular complications resulting from obesity such as hypertension and heart disease. Obese patients have high levels of circulating leptin due to increased fat mass. Clinical and population studies have correlated high levels of circulating leptin with the development of cardiac hypertrophy in obesity. Leptin has also been demonstrated to increase the growth of cultured cardiomyocytes. However, several animal studies of obese leptin deficient mice have not supported a role for leptin in promoting cardiac hypertrophy so the role of leptin in this pathological process remains unclear. Leptin is also an important hormone in the regulation of cardiac metabolism where it supports oxidation of glucose and fatty acids. In addition, leptin plays a critical role in protecting the heart from excess lipid accumulation and the formation of toxic lipids in obesity a condition known as cardiac lipotoxicity. This paper focuses on the data supporting and refuting leptin’s role in promoting cardiac hypertrophy as well as its important role in the regulation of cardiac metabolism and protection against cardiac lipotoxicity.
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Fillmore N, Keung W, Kelly SE, Proctor SD, Lopaschuk GD, Ussher JR. Accumulation of ceramide in slow-twitch muscle contributes to the development of insulin resistance in the obese JCR:LA-cp rat. Exp Physiol 2015; 100:730-41. [DOI: 10.1113/ep085052] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2015] [Accepted: 03/17/2015] [Indexed: 12/30/2022]
Affiliation(s)
- Natasha Fillmore
- Cardiovascular Translational Science Institute; University of Alberta; Edmonton Alberta Canada
- Mazankowski Alberta Heart Institute; University of Alberta; Edmonton Alberta Canada
| | - Wendy Keung
- Mazankowski Alberta Heart Institute; University of Alberta; Edmonton Alberta Canada
| | - Sandra E. Kelly
- Mazankowski Alberta Heart Institute; University of Alberta; Edmonton Alberta Canada
- Alberta Diabetes Institute; University of Alberta; Edmonton Alberta Canada
| | - Spencer D. Proctor
- Mazankowski Alberta Heart Institute; University of Alberta; Edmonton Alberta Canada
- Alberta Diabetes Institute; University of Alberta; Edmonton Alberta Canada
| | - Gary D. Lopaschuk
- Cardiovascular Translational Science Institute; University of Alberta; Edmonton Alberta Canada
- Mazankowski Alberta Heart Institute; University of Alberta; Edmonton Alberta Canada
- Alberta Diabetes Institute; University of Alberta; Edmonton Alberta Canada
| | - John R. Ussher
- Cardiovascular Translational Science Institute; University of Alberta; Edmonton Alberta Canada
- Alberta Diabetes Institute; University of Alberta; Edmonton Alberta Canada
- Faculty of Pharmacy and Pharmaceutical Sciences; University of Alberta; Edmonton Alberta Canada
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Davis C, Mudd J, Hawkins M. Neuroprotective effects of leptin in the context of obesity and metabolic disorders. Neurobiol Dis 2014; 72 Pt A:61-71. [DOI: 10.1016/j.nbd.2014.04.012] [Citation(s) in RCA: 55] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2014] [Revised: 04/09/2014] [Accepted: 04/21/2014] [Indexed: 12/16/2022] Open
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Yi X, Yuan D, Farr SA, Banks WA, Poon CD, Kabanov AV. Pluronic modified leptin with increased systemic circulation, brain uptake and efficacy for treatment of obesity. J Control Release 2014; 191:34-46. [PMID: 24881856 PMCID: PMC4197010 DOI: 10.1016/j.jconrel.2014.05.044] [Citation(s) in RCA: 34] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/25/2014] [Revised: 05/12/2014] [Accepted: 05/21/2014] [Indexed: 11/30/2022]
Abstract
Modification of hydrophilic proteins with amphiphilic block copolymers capable of crossing cell membranes is a new strategy to improve protein delivery to the brain. Leptin, a candidate for the treatment of epidemic obesity, has failed in part because of impairment in its transport across the blood-brain barrier (BBB) that develops with obesity. We posit that modification of leptin with poly(ethylene oxide)-b-poly(propylene oxide)-b-poly(ethylene oxide), Pluronic P85 (P85) might permit this protein to penetrate the BBB independently of its transporter, thereby overcoming peripheral leptin resistance. Here we report that peripherally administered leptin-P85 conjugates exhibit biological activity by reducing food intake in mouse models of obesity (ob/ob, and diet-induced obese mouse). We further generated two new leptin-P85 conjugates: one, Lep(ss)-P85(L), containing one P85 chain and another, Lep(ss)-P85(H), containing multiple P85 chains. We report data on their purification, analytical characterization, peripheral and brain pharmacokinetics (PK). Lep(ss)-P85(L) crosses the BBB using the leptin transporter, and exhibits improved peripheral PK along with increased accumulation in the brain compared to unmodified leptin. Lep(ss)-P85(H) also has improved peripheral PK but in a striking difference to the first conjugate penetrates the BBB independently of the leptin transporter via a non-saturable mechanism. The results demonstrate that leptin analogs can be developed through chemical modification of the native leptin with P85 to overcome leptin resistance at the level of the BBB, thus improving the potential for the treatment of obesity.
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Affiliation(s)
- Xiang Yi
- Center for Nanotechnology in Drug Delivery and Division of Molecular Pharmaceutics, Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
| | - Dongfen Yuan
- Center for Nanotechnology in Drug Delivery and Division of Molecular Pharmaceutics, Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
| | - Susan A Farr
- Research and Development, VA Medical Center and Division of Geriatrics, St. Louis University School of Medicine, St. Louis, MI, USA
| | - William A Banks
- Geriatric Research, Education, and Clinical Center, Veterans Affairs Puget Sound Health Care System, Seattle, WA 98108, USA; Division of Gerontology and Geriatric Medicine, Department of Medicine, University of Washington School of Medicine, Seattle, WA 98108, USA
| | - Chi-Duen Poon
- Research Computer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
| | - Alexander V Kabanov
- Center for Nanotechnology in Drug Delivery and Division of Molecular Pharmaceutics, Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA; Faculty of Chemistry, M.V. Lomonosov Moscow State University, 119899 Moscow, Russia.
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Wada N, Hirako S, Takenoya F, Kageyama H, Okabe M, Shioda S. Leptin and its receptors. J Chem Neuroanat 2014; 61-62:191-9. [PMID: 25218975 DOI: 10.1016/j.jchemneu.2014.09.002] [Citation(s) in RCA: 97] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2014] [Revised: 09/02/2014] [Accepted: 09/03/2014] [Indexed: 12/11/2022]
Abstract
Leptin is mainly produced in the white adipose tissue before being secreted into the blood and transported across the blood-brain barrier. Leptin binds to a specific receptor (LepR) that has numerous subtypes (LepRa, LepRb, LepRc, LepRd, LepRe, and LepRf). LepRb, in particular, is expressed in several brain nuclei, including the arcuate nucleus, the paraventricular nucleus, and the dorsomedial, lateral and ventromedial regions of the hypothalamus. LepRb is also co-expressed with several neuropeptides, including proopiomelanocortin, neuropeptide Y, galanin, galanin-like peptide, gonadotropin-releasing hormone, tyrosine hydroxylase and neuropeptide W. Functionally, LepRb induces activation of the JAK2/ERK, /STAT3, /STAT5 and IRS/PI3 kinase signaling cascades, which are important for the regulation of energy homeostasis and appetite in mammals. In this review, we discuss the structure, genetics and distribution of the leptin receptors, and their role in cell signaling mechanisms.
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Affiliation(s)
- Nobuhiro Wada
- Department of Anatomy, Showa University School of Medicine, 1-5-8 Hatanodai Shinagawa-ku, Tokyo 142-8555, Japan
| | - Satoshi Hirako
- Department of Anatomy, Showa University School of Medicine, 1-5-8 Hatanodai Shinagawa-ku, Tokyo 142-8555, Japan
| | - Fumiko Takenoya
- Department of Anatomy, Showa University School of Medicine, 1-5-8 Hatanodai Shinagawa-ku, Tokyo 142-8555, Japan; Department of Physical Education, Hoshi University School of Pharmacy and Pharmaceutical Science, Tokyo 142-8501, Japan
| | - Haruaki Kageyama
- Department of Anatomy, Showa University School of Medicine, 1-5-8 Hatanodai Shinagawa-ku, Tokyo 142-8555, Japan; Department of Nutrition, Faculty of Health Care, Kiryu University, 606-7 Kasakakecho Azami, Midori City 379-2392, Gunma, Japan
| | - Mai Okabe
- Department of Anatomy, Showa University School of Medicine, 1-5-8 Hatanodai Shinagawa-ku, Tokyo 142-8555, Japan; Tokyo Shokuryo Dietitian Academy, Tokyo 154-0001, Japan
| | - Seiji Shioda
- Department of Anatomy, Showa University School of Medicine, 1-5-8 Hatanodai Shinagawa-ku, Tokyo 142-8555, Japan.
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Leblanc S, Battista MC, Noll C, Hallberg A, Gallo-Payet N, Carpentier AC, Vine DF, Baillargeon JP. Angiotensin II type 2 receptor stimulation improves fatty acid ovarian uptake and hyperandrogenemia in an obese rat model of polycystic ovary syndrome. Endocrinology 2014; 155:3684-93. [PMID: 24971613 DOI: 10.1210/en.2014-1185] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
Polycystic ovary syndrome (PCOS) is mainly defined by hyperandrogenism but is also characterized by insulin resistance (IR). Studies showed that overexposure of nonadipose tissues to nonesterified fatty acids (NEFA) may explain both IR and hyperandrogenism. Recent studies indicate that treatment with an angiotensin II type 2 receptor (AT2R)-selective agonist improves diet-induced IR. We thus hypothesized that PCOS hyperandrogenism is triggered by ovarian NEFA overexposure and is improved after treatment with an AT2R agonist. Experiments were conducted in 12-week-old female JCR:LA-cp/cp rats, which are characterized by visceral obesity, IR, hyperandrogenism, and polycystic ovaries. Control JCR:LA +/? rats have a normal phenotype. Rats were treated for 8 days with saline or the selective AT2R agonist C21/M24 and then assessed for: 1) fasting testosterone, NEFA, and insulin levels; and 2) an iv 14(R,S)-[(18)F]fluoro-6-thia-heptadecanoic acid test to determine NEFA ovarian tissue uptake (Km). Compared with controls, saline-treated PCOS/cp rats displayed higher insulin (100 vs 5.6 μU/mL), testosterone (0.12 vs 0.04 nmol/L), NEFA (0.98 vs 0.48 mmol/L), and Km (20.7 vs 12.9 nmol/g·min) (all P < .0001). In PCOS/cp rats, C21/M24 did not significantly improve insulin or NEFA but normalized testosterone (P = .004) and Km (P = .009), which were strongly correlated together in all PCOS/cp rats (ρ = 0.74, P = .009). In conclusion, in an obese PCOS rat model, ovarian NEFA uptake and testosterone levels are strongly associated and are both significantly reduced after short-term C21/M24 therapy. These findings provide new information on the role of NEFA in PCOS hyperandrogenemia and suggest a potential role for AT2R agonists in the treatment of PCOS.
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Affiliation(s)
- Samuel Leblanc
- Division of Endocrinology (S.L., M.-C.B., C.N., N.G.-P., A.C.C., J.-P.B.), Department of Medicine, Faculty of Medicine and Health Sciences, Université de Sherbrooke, Sherbrooke, Quebec, Canada J1H 5N4; Department of Medicinal Chemistry (A.H.), Biomedicinska Centrum, Uppsala University, Uppsala, Sweden 751 23; Alberta Institute for Human Nutrition, Metabolic and Cardiovascular Disease Laboratory (D.F.V.), University of Alberta, Edmonton, Alberta, Canada T6G 2E1; and Centre de Recherche Étienne-Lebel (N.G.-P., A.C.C., J.-P.B.), Centre Hospitalier Universitaire de Sherbrooke, Sherbrooke, Quebec, Canada J1H 5N4
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Yi X, Kabanov AV. Brain delivery of proteins via their fatty acid and block copolymer modifications. J Drug Target 2014; 21:940-55. [PMID: 24160902 DOI: 10.3109/1061186x.2013.847098] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
It is well known that hydrophobic small molecules penetrate cell membranes better than hydrophilic molecules. Amphiphilic molecules that dissolve both in lipid and aqueous phases are best suited for membrane transport. Transport of biomacromolecules across physiological barriers, e.g. the blood-brain barrier, is greatly complicated by the unique structure and function of such barriers. Two decades ago we adopted a simple philosophy that to increase protein delivery to the brain one needs to modify this protein with hydrophobic moieties. With this general idea we began modifying proteins (antibodies, enzymes, hormones, etc.) with either hydrophobic fatty acid residues or amphiphilic block copolymer moieties, such as poy(ethylene oxide)-poly(propylene oxide)-poly(ethylene oxide) (pluronics or poloxamers) and more recently, poly(2-oxasolines). This simple approach has resulted in impressive successes in CNS drug delivery. We present a retrospective overview of these works initiated in the Soviet Union in 1980s, and then continued in the United States and other countries. Notably some of the early findings were later corroborated by brain pharmacokinetic data. Industrial development of several drug candidates employing these strategies has followed. Overall modification by hydrophobic fatty acids residues or amphiphilic block copolymers represents a promising and relatively safe strategy to deliver proteins to the brain.
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Affiliation(s)
- Xiang Yi
- Division of Molecular Pharmaceutics and Center for Nanotechnology in Drug Delivery, UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill , Chapel Hill, NC , USA and
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Diane A, Vine DF, Russell JC, Heth CD, Pierce WD, Proctor SD. Interrelationship of CB1R and OBR pathways in regulation of metabolic, neuroendocrine, and behavioral responses to food restriction and voluntary wheel running. J Appl Physiol (1985) 2014; 117:97-104. [PMID: 24903921 DOI: 10.1152/japplphysiol.01303.2013] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/26/2023] Open
Abstract
We hypothesized the cannabinoid-1 receptor and leptin receptor (ObR) operate synergistically to modulate metabolic, neuroendocrine, and behavioral responses of animals exposed to a survival challenge (food restriction and wheel running). Obese-prone (OP) JCR:LA-cp rats, lacking functional ObR, and lean-prone (LP) JCR:LA-cp rats (intact ObR) were assigned to OP-C and LP-C (control) or CBR1-antagonized (SR141716, 10 mg/kg body wt in food) OP-A and LP-A groups. After 32 days, all rats were exposed to 1.5-h daily meals without the drug and 22.5-h voluntary wheel running, a survival challenge that normally culminates in activity-based anorexia (ABA). Rats were removed from the ABA protocol when body weight reached 75% of entry weight (starvation criterion) or after 14 days (survival criterion). LP-A rats starved faster (6.44 ± 0.24 days) than LP-C animals (8.00 ± 0.29 days); all OP rats survived the ABA challenge. LP-A rats lost weight faster than animals in all other groups (P < 0.001). Consistent with the starvation results, LP-A rats increased the rate of wheel running more rapidly than LP-C rats (P = 0.001), with no difference in hypothalamic and primary neural reward serotonin levels. In contrast, OP-A rats showed suppression of wheel running compared with the OP-C group (days 6-14 of ABA challenge, P < 0.001) and decreased hypothalamic and neural reward serotonin levels (P < 0.01). Thus there is an interrelationship between cannabinoid-1 receptor and ObR pathways in regulation of energy balance and physical activity. Effective clinical measures to prevent and treat a variety of disorders will require understanding of the mechanisms underlying these effects.
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Affiliation(s)
- Abdoulaye Diane
- Metabolic and Cardiovascular Diseases Laboratory, Alberta Institute for Human Nutrition, Alberta Diabetes Institute, University of Alberta, Alberta, Edmonton, Canada
| | - Donna F Vine
- Metabolic and Cardiovascular Diseases Laboratory, Alberta Institute for Human Nutrition, Alberta Diabetes Institute, University of Alberta, Alberta, Edmonton, Canada
| | - James C Russell
- Metabolic and Cardiovascular Diseases Laboratory, Alberta Institute for Human Nutrition, Alberta Diabetes Institute, University of Alberta, Alberta, Edmonton, Canada
| | - C Donald Heth
- Department of Psychology, University of Alberta, Alberta, Edmonton, Canada
| | - W David Pierce
- Department of Sociology, University of Alberta, Alberta, Edmonton, Canada; and
| | - Spencer D Proctor
- Metabolic and Cardiovascular Diseases Laboratory, Alberta Institute for Human Nutrition, Alberta Diabetes Institute, University of Alberta, Alberta, Edmonton, Canada
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Wang B, Chandrasekera PC, Pippin JJ. Leptin- and leptin receptor-deficient rodent models: relevance for human type 2 diabetes. Curr Diabetes Rev 2014; 10:131-45. [PMID: 24809394 PMCID: PMC4082168 DOI: 10.2174/1573399810666140508121012] [Citation(s) in RCA: 369] [Impact Index Per Article: 33.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/07/2014] [Revised: 05/06/2014] [Accepted: 05/07/2014] [Indexed: 12/11/2022]
Abstract
Among the most widely used animal models in obesity-induced type 2 diabetes mellitus (T2DM) research are the congenital leptin- and leptin receptor-deficient rodent models. These include the leptin-deficient ob/ob mice and the leptin receptor-deficient db/db mice, Zucker fatty rats, Zucker diabetic fatty rats, SHR/N-cp rats, and JCR:LA-cp rats. After decades of mechanistic and therapeutic research schemes with these animal models, many species differences have been uncovered, but researchers continue to overlook these differences, leading to untranslatable research. The purpose of this review is to analyze and comprehensively recapitulate the most common leptin/leptin receptor-based animal models with respect to their relevance and translatability to human T2DM. Our analysis revealed that, although these rodents develop obesity due to hyperphagia caused by abnormal leptin/leptin receptor signaling with the subsequent appearance of T2DM-like manifestations, these are in fact secondary to genetic mutations that do not reflect disease etiology in humans, for whom leptin or leptin receptor deficiency is not an important contributor to T2DM. A detailed comparison of the roles of genetic susceptibility, obesity, hyperglycemia, hyperinsulinemia, insulin resistance, and diabetic complications as well as leptin expression, signaling, and other factors that confound translation are presented here. There are substantial differences between these animal models and human T2DM that limit reliable, reproducible, and translatable insight into human T2DM. Therefore, it is imperative that researchers recognize and acknowledge the limitations of the leptin/leptin receptor- based rodent models and invest in research methods that would be directly and reliably applicable to humans in order to advance T2DM management.
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Affiliation(s)
| | | | - John J Pippin
- Physicians Committee for Responsible Medicine, 5100 Wisconsin Avenue NW, Suite 400, Washington, DC 20016, USA.
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Down-regulation of hypothalamic pro-opiomelanocortin (POMC) expression after weaning is associated with hyperphagia-induced obesity in JCR rats overexpressing neuropeptide Y. Br J Nutr 2013; 111:924-32. [DOI: 10.1017/s0007114513003061] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/07/2022]
Abstract
We hypothesised that hypothalamic feeding-related neuropeptides are differentially expressed in obese-prone and lean-prone rats and trigger overeating-induced obesity. To test this hypothesis, in the present study, we measured energy balance and hypothalamic neuropeptide Y (NPY) and pro-opiomelanocortin (POMC) mRNA expressions in male JCR:LA-cp rats. We compared, in independent cohorts, free-feeding obese-prone (Obese-FF) and lean-prone (Lean-FF) rats at pre-weaning (10 d old), weaning (21–25 d old) and early adulthood (8–12 weeks). A group of Obese-pair-feeding (PF) rats pair-fed to the Lean-FF rats was included in the adult cohort. The body weights of 10-d-old Obese-FF and Lean-FF pups were not significantly different. However, when the pups were shifted from dams' milk to solid food (weaning), the obese-prone rats exhibited more energy intake over the days than the lean-prone rats and higher body and fat pad weights and fasting plasma glucose, leptin, insulin and lipid levels. These differences were consistent with higher energy consumption and lower energy expenditure. In the young adult cohort, the differences between the Obese-FF and Lean-FF rats became more pronounced, yielding significant age effects on most of the parameters of the metabolic syndrome, which were reduced in the Obese-PF rats. The obese-prone rats displayed higher NPY expression than the lean-prone rats at pre-weaning and weaning, and the expression levels did not differ by age. In contrast, POMC expression exhibited significant age-by-genotype differences. At pre-weaning, there was no genotype difference in POMC expression, but in the weanling cohort, obese-prone pups exhibited lower POMC expression than the lean-prone rats. This genotype difference became more pronounced at adulthood. Overall, the development of hyperphagia-induced obesity in obese-prone JCR rats is related to POMC expression down-regulation in the presence of established NPY overexpression.
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Abstract
The focus of this overview is on the animal models of obesity most commonly utilized in research. The models include monogenic models in the leptin pathway, polygenic diet-dependent models, and, in particular for their historical perspective, surgical and chemical models of obesity. However, there are far too many models to consider all of them comprehensively, especially those caused by selective molecular genetic approaches modifying one or more genes in specific populations of cells. Further, the generation and use of inducible transgenic animals (induced knock-out or knock-in) is not covered, even though they often carry significant advantages compared to traditional transgenic animals, e.g., influences of the genetic modification during the development of the animals can be minimized. The number of these animal models is simply too large to be covered in this unit.
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Affiliation(s)
- Thomas A Lutz
- University of Zurich, Institute of Veterinary Physiology, Zurich Center of Integrative Human Physiology, Zurich, Switzerland
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Diane A, Pierce WD, Heth CD, Russell JC, Richard D, Proctor SD. Feeding history and obese-prone genotype increase survival of rats exposed to a challenge of food restriction and wheel running. Obesity (Silver Spring) 2012; 20:1787-95. [PMID: 22016097 DOI: 10.1038/oby.2011.326] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/30/2022]
Abstract
We hypothesized that obese-prone genotype and history of food restriction confer a survival advantage to genetically obese animals under environmental challenge. Male juvenile JCR:LA-cp rats, obese-prone and lean-prone, were exposed to 1.5 h daily meals and 22.5-h voluntary wheel running, a procedure inducing activity anorexia (AA). One week before the AA challenge, obese-prone rats were freely fed (obese-FF), or pair fed (obese-PF) to lean-prone, free-feeding rats (lean-FF). Animals were removed from protocol at 75% of initial body weight (starvation criterion) or after 14 days (survival criterion). AA challenge induced weight loss in all rats, but percent weight loss was more rapid and sustained in lean-FF rats than in obese-FF or obese-PF animals (P < 0.04). Weight loss was significantly higher in obese-FF rats than obese-PF rats, 62% of which achieved survival criterion and stabilized with zero weight loss. Obese-PF rats survived longer, on average (12.0 ± 1.1 day) than obese-FF (8.2 ± 1.1 day) and lean-FF rats (3.5 ± 0.2 day) (P < 0.02). Wheel running increased linearly in all groups; lean-FF increased more rapidly than obese-FF (P < 0.05); obese-PF increased at an intermediate rate (P < 0.02), and those rats that survived stabilized daily rates of wheel running. Prior food restriction of juvenile obese-prone rats induces a survival benefit beyond genotype, that is related to achievement of homeostasis. This metabolic adaptive process may help explain the development of human obesity in the presence of an unstable food environment which subsequently transitions to an abundant food supply.
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Affiliation(s)
- Abdoulaye Diane
- Metabolic and Cardiovascular Diseases Laboratory, Alberta Diabetes Institute University of Alberta, Edmonton, Alberta, Canada
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Chung WK. An overview of mongenic and syndromic obesities in humans. Pediatr Blood Cancer 2012; 58:122-8. [PMID: 21994130 PMCID: PMC3215910 DOI: 10.1002/pbc.23372] [Citation(s) in RCA: 33] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/06/2011] [Accepted: 09/06/2011] [Indexed: 12/16/2022]
Abstract
Obesity is increasing in prevalence in the United States with over 65% of adults considered overweight and 16% of children with BMI > 95 percentile. The heritability of obesity is estimated between 40% and 70%, but the genetics of obesity for most individuals are complex and involve the interaction of multiple genes and environment. There are however several syndromic and non-syndromic forms of obesity that are monogenic and oligogenic that provide insight into the underlying molecular control of food intake and the neural networks that control ingestive behavior and satiety to regulate body weight and which may interact with treatment exposures to produce or exacerbate obesity in childhood cancer survivors.
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Affiliation(s)
- Wendy K Chung
- Division of Molecular Genetics and Naomi Berrie Diabetes Center, Columbia University Medical College, Russell Berrie Medical Science Pavilion, New York, New York 10032, USA.
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Kastin AJ, Pan W. Concepts for biologically active peptides. Curr Pharm Des 2011; 16:3390-400. [PMID: 20726835 DOI: 10.2174/138161210793563491] [Citation(s) in RCA: 33] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/07/2010] [Accepted: 08/12/2010] [Indexed: 12/21/2022]
Abstract
Here we review a unique aspect of CNS research on biologically active peptides that started against a background of prevalent dogmas but ended by exerting considerable influence on the field. During the course of refuting some doctrines, we introduced several concepts that were unconventional and paradigm-shifting at the time. We showed that (1) hypothalamic peptides can act 'up' on the brain as well as 'down' on the pituitary, (2) peripheral peptides can affect the brain, (3) peptides can cross the blood-brain barrier, (4) the actions of peptides can persist longer than their half-lives in blood, (5) perinatal administration of peptides can exert actions persisting into adulthood, (6) a single peptide can have more than one action, (7) dose-response relationships of peptides need not be linear, (8) the brain produces antiopiate as well as opiate peptides, (9) there is a selective high affinity endogenous peptide ligand for the mu-opiate receptor, (10) a peptide's name does not restrict its effects, and (11) astrocytes assume an active role in response to metabolic disturbance and hyperleptinemia. The evolving questions in our laboratories reflect the diligent effort of the neuropeptide community to identify the roles of peptides in the CNS. The next decade is expected to see greater progress in the following areas: (a) interactions of peptides with other molecules in the CNS; (b) peptide involvement in cell-cell interactions; and (c) peptides in neuropsychiatric, autoimmune, and neurodegenerative diseases. The development of peptidomics and gene silencing approaches will expedite the formation of many new concepts in a new era.
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Affiliation(s)
- Abba J Kastin
- Blood-Brain Barrier Group, Pennington Biomedical Research Center, Baton Rouge, LA 70808, USA.
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Gorska E, Popko K, Stelmaszczyk-Emmel A, Ciepiela O, Kucharska A, Wasik M. Leptin receptors. Eur J Med Res 2011; 15 Suppl 2:50-4. [PMID: 21147620 PMCID: PMC4360333 DOI: 10.1186/2047-783x-15-s2-50] [Citation(s) in RCA: 133] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022] Open
Abstract
Leptin or obesity receptor (Ob-R) is a member of class I cytokine receptor family. Ob-R, expressed in six isoforms, is the product of alternative RNA splicing of db gene. According to its structural differences, the receptor's isoforms are divided into three classes: long, short, and secretory isoforms. A long, fully active isoform of Ob-Rb is expressed mainly in the hypothalamus, where it takes part in energy homeostasis and in the regulation of secretory organs' activity. Ob-Rb is also present on all types of immune cells, involved in innate and adaptive immunity. Short leptin isoforms (Ob-Ra, Ob-Rc, Ob-Rd, and Ob-Re) that contain box 1 motif are able to bind JAK kinases (Janus kinases) as well as to activate some other signal transduction cascades. A soluble isoform (Ob-Re) can regulate serum leptin concentration and serve as a carrier protein delivering the hormone to its membrane receptors and is able to transduce the signal into the cell. JAK/STAT pathway plays the major role in leptin signal transduction through membrane receptors. Among all Ob-R isoforms, only full-length isoform (Ob-Rb) is able to fully transduce activation signal into the cell.
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Affiliation(s)
- Elzbieta Gorska
- Department of Laboratory Diagnostics, Warsaw Medical University, Warsaw, Poland.
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Rong X, Li Y, Ebihara K, Zhao M, Kusakabe T, Tomita T, Murray M, Nakao K. Irbesartan treatment up-regulates hepatic expression of PPARalpha and its target genes in obese Koletsky (fa(k)/fa(k)) rats: a link to amelioration of hypertriglyceridaemia. Br J Pharmacol 2010; 160:1796-807. [PMID: 20649581 DOI: 10.1111/j.1476-5381.2010.00835.x] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/25/2023] Open
Abstract
BACKGROUND AND PURPOSE Hypertriglyceridaemia is associated with an increased risk of cardiovascular disease. Irbesartan, a well-established angiotensin II type 1 receptor (AT(1)) blocker, improves hypertriglyceridaemia in rodents and humans but the underlying mechanism of action is unclear. EXPERIMENTAL APPROACH Male obese Koletsky (fa(k)/fa(k)) rats, which exhibit spontaneous hypertension and metabolic abnormalities, received irbesartan (40 mg x kg(-1) x day(-1)) or vehicle by oral gavage over 7 weeks. Adipocyte-derived hormones in plasma were measured by ELISA. Gene expression in liver and other tissues was assessed by real-time PCR and Western immunoblotting. KEY RESULTS In Koletsky (fa(k)/fa(k)) rats irbesartan lowered plasma concentrations of triglycerides and non-esterified fatty acids, and decreased plasma insulin concentrations and the homeostasis model assessment of insulin resistance index. However, this treatment did not affect food intake, body weight, epididymal white adipose tissue weight, adipocyte size and plasma leptin concentrations, although plasma adiponectin was decreased. Irbesartan up-regulated hepatic expression of mRNAs corresponding to peroxisome proliferator-activated receptor (PPAR)alpha and its target genes (carnitine palmitoyltransferase-1a, acyl-CoA oxidase and fatty acid translocase/CD36) that mediate hepatic fatty acid uptake and oxidation; the increase in hepatic PPARalpha expression was confirmed at the protein level. In contrast, irbesartan did not affect expression of adipose PPARgamma and its downstream genes or hepatic genes that mediate fatty acid synthesis. CONCLUSIONS AND IMPLICATIONS These findings demonstrate that irbesartan treatment up-regulates PPARalpha and several target genes in liver of obese spontaneously hypertensive Koletsky (fa(k)/fa(k)) rats and offers a novel insight into the lipid-lowering mechanism of irbesartan.
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Affiliation(s)
- X Rong
- Department of Medicine and Clinical Science, Kyoto University Graduate School of Medicine, Sakyo-ku, Kyoto, Japan
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Huber M, Heiduschka P, Ziemssen F, Bolbrinker J, Kreutz R. Microangiopathy and visual deficits characterize the retinopathy of a spontaneously hypertensive rat model with type 2 diabetes and metabolic syndrome. Hypertens Res 2010; 34:103-12. [PMID: 20927114 DOI: 10.1038/hr.2010.168] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/19/2023]
Abstract
Retinopathy has been increasing in prevalence as a consequence of type 2 diabetes and a cluster of coexisting risk factors characterized as the metabolic syndrome. However, the combined effects of these conditions on the retina are poorly understood. Therefore, we focused on the spontaneously hypertensive corpulent rat (SHR/N-cp), a model with type 2 diabetes, obesity and features of the metabolic syndrome to characterize retinal changes at a structural and functional level. SHR/N-cp males at 4 and 8 months of age were used in this study. Metabolic parameters and blood pressure were measured by standard methods. Morphology was investigated by histological techniques supplemented by nicotinamide adenine dinucleotide phosphate-diaphorase staining of whole mounts and fluorescein angiography to analyze the retinal vasculature. The in vivo function of the retina was examined by electroretinography (ERG). Obese SHR/N-cp rats were hypertensive and showed significant increases in body weight, serum levels of glucose, triglycerides, total cholesterol and urinary glucose excretion compared with lean controls (P < 0.01 for each). Histology indicated an overall intact integrity of the retina and aspects of microangiopathy in obese SHR/N-cp rats. ERG revealed intact processing of light signals but significantly decreased amplitudes of b-waves for all (P < 0.01) and of a-waves for some examined light intensities (P < 0.05). Oscillatory potentials were significantly protracted (P < 0.01), whereas amplitudes were not reduced. Microangiopathy and electroretinographic deficits combine to produce an early non-proliferative retinopathy phenotype in the obese SHR/N-cp rats. Thus, this model represents a valuable experimental tool to obtain further insights into the mechanisms of retinopathy in the context of obesity, type 2 diabetes and metabolic syndrome.
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Affiliation(s)
- Matthias Huber
- Institut für Klinische Pharmakologie und Toxikologie, Charité Centrum für Therapieforschung, Charité-Universitätsmedizin Berlin, Berlin, Germany.
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Russell JC, Kelly SE, Diane A, Wang Y, Mangat R, Novak S, Vine DF, Proctor SD. Rimonabant-mediated changes in intestinal lipid metabolism and improved renal vascular dysfunction in the JCR:LA-cp rat model of prediabetic metabolic syndrome. Am J Physiol Gastrointest Liver Physiol 2010; 299:G507-16. [PMID: 20508159 DOI: 10.1152/ajpgi.00173.2010] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
Rimonabant (SR141716) is a specific antagonist of the cannabinoid-1 receptor. Activation of the receptor initiates multiple effects on central nervous system function, metabolism, and body weight. The hypothesis that rimonabant has protective effects against vascular disease associated with the metabolic syndrome was tested using JCR:LA-cp rats. JCR:LA-cp rats are obese if they are cp/cp, insulin resistant, and exhibit associated micro- and macrovascular disease with end-stage myocardial and renal disease. Treatment of obese rats with rimonabant (10 mg.kg(-1).day(-1), 12-24 wk of age) caused transient reduction in food intake for 2 wk, without reduction in body weight. However, by 4 wk, there was a modest, sustained reduction in weight gain. Glycemic control improved marginally compared with controls, but at the expense of increased insulin concentration. In contrast, rimonabant normalized fasting plasma triglyceride and reduced plasma plasminogen activator inhibitor-1 and acute phase protein haptoglobin in cp/cp rats. Furthermore, these changes were accompanied by reduced postprandial intestinal lymphatic secretion of apolipoprotein B48, cholesterol, and haptoglobin. While macrovascular dysfunction and ischemic myocardial lesion frequency were unaffected by rimonabant treatment, both microalbuminuria and glomerular sclerosis were substantially reduced. In summary, rimonabant has a modest effect on body weight in freely eating obese rats and markedly reduces plasma triglyceride levels and microvascular disease, in part due to changes in intestinal metabolism, including lymphatic secretion of apolipoprotein B48 and haptoglobin. We conclude that rimonabant improves renal disease and intestinal lipid oversecretion associated with an animal model of the metabolic syndrome that appears to be independent of hyperinsulinemia or macrovascular dysfunction.
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Affiliation(s)
- James C Russell
- Alberta Institute for Human Nutrition, University of Alberta, Edmonton, Canada.
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Selecting exercise regimens and strains to modify obesity and diabetes in rodents: an overview. Clin Sci (Lond) 2010; 119:57-74. [PMID: 20402668 DOI: 10.1042/cs20090389] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/26/2023]
Abstract
Exercise is part of a healthy lifestyle and frequently is an important component in combating chronic diseases, such as obesity and diabetes. Understanding the molecular events initiated by regular exercise is best studied in laboratory animals, with mice and rats being favoured for a number of reasons. However, the wide variety of rodent strains available for biomedical research often makes it challenging to select an animal strain suitable for studying specific disease outcomes. In the present review we focus on exercise as a management strategy for obesity and diabetes and we discuss: (i) exercise paradigms in humans shown to ameliorate signs and symptoms of obesity and diabetes; (ii) different rodent strains in terms of their advantages, disadvantages and limitations when using specific forms of exercise; (iii) the strengths and weaknesses of commonly used laboratory methods for rodent exercise; and (iv) the unintended consequences of exercise that are often manifested by increased hormonal and oxidative stress responses.
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Banks WA. Gut-brain communications: not the same at all ages. Endocrinology 2010; 151:852-4. [PMID: 20172973 PMCID: PMC3213759 DOI: 10.1210/en.2009-1442] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/19/2022]
Affiliation(s)
- William A Banks
- Geriatric Research Educational and Clinical Center, Veterans Affairs Medical Center-St. Louis and Saint Louis University School of Medicine, Division of Geriatrics, Department of Internal Medicine, St. Louis, Missouri 63106, USA.
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Furuhata Y, Nishihara M, Takahashi M. Effects of pulsatile secretion of growth hormone (GH) on fat deposition in human GH transgenic rats. Nutr Res Rev 2009; 15:231-44. [PMID: 19087406 DOI: 10.1079/nrr200243] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/11/2022]
Abstract
Growth hormone (GH) is an endocrine regulator of glucose and lipid metabolism as well as body growth. GH levels are decreased and a unique pulsatile secretory pattern becomes obvious after puberty particularly in males. Coincidentally with this, males tend to deposit body fat. Experimental and clinical evidence has accumulated that obesity is associated with a decrease in GH levels. A strain of transgenic rats has been generated with severe obesity but normal nose-to-tail length, which has low circulating GH levels without pulsatility (human growth hormone (hGH) transgenic rats). The present review mainly focuses on recent and current work analysing the relationship between the occurrence of obesity and low GH levels and/or the absence of GH pulsatility in this transgenic animal model. This model has elevated blood glucose, non-esterified fatty acid, insulin and leptin levels associated with hyperphagia, suggesting that these rats also carry insulin- and leptin-resistant characteristics. hGH transgenic rats were subjected to a pair-feeding treatment to normalize food intake and chronic GH replacement to normalize GH levels. While the pair-feeding for 8 weeks successfully suppressed body-weight gain, the fat pad : body weight ratio remained very similar to freely-eating control hGH transgenic rats, which indicates the hyperphagia is not the sole contributor to the excess fat accumulation in this model. However, continuous elevation of peripheral hGH levels (approximately 2-fold) for 8 weeks by means of a slow-release vehicle resulted in a significant decrease in the fat mass : body weight ratios by 30 %. This GH treatment altered neither food intake nor body-weight gain. Thus, two characteristic phenotypes observed in the hGH transgenic rats, hyperphagia and obesity, seem to be closely related to GH levels and GH secretory pattern. This relationship might be working in the regulation of changes in seasonal body composition in wild animals.
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Affiliation(s)
- Yasufumi Furuhata
- Department of Veterinary Physiology, Veterinary Medical Science, University of Tokyo, 1-1-1 Yayoi, Bunkyo-ku, Tokyo 113-8657, Japan
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Moralejo DH, Hansen CT, Treuting P, Hessner MJ, Fuller JM, Van Yserloo B, Jensen R, Osborne W, Kwitek AE, Lernmark A. Differential effects of leptin receptor mutation on male and female BBDR Gimap5-/Gimap5- spontaneously diabetic rats. Physiol Genomics 2009; 41:9-20. [PMID: 19996157 DOI: 10.1152/physiolgenomics.00186.2009] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/09/2023] Open
Abstract
Rodents homozygous for autosomal leptin receptor gene mutations not only become obese, insulin resistant, and hyperleptinemic but also develop a dysregulated immune system. Using marker-assisted breeding to introgress the Koletsky rat leptin receptor mutant (lepr-/lepr-), we developed a novel congenic BBDR.(lepr-/lepr-) rat line to study the development of obesity and type 2 diabetes (T2D) in the BioBreeding (BB) diabetes-resistant (DR) rat. While heterozygous lepr (-/+) or homozygous (+/+) BBDR rats remained lean and metabolically normal, at 3 wk of age all BBDR.(lepr-/lepr-) rats were obese without hyperglycemia. Between 45 and 70 days of age, male but not female obese rats developed T2D. We had previously developed congenic BBDR.(Gimap5-/Gimap5-) rats, which carry an autosomal frameshift mutation in the Gimap5 gene linked to lymphopenia and spontaneous development of type 1 diabetes (T1D) without sex differences. Because the autoimmune-mediated destruction of pancreatic islet beta-cells may be affected not only by obesity but also by the absence of leptin receptor signaling, we next generated BBDR.(lepr-/lepr-,Gimap5-/Gimap5-) double congenic rats carrying the mutation for Gimap5 and T1D as well as the Lepr mutation for obesity and T2D. The hyperleptinemia rescued end-stage islets in BBDR.(lepr-/lepr-,Gimap5-/Gimap5-) congenic rats and induced an increase in islet size in both sexes, while T1D development was delayed and reduced only in females. These results demonstrate that obesity and T2D induced by introgression of the Koletsky leptin receptor mutation in the BBDR rat result in islet expansion associated with protection from T1D in female but not male BBDR.(lepr-/lepr-,Gimap5-/Gimap5-) congenic rats. BBDR.(lepr-/lepr-,Gimap5-/Gimap5-) congenic rats should prove valuable to study interactions between lack of leptin receptor signaling, obesity, and sex-specific T2D and T1D.
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Affiliation(s)
- Daniel H Moralejo
- Departments of Comparative Medicine, University of Washington, Seattle, Washington 98195, USA.
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Banks WA. Mouse models of neurological disorders: a view from the blood-brain barrier. Biochim Biophys Acta Mol Basis Dis 2009; 1802:881-8. [PMID: 19879356 DOI: 10.1016/j.bbadis.2009.10.011] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2009] [Revised: 10/20/2009] [Accepted: 10/23/2009] [Indexed: 12/16/2022]
Abstract
The number of disease models that involve an aspect of blood-brain barrier (BBB) dysregulation have increased tremendously. The main factors contributing to this expansion have been an increased number of diseases in which the BBB is known to be involved, an increase in the known functions of the BBB, and an increase in the number of models and tools with which those diverse functions can be studied. In many cases, the BBB may be a target of disease; current thinking would include hypertensive encephalopathy and perhaps stroke in this category. Another category are those diseases in which special attributes of the BBB may predispose to disease; for example, the ability of a pathogen to cross the BBB often depends on the pathogen's ability to invoke transcytotic pathways in the brain endothelial or choroid plexus cell. Of special interest are those diseases in which the BBB may be the primary seat of disease or play a major role in the onset or progression of the disease. An increasing number of diseases are so categorized in which BBB dysfunction or dysregulation plays a major role; this review highlights such roles for the BBB including those proposed for Alzheimer's disease and obesity.
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Affiliation(s)
- William A Banks
- GRECC, Veterans Affairs Medical Center-St. Louis and Saint Louis University School of Medicine, Division of Geriatrics, Department of Internal Medicine, 915 N. Grand Blvd, St. Louis, MO 63106, USA.
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Russell JC, Kelly SE, Vine DF, Proctor SD. Irbesartan-mediated reduction of renal and cardiac damage in insulin resistant JCR : LA-cp rats. Br J Pharmacol 2009; 158:1588-96. [PMID: 19814728 DOI: 10.1111/j.1476-5381.2009.00417.x] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/27/2022] Open
Abstract
BACKGROUND AND PURPOSE Angiotensin II receptor antagonists (ARBs), originally developed for antihypertensive properties, have pleiotropic effects including direct vascular actions. We tested the hypothesis that the ARB irbesartan would be effective against micro- and macrovascular complications of the prediabetic metabolic syndrome using the obese, insulin-resistant JCR : LA-cp rat that exhibits micro- and macrovascular disease with ischaemic myocardial lesions and renal disease. EXPERIMENTAL APPROACH Obese male rats were treated with irbesartan (30 mg.kg(-1).day(-1), incorporated into chow) from 12 to 25 weeks of age. KEY RESULTS Irbesartan treatment caused no change in food intake or body weight. Fasting glycaemic control of the JCR : LA-cp rats was marginally improved, at the expense of increased plasma insulin levels ( approximately 50%). Fasting plasma triglycerides were marginally reduced ( approximately 25%), while cholesterol concentrations were unchanged. Elevated concentrations of adiponectin, monocyte chemotactic protein-1 and plasminogen activator inhibitor-1 were reduced along with severity of glomerular sclerosis. Macrovascular dysfunction (aortic hypercontractile response to noradrenergic stimulus and reduced endothelium-dependent relaxation) was improved and frequency of ischaemic myocardial lesions reduced (62%). CONCLUSIONS AND IMPLICATIONS Irbesartan reduces markers of inflammation and prothombotic status, improves macrovascular function and reduces glomerular sclerosis and myocardial lesions in a model of the metabolic syndrome. Unlike pharmaceutical agents targeted on metabolic dysfunction, irbesartan reduced end-stage disease without major reduction of plasma lipids or insulin. The protective effects appear to be secondary to unknown intracellular mechanisms, probably involving signal transduction pathways. Understanding these would offer novel pharmaceutical approaches to protection against cardiovascular disease.
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Affiliation(s)
- J C Russell
- Alberta Institute for Human Nutrition, University of Alberta, Edmonton, Canada.
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Shi D, Dyck MK, Uwiera RRE, Russell JC, Proctor SD, Vine DF. A unique rodent model of cardiometabolic risk associated with the metabolic syndrome and polycystic ovary syndrome. Endocrinology 2009; 150:4425-36. [PMID: 19470707 DOI: 10.1210/en.2008-1612] [Citation(s) in RCA: 40] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/19/2022]
Abstract
Polycystic ovary syndrome (PCOS) is characterized by hyperandrogenism, oligo-/anovulation, and polycystic ovarian morphology and is a complex endocrine disorder that also presents with features of the metabolic syndrome, including obesity, insulin resistance, and dyslipidemia. These latter symptoms form cardiometabolic risk factors predisposing individuals to the development of type 2 diabetes and cardiovascular disease (CVD). To date, animal models to study PCOS in the context of the metabolic syndrome and CVD risk have been lacking. The aim of this study was to investigate the JCR:LA-cp rodent as an animal model of PCOS associated with the metabolic syndrome. Metabolic indices were measured at 6 and 12 wk, and reproductive parameters including ovarian morphology and estrous cyclicity were assessed at 12 wk or adulthood. At 6 wk of age, the cp/cp genotype of the JCR:LA-cp strain developed visceral obesity, insulin resistance, and dyslipidemia (hypertriglyceridemia and hypercholesterolemia) compared with control animals. Serum testosterone concentrations were not significantly different between groups at 6 wk of age. However, at 12 wk, the cp/cp genotype had higher serum testosterone concentrations, compared with control animals, and presented with oligoovulation, a decreased number of corpora lutea, and an increased number of total follicles, in particular atretic and cystic follicles. The cardiometabolic risk factors in the cp/cp animals were exacerbated at 12 wk including obesity, insulin resistance, and dyslipidemia. The results of this study demonstrate that the JCR:LA-cp rodent may be a useful PCOS-like model to study early mechanisms involved in the etiology of cardiometabolic risk factors in the context of both PCOS and the metabolic syndrome.
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Affiliation(s)
- Danni Shi
- Alberta Institute for Human Nutrition, University of Alberta, Edmonton, Alberta, Canada
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Osborn O, Sanchez-Alavez M, Brownell SE, Ross B, Klaus J, Dubins J, Beutler B, Conti B, Bartfai T. Metabolic characterization of a mouse deficient in all known leptin receptor isoforms. Cell Mol Neurobiol 2009; 30:23-33. [PMID: 19582570 DOI: 10.1007/s10571-009-9427-x] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/20/2008] [Accepted: 06/05/2009] [Indexed: 01/19/2023]
Abstract
We have characterized a newly generated mouse model of obesity, a mouse strain deficient in all five previously described leptin receptor isoforms. These transgenic mice, named the db (333)/db (333) mice, were identified from an ENU mutagenesis screen and carry a point mutation in the seventh exon of the db gene encoding the leptin receptor, resulting in a premature stop codon (Y(333)Stop) and gene product that lacks STAT signaling domains. db (333)/db (333) mice have a morbidly obese phenotype, with body weights diverging from wild type as early as 4 weeks of age (P < 0.05). To determine the contribution of the short isoforms of the leptin receptor in this metabolic phenotype, we performed an extensive metabolic characterization of the db (333)/db (333) mouse in relation to the well-characterized db/db mouse lacking only the long form of the leptin receptor. db (333)/db (333) mice have similar endocrine and metabolic parameters as previously described in other leptin receptor transgenic mice including db/db mice that lack only the long isoform of the leptin receptor. However, db (333)/db (333) mice show a subtle trend toward higher body weight and insulin levels, lower oxygen, carbon dioxide production, respiratory exchange ratio (RER), and temperature than db/db mice suggesting the short isoforms may play an additional role in energy homeostasis.
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Affiliation(s)
- Olivia Osborn
- Molecular and Integrative Neurosciences Department, The Harold L. Dorris Neurological Research Institute, The Scripps Research Institute, La Jolla, CA 92037, USA.
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Heep H, Hilken G, Hofmeister S, Wedemeyer C. Osteoarthitis of leptin-deficient ob/ob mice in response to biomechanical loading in micro-CT. Int J Biol Sci 2009; 5:265-75. [PMID: 19343112 PMCID: PMC2664549 DOI: 10.7150/ijbs.5.265] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2009] [Accepted: 03/14/2009] [Indexed: 01/31/2023] Open
Abstract
Objective: Mechanotransduction is the mechanism that due to reacting chondrocytes on biomechanical loading of body mass. Higher biomechanical loading lead to increased degeneration of chondrocytes, whereas moderate loading is protecting. This suggests that body fat regulates bone metabolism first by means of hormonal factors and second that the effects of muscle and loading are signaling factors in mechanotransduction. Leptin, a peptide hormone produced predominantly by white fat cells, is one of these hormonal factors. The aim of this study was to investigate and measure the different effects of weight-bearing on trabecular bone formation in mice without the stimulation of leptin and with or without osteoarthritis. Materials and methods: 40 C57BL/ 6J ob/ob-mice in the age of 20 weeks have been devided into two groups with an ad-libitum-diet and with reduced diet. The hip- and knee-joints have been examinated in micro-CT-scan and histomorphologically. Results: Animals with an ad-libitum-diet were found to increase body weight significantly at the age of six weeks in comparison with lean mice. At the age of twenty weeks the obese mice were almost twice as heavy as the lean mice. Significant statistical differences are shown between the two groups for body weight and bone mineral density. Examination of trabecular bone in micro-CT revealed that the only statistically significant difference between the two groups was the trabecular number for the proximal femur. High weight-bearing insignificantly improved all trabecular bone parameters in the obese mice. Correlation was found between trabecular number and bone mineral density on the one hand and body weight on the other hand. The correlation between body weight and osteoarthritis shows a significant increase in grade of osteoarthritis as body weight increases in hip-joint and knee-joint but not in osteoarthritis-positive (OP) versus osteoarthritis-negative (ON) mices. The correlation of the hip-joint between micro-CT data and body weight shows an increase in these data as body weight increases in OP mices. The correlation of the hip-joint between micro-CT data and osteoarthritis shows a decrease in these data as osteoarthritis increases in OP mices. The correlation of the knee-joint between micro-CT data and body weight shows differencies between ON and OP mices. The correlation of the knee-joint between micro-CT data and osteoarthritis shows an increase in these data as osteoarthritis increases in OP mices. Conclusion: biomechanical loading led to decreased bone mineral density by a decrease in the number of trabeculae. Trabecular thickness was not increased by biomechanical loading in growing mice. Decreased body weight in leptin-deficient mice protects against bone loss. This finding is consistent with the principle of light-weight construction of bone. Differences in osteoarthritis-positive and osteoarthritis-negative mices show the eventual importance of diet in leptin-deficience. It is not possible to conclude that these results also apply to human beings.
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Affiliation(s)
- Hansjoerg Heep
- Department of Orthopaedics, University of Duisburg-Essen, Pattbergstrasse, Germany.
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Abstract
Evolutionary considerations relating to efficiency in reproduction, and survival in hostile environments, suggest that body energy stores are sensed and actively regulated, with stronger physiological and behavioral responses to loss than gain of stored energy. Many physiological studies support this inference, and suggest that a critical axis runs between body fat and the hypothalamus. The molecular cloning of leptin and its receptor-projects based explicitly on the search for elements in this axis-confirmed the existence of this axis and provided important tools with which to understand its molecular physiology. Demonstration of the importance of this soma-brain reciprocal connection in body weight regulation in humans has been pursued using both classical genetic approaches and studies of physiological responses to experimental weight perturbation. This paper reviews the history of the rationale and methodology of the cloning of leptin (Lep) and the leptin receptor (Lepr), and describes some of the clinical investigation characterizing this axis.
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Affiliation(s)
- R L Leibel
- Division of Molecular Genetics and Naomi Berrie Diabetes Center, Columbia University College of Physicians and Surgeons, New York, NY 10032, USA.
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