Preclinical models for obesity research

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amphetamine 10433 leading to increased food intake, whereas the other expresses proopiomelanocortin (POMC) and cocaine- and amphetamine -regulated transcript (CART), resulting in reduced food intake. These neurons are key targets for leptin,
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obesity 57 Title: Disease Models & MechanismsPreclinical models for obesity researchPerry BarrettJulian G. MercerPeter J. MorganForesterhill, Aberdeen AB25 2ZD, UKPublication date
obesity 289 11/2016Publication date (pmc-release): 11/2016AbstractABSTRACTA multi-dimensional strategy to tackle the global obesity epidemic requires an in-depth understanding of the mechanisms that underlie this complex condition.
obesity 726 its root causes, particularly the over-consumption of calories and unbalanced diets. As with human obesity , obesity in rodents is the result of complex gene–environment interactions. Here, we review the traditional
obesity 735 causes, particularly the over-consumption of calories and unbalanced diets. As with human obesity, obesity in rodents is the result of complex gene–environment interactions. Here, we review the traditional
obesity 864 result of complex gene–environment interactions. Here, we review the traditional monogenic models of obesity , their contemporary optogenetic and chemogenetic successors, and the use of dietary manipulations and
obesity 1035 and the use of dietary manipulations and meal-feeding regimes to recapitulate the complexity of human obesity . We critically appraise the strengths and weaknesses of these different models to explore the underlying
obesity 1309 behaviours such as appetite control. We also discuss the use of these models for testing and screening anti- obesity drugs, beneficial bio-actives, and nutritional strategies, with the goal of ultimately translating these
obesity 1458 nutritional strategies, with the goal of ultimately translating these findings for the treatment of human obesity .PrecisSummary: We review genetic models of obesity, their optogenetic and chemogenetic successors, and
obesity 1509 translating these findings for the treatment of human obesity.PrecisSummary: We review genetic models of obesity , their optogenetic and chemogenetic successors, and the use of dietary manipulations and meal-feeding
obesity 1663 successors, and the use of dietary manipulations and meal-feeding regimes.IntroductionThe scale of the global obesity epidemic demands a multidisciplinary response that utilizes all of the resources available to biomedical
obesity 2144 Observatory; http://www.who.int/gho/ncd/risk_factors/overweight/en/). In addition, the prevalence of obesity has more than doubled since 1980 (http://www.who.int/mediacentre/factsheets/fs311/en/). Obesity is a
obesity 2843 (http://www.who.int/gho/ncd/en/). Because the overconsumption of energy lies at the heart of the increasing prevalence of obesity worldwide, improving our knowledge of the fundamental mechanisms of food intake and energy balance is
obesity 5383 and cardiovascular control.Preclinical animal models are a key research tool in the quest to combat obesity , an effort that is likely to be ongoing for decades to come. One thrust of this research focuses on
obesity 5528 ongoing for decades to come. One thrust of this research focuses on laboratory (mainly rodent) models of obesity . The currently available models are either genetic, such as spontaneous mutants or transgenic lines,
obesity 5762 latter are the product of the same gene–environment interactions that underlie the majority of human obesity cases. Spontaneous-mutant and genetically engineered rodents provide valuable models of extreme obesity.
obesity 5866 obesity cases. Spontaneous-mutant and genetically engineered rodents provide valuable models of extreme obesity . Such models have been used with considerable success to examine the contribution of individual genes
obesity 6211 obvious importance of individual genes involved in energy homeostasis (e.g. [101]), most cases of human obesity are polygenic rather than monogenic in nature, with contributions from different susceptibility genes.
obesity 6392 different susceptibility genes. Progress has been made with the development of polygenic diet-induced obesity (DIO) models, but more work is required to better mimic human behaviours. This could include greater
obesity 6961 restricted to a compulsory dietary change in isolation.In this Review, we discuss various models of obesity , beginning with the traditional genetic models and the DIO models that involve intake of human foods,
obesity 8011 control food-intake behaviour, the disruption of which ultimately leads to altered energy balance and obesity . These new models should advance understanding of relevant pathways. We discuss the strengths and weaknesses
obesity 8289 evidence base and lead to the development of therapeutic interventions.Traditional genetic models of obesity Human obesity is a complex genetic trait in which multiple genes and pathways contribute to overall energy
obesity 8302 and lead to the development of therapeutic interventions.Traditional genetic models of obesityHuman obesity is a complex genetic trait in which multiple genes and pathways contribute to overall energy balance.
obesity 8479 contribute to overall energy balance. Genome-wide association studies (GWAS) have shown that the risk of obesity is determined by the cumulative contribution of many allelic variants ([86]), indicative of obesity
obesity 8579 obesity is determined by the cumulative contribution of many allelic variants ([86]), indicative of obesity being a polygenic trait. Despite this, the biggest advances in our mechanistic understanding of appetite
obesity 8809 balance have stemmed from studies of monogenic mouse models. There are over 200 mouse models of monogenic obesity ([85]; [61]; [99]). Some of these arose as natural mutations (for example, the ob/ob mouse), whereas
obesity 9156 (TrkB; also known as tropomyosin receptor kinase B) knock-in mouse ([23]) and the FTO (fat mass and obesity -associated protein) overexpression mouse ([30]). The most important obese model is the ob/ob mouse.
obesity 10993 Npy and Agrp genes also failed to induce a phenotype ([75]), whereas overexpression of Agrp led to obesity ([46]). The PVN is another important area, receiving neuronal projections from the ARC (including NPY/AgRP
obesity 11698 this gene results in an obese phenotype in mice ([49]). In support of a role for this gene in human obesity , MC4R mutations are relatively common in obese individuals ([43]). Fig. 1.Brain regions involved in
obesity 14213 in the field is now increasingly shifting from what we might consider as useful ‘mouse models of obesity ’ towards the concept of ‘mouse models to understand obesity’, where the model may not itself be
obesity 14277 consider as useful ‘mouse models of obesity’ towards the concept of ‘mouse models to understand obesity ’, where the model may not itself be obese, but gives access to energy-balance mechanisms.Models of
obesity 14481 mechanisms.Models of DIOChanges in the human food environment (see Box 2) and the rise in the prevalence of global obesity have increased interest in rodent models of DIO and their applications. These models feature relatively
obesity 14600 increased interest in rodent models of DIO and their applications. These models feature relatively subtle obesity phenotypes in which body fat accumulates over a relatively long time period, although the detrimental
obesity 15195 even if only by a small proportion. Box 2. The human food environmentThe global rise in prevalence of obesity over the last four decades in relatively (genetically) stable human populations emphasises that most
obesity 15310 the last four decades in relatively (genetically) stable human populations emphasises that most human obesity represents the outcome of gene–environment interactions. Significantly, there has been a revolution
obesity 17665 diets supplied by Research Diets, Inc. (D12451 and D12492). Examples of other diets used to induce obesity include a pure fat supplement to a chow diet (providing a measure of choice), or fat mixed with chow
obesity 22453 faecal microbiota ([53]). Reward mechanisms are likely to play a major role in cafeteria-diet-induced obesity . This was further evidenced by a study reporting that a cafeteria diet of sweet and savoury human foods
obesity 22588 by a study reporting that a cafeteria diet of sweet and savoury human foods led to weight gain and obesity in male Wistar rats (fed for 18-23 h per day over a 40-day period), and these metabolic effects were
obesity 23675 increase in the number of meals due to drinking of sugary liquid without a change in meal size. This obesity model has the attraction of inducing the overconsumption of calories while feeding to appetite on a
obesity 24908 responsive meal-feeding behaviours. The marginal caloric overconsumption that lies at the root of much human obesity is based around choice and the provision of relatively regular meals, snacks and caloric beverages.
obesity 25737 feeding has been used to study hunger and satiety, and the brain response to food ingestion, rather than obesity . For example, this regime has been used to examine hypothalamic and brainstem activation in anticipation
obesity 27452 continuous) access to the food, and that this non-homeostatic consumption can occur independently of obesity ([34]). In a binge-like eating model in which continuous access to chow was supplemented for 2 h with
obesity 28818 case without increased body adiposity ([6]).Impact of maternal diet on offspringIn humans, maternal obesity contributes to a higher risk of obesity, metabolic dysfunction, type 2 diabetes and cardiovascular disease
obesity 28858 ([6]).Impact of maternal diet on offspringIn humans, maternal obesity contributes to a higher risk of obesity , metabolic dysfunction, type 2 diabetes and cardiovascular disease in offspring ([100]), and the proportion
obesity 32133 programming. Rodents will continue to be valuable models in which to determine the effect of maternal diet and obesity on physiological and molecular consequences in offspring. These models will be particularly useful in
obesity 34191 later diet choice ([20]). It is therefore important to accurately assess behavioural phenotypes in obesity models. However, many preclinical studies still limit food-intake data to extended periods (hours or
obesity 35857 (Fig. 2).The dietary manipulations and feeding regimes outlined above are frequently used to induce obesity or feeding behaviours of interest in otherwise normal rodents. These animals can be drawn from inbred
obesity 36310 reflecting relative susceptibility or resistance to DIO, a situation assumed to reflect human polygenic obesity . The various diets and feeding regimes can also be used as tools to manipulate spontaneous genetic and
obesity 36455 regimes can also be used as tools to manipulate spontaneous genetic and genetically manipulated models of obesity to interrogate specific mechanisms involved in the gene–environment interplay underlying obesity.Modulation
obesity 36554 obesity to interrogate specific mechanisms involved in the gene–environment interplay underlying obesity .Modulation of genetic models: new approachesAs described earlier, transgenic knockout animals have been
obesity 40033 specific neurons or neuronal subsets and feeding behaviour, transforming how we can use animal models in obesity research.Chemogenetics involves the targeted introduction of an engineered gene into specific cell types
obesity 47717 technologies are providing new animal models that take us way beyond the single-gene-mutation models of obesity , and are starting to give us a glimpse into real-time control of food-intake behaviour through temporally
obesity 47910 behaviour through temporally and spatially defined neural circuits.Strengths and limitations of preclinical obesity modelsIn assessing the comparative strengths and weaknesses of the models described above, a key consideration
obesity 48520 balance and appetite mechanisms? If the former, how relevant are these rather simple models to human obesity , a multifaceted condition with infinite root causes, trajectories and outcomes? Another limitation could
obesity 49037 many such models are not actually obese, and the molecular manipulations employed might not induce obesity .Although recent reports, outlined above, have begun to move dietary obesity models towards manipulations
obesity 49113 employed might not induce obesity.Although recent reports, outlined above, have begun to move dietary obesity models towards manipulations that more closely mimic the human situation (developments that should be
obesity 50448 energy expenditure (by calorimetry) or as physical or locomotor activity. A sophisticated model of obesity might also build in graded levels of sedentariness or activity, but again there would be a need to move
obesity 50649 need to move beyond a binary choice of extremes of activity level.The strength of monogenic models of obesity has been in the identification of specific genes and their role in the regulation of energy balance.
obesity 51180 important to energy balance, no single molecular target has led to the creation of a blockbuster drug for obesity . This is because discrete neural circuits rather than single molecular targets underlie the control
obesity 51403 behaviour. Furthermore, where specific molecular targets are important to food-intake behaviour and obesity , they are also important to other behaviours and physiological responses, and targeting these gives
obesity 51747 receptor is also thought to stimulate penile erection ([1]). This underscores the need for new models of obesity that enable both temporal and spatial dissection of the neural circuits involved in food-intake behaviour
obesity 51865 enable both temporal and spatial dissection of the neural circuits involved in food-intake behaviour and obesity . From the more sophisticated tools that we now have, a more comprehensive picture of the neural pathways
obesity 52116 taking us beyond the simple ‘one-drug-targeting’ and ‘one-receptor-subtype’ concepts to address obesity as a behavioural deficiency. In turn, this is challenging us to think more radically about drug development
obesity 52323 development in the future, as discussed below.Therapeutics and translation: the future for preclinical obesity researchPreclinical research into obesity has the potential to drive the development and characterisation
obesity 52365 below.Therapeutics and translation: the future for preclinical obesity researchPreclinical research into obesity has the potential to drive the development and characterisation of dietary interventions, as well as
obesity 52790 lifestyle change, an aspect that is not easily mimicked in experimental animals.Diet-based strategies for obesity and weight management include weight loss in the obese, where even small amounts of weight loss can
obesity 53103 achieved by caloric restriction. For overweight individuals who might be on an upward trajectory towards obesity if they cannot limit future weight gain, prevention of weight gain is a viable target. Suitable dietary
obesity 54270 earlier, the focus of drug effects is mainly food intake, the most common pharmacological target for anti- obesity drugs, although secondary metabolic disease is also of therapeutic interest. Candidate drugs are generally
obesity 54660 models and dietary manipulations into a testing regime.Development of therapeutics for the treatment of obesity has relied upon traditional approaches to drug development. This has involved targeting specific receptors
obesity 54967 involved in the physiological response. Invariably, this offers a low level of discrimination; thus, anti- obesity therapeutics often elicit many unwanted side effects. Also, the behaviours involved, such as appetite
obesity 55298 achieve the level of therapeutic efficacy and benefit desired. For these reasons, many drugs aimed at the obesity market have ultimately been withdrawn from the market after only a short period ([54]). Animal models
obesity 55551 as optogenetics and chemogenetics to explore the neural circuits that control behaviours relevant to obesity are leading to new ways of thinking about the development of therapeutics, as well as new methods of
obesity 56214 the new animal models involving opto- and chemo-genetics to explore the neural circuits underlying obesity are key to defining where and how the designer targets are located.The future for preclinical models
obesity 56326 key to defining where and how the designer targets are located.The future for preclinical models in obesity research should also see more sophisticated phenotyping of feeding behaviours, including food choice
obesity 56518 including food choice and intake microstructure, being applied across a range of monogenic and polygenic obesity models, as well as to contemporary genetically manipulated animals designed to give access to detailed
obesity 57915 relative naivety of current approaches to studying the influence of diet, choice and dietary components on obesity and energy homeostasis are unhelpful for advancing our mechanistic understanding of these complex processes
obesity 58099 understanding of these complex processes and for developing therapeutics. Over the last decade, the field of obesity research has moved on from an over-reliance on knockout rodent models with an obese phenotype towards
obesity 58437 circuits involved in the control of food intake and energy balance. The future of preclinical research in obesity should be based on more realistic models of feeding and obesity, better characterisation of feeding
obesity 58501 The future of preclinical research in obesity should be based on more realistic models of feeding and obesity , better characterisation of feeding behaviour, and the application of molecular and genetic tools to

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