Common Human Obesity Research Articles

An Overview of Rodent Models of Obesity and Type 2 Diabetes.

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 maintainingexcessive 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.

The Effect of Diet-induced Obesity on Toxicological Parameters in the Polygenic Sprague-Dawley Rat Model.

The obese rodent serves as an indispensable tool for proof-of-concept efficacy and mode-of-action pharmacology studies. Yet the utility of this disease model as an adjunct to the conventional healthy animal in the nonclinical safety evaluation of anti-obesity pharmacotherapies has not been elucidated. Regulatory authorities have recommended employing disease models in toxicology studies when necessary. Our study investigated standard and exploratory toxicology parameters in the high-fat diet (HFD)-induced obese, polygenic Sprague-Dawley rat model in comparison to chow diet (CD)-fed controls. We sought to establish feasibility of the model for safety testing and relevance to human obesity pathophysiology. We report that both sexes fed a 45% kcal HFD for 29 weeks developed obesity and metabolic derangements that mimics to a certain extent, common human obesity. Minor clinical pathologies were observed in both sexes and considered related to CD versus HFD differences. Histopathologically, both sexes exhibited mild obesity-associated findings in brown and subcutaneous white fat, bone, kidneys, liver, lung, pancreas, salivary parotid glands, and skeletal muscle. We conclude that chronic HFD feeding in both sexes led to the development of an obese but otherwise healthy rat. Therefore, the diet-induced obese Sprague-Dawley rat may serve as a suitable model for evaluating toxicity findings encountered with anti-obesity compounds.

Gastro-oesophageal reflux - an important causative factor of severe tooth wear in Prader-Willi syndrome?

BackgroundPrader-Willi syndrome (PWS) is the most common genetic human obesity syndrome and is characterized by hypotonia, endocrine disturbances, hyperphagia, obesity and mild mental retardation. Oral abnormalities, such as decreased salivary flow rates and extreme tooth wear, have also been described. Studies have shown a significant increase in reflux symptoms in individuals with obstuctive sleep apnoea syndrome and increased BMI, both of which are typical findings in PWS. Gastro-oesophageal reflux disease (GORD) has been identified in some individuals with PWS and is a significant intrinsic factor in dental tooth wear. The aim of this study was therefore to estimate the prevalence of GORD in adults and children and to evaluate a possible correlation between GORD and tooth wear in adults with PWS. They were all registered at the TAKO-centre.ResultsTwenty-nine individuals, 17 adults with a mean age of 32.6 years (range 18–48) and 12 children with a mean age of 8.8 years (range 3–17), agreed to undergo 24-hour oesophageal pH monitoring, and 90% of those enrolled managed to complete the examination. Four children and eleven adults were diagnosed with pathological gastro-oesophageal reflux, which is defined as acid exposure (pH less than 4) more than 3.6 or 4.3 percent of the time, respectively. Manometry performed in the adult group showed a pathologically high lower oesophageal sphincter pressure in four of the five individuals who had normal oesophageal pH values (pH under 4 less than 4.3% of the time). The two groups (reflux and non-reflux) were well balanced according to BMI, genotype, tooth grinding and hyposalivation. However, twice as many individuals in the reflux group as in the non-reflux group reported high consumption of acidic foods and drinks. Increased tooth wear was significantly correlated with GORD in the two groups (reflux n=6 and non-reflux n=6).ConclusionsThe prevalence of gastro-oesophageal reflux is high in individuals with PWS. Tooth wear was strongly associated with GORD and acidic drinks, and both may be important aetiological factors underlying the extreme tooth wear in this group. Our data suggest a need for routine screening for GORD and dental wear in young individuals with Prader-Willi syndrome.

Expression of New Loci Associated With Obesity in Diet‐Induced Obese Rats: From Genetics to Physiology

Genome-wide association studies (GWAS) are a powerful tool for revealing genes associated with common human obesity. New loci associated with obesity have recently been reported, but their function and metabolic implications remain to be elucidated. In order to begin identifying the role of some of these obesity-related loci, the closest genes to the polymorphism of each locus were selected and their expression was compared in the hypothalamus, adipose tissue, liver, soleus muscle, and extensor digitorum longus muscle (EDL) of Long-Evans rats maintained on chow or a high-fat diet (HFD) for 6 weeks. From a total of 19 genes analyzed, seven genes (ETV5, FTO, GNPDA2, KCTD15, TMEM18, MC4R, and SH2B1) were down-regulated in the hypothalamus of HFD compared to chow-fed rats. In adipose tissue of rats fed on HFD, the mRNA levels of BCDIN3, KCTD15, and SULT1A1 were down-regulated, whereas those of MTCH2, PTER, and TUFM were up-regulated. In the liver, three genes were up-regulated (PTER, SULT1A1, and TUFM) in HFD relative to chow-fed rats, and TMEM18 was down-regulated. Finally, in soleus muscle of HFD-fed rats, BCDIN3, BDNF, and TMEM18 were down-regulated, and in the EDL muscle SH2B1 and TUFM were up-regulated. mRNA levels in the hypothalamus were compared between fed and fasted states, and only KCTD15 was down-regulated during fasting when fed a chow diet. In conclusion, novel genes found to be associated with obesity are regulated by a HFD and the mRNA levels of KCTD15 is dependent on the nutritional status. These results suggest a potential role of these genes in the regulation of energy balance.

The Niemann‐Pick C1 gene interacts with a high‐fat diet and modifying genes to promote weight gain

The Niemann-Pick C1 gene in both humans (NPC1) and mice (Npc1) is localized to chromosome 18 and encodes a large complex membrane-boundproteinwith extensive structural homologywith members of the resistance-nodulation-division (RND) family of prokaryotic permeases [Davies et al., 2000; Davies and Ioannou, 2000]. Although exact function of the NPC1 protein remains undefined, studies indicate that this protein has a central role in regulating the transport of cholesterol and fatty acids from late endosomes/lysosomes to other cellular compartments and therefore maintaining cellular, tissue, and whole body lipid homeostasis [Xie et al., 1999;Chen et al., 2005]. Since themid 1980 sec, theNPC1 gene has been investigated only in relation to a rare autosomalrecessive lipid-storage disorder characterized by clinical manifestations involving the liver and brain [Garver et al., 2007]. However, a recent genome-wide association study has revealed that theNPC1 gene is also associated with common childhood and adult obesity, a disparate metabolic disease that has now reached epidemic proportions worldwide [Meyre et al., 2009]. Consistent with this report, subsequent studies performed using BALB/cJ and hybrid BALB/cJ-C57BL/6J Npc1 mouse models found that Npc1 gene haploinsufficiency promotes weight gain, therefore validating the NPC1 gene as a legitimate candidate responsible for common human obesity [Jelinek et al., 2010a,b]. The present research letter provides evidence indicating that theNpc1 gene interacts with both a high-fat diet and modifying genes to promote weight gain, consistent with common human obesity being a complex multifactorial disease. A breeding pair of BALB/cJ Npc1 heterozygous (Npc1þ/ ) mice and C57BL/6JNpc1 normal (Npc1þ/þ) mice was obtained from the Jackson Laboratory (Bar Harbor, ME). These mice were bred to generate pure BALB/cJ Npc1þ/þ and Npc1þ/ mice and hybrid BALB/cJ-C57BL/6J Npc1þ/þ and Npc1þ/ mice as previously described [Jelinek et al., 2010a,b]. The Npc1 genotype was determined at the time of weaning (21 days) using a polymerase chain reaction [Loftus et al., 1997]. One week after weaning, the male Npc1þ/þ and Npc1þ/ mice were placed on either a low-fat diet (10–14% kcal from fat) or high-fat diet (45% kcal from fat), maintained and fed (ad libitum), and weighed at 10 weeks of age. The mice were initially produced and maintained at the University of Arizona Animal Care Facility and subsequently at the University of New Mexico Health Sciences Center Animal Resources Facility in accordance to the Institutional Animal Care and Use Committee. The results showed no significant difference in the body weights of BALB/cJNpc1þ/þ andNpc1þ/ mice fed a low-fat diet. However, when these BALB/cJ mice were fed a high-fat diet, Npc1þ/ mice had significantly increased (8.8%) body weights compared to Npc1þ/þ mice at 10 weeks of age, indicating an Npc1 gene–diet interaction in relation to weight gain (Fig. 1A). Similarly, when BALB/cJ-C57BL/6JNpc1þ/þ andNpc1þ/ mice were fed a high-fat diet, Npc1þ/ mice had significantly increased (37.4%) body weights compared to Npc1þ/þ mice at 10 weeks of age, again indicating an Npc1 gene–diet interaction in relation to weight gain (Fig. 1B). However, unlike BALB/cJ Npc1þ/ mice fed a low-fat diet, BALB/cJ-C57BL/6J Npc1þ/ mice fed a low-fat diet also had significantly increased (16.1%) body weights compared to BALB/cJ-C57BL/6J Npc1þ/þ mice at 10 weeks of age, therefore indicating an Npc1 gene–modifying gene interaction in relation to weight gain. Together, BALB/cJ-C57BL/6J Npc1þ/ mice fed a high-fat diet had significantly increased (51%) body weights compared to BALB/cJ-C57BL/6J Npc1þ/þ mice fed a low-fat

Dietary Therapy for Obesity: An Emperor With No Clothes

The prevalence of obesity has increased substantially in the past 3 decades and is projected to increase further in the years ahead. It increases the risk of diabetes mellitus, dyslipidemia, hypertension, cardiovascular disease, sleep apnea, nonalcoholic hepatic steatosis, gallbladder disease, osteoarthritis, and cancer. The prevention and treatment of obesity is, therefore, a leading challenge facing public health and medicine in the 21st century. Two stereotypes have dominated thinking in public health, medicine, and the media about obesity. The first stereotype is that the recent surge in prevalence of obesity reflects almost entirely environmental and psychological factors and excludes an important contribution of genetic biological factors. The second stereotype is that obesity should and can be treated primarily by diet and behavioral modification. In this review, I challenge these tenets. I summarize evidence for a strong genetic neurobiological contribution to adiposity and body weight and assert that common human obesity is, like essential hypertension, a complex multifactorial disease where genetic factors promote sensitivity or resistance to obesity in a toxic environment. This concept of a genetic resistance versus sensitivity to obesity helps explain why many people remain thin in a toxic environment whereas others develop profound obesity. I then discuss evidence that dietary therapy for obesity generally fails to achieve weight loss maintenance. There is mounting indication that the high rate of relapse from weight loss during dietary therapy occurs because of compensatory biological adaptations that promote lack of compliance and effectiveness. Relapse from weight loss during dietary therapy is not caused simply by lack of discipline and will power. Finally, I briefly discuss the alternatives to dietary and behavioral therapy, namely bariatric surgery and pharmacotherapy. As a prelude to my critique of dietary therapy, I begin with a discussion of the role of genetic neurobiological factors in obesity. The surge …

Brain responses to obesogenic diets and diet-induced obesity

Rodent models of diet-induced obesity (DIO) mimic common human obesity more accurately than obese single-gene mutation lines, such as the ob/ob mouse. Sprague-Dawley rats sourced in the UK develop obesity when fed a high-energy diet, but susceptibility to DIO is normally distributed, as might be anticipated for a polygenic trait in an outbred population, in contrast to reports in the literature using ostensibly the same strain of rats sourced in the USA. Nevertheless, the responses of these rats to solid and liquid obesogenic diets are very similar to those reported elsewhere, and this model of DIO has much to commend it as a vehicle for the mechanistic study of susceptibility to DIO, development and reversal of obesity on solid and liquid diets and the response of peripheral and central energy balance systems to the development of obesity and to the obesogenic diets themselves. In general, hypothalamic energy-balance-related systems respond to obesogenic diets and developing obesity with activity changes that appear designed to counter the further development of the obese state. However, these hypothalamic changes are apparently unable to maintain body weight and composition within normal limits, suggesting that attributes of the obesogenic diets either evade the normal regulatory systems and/or engage with reward pathways that override the homeostatic systems. Since diets are a risk factor in the development of obesity, it will be important to establish how obesogenic diets interact with energy-balance pathways and whether there is potential for diets to be manipulated with therapeutic benefit.

DIETARY THERAPY FOR OBESITY IS A FAILURE AND PHARMACOTHERAPY IS THE FUTURE: A POINT OF VIEW

1. We confront an escalating epidemic of obesity. The precipitating factors are undoubtedly environmental and include increasingly immobilizing occupations and technologies and an abundance of food in many societies. This understanding has led to the view that the obesity epidemic is entirely environmental and that obesity should be treated primarily by behavioural (particularly dietary) therapy. That is, a prominent view is that common human obesity is an environmental disease and is not, like hypertension and hypercholesterolaemia, a complex, multifactorial disease resulting from the interaction of genetic and environmental variance. 2. In the first part of the present article, I argue that this view has obscured a strong genetic-biological contribution to body mass and adiposity in humans. This is supported by studies of adopted children and twins and by rare Mendelian forms of human obesity. 3. In the second part of the present article, I argue that behavioural therapy for maintenance of weight loss is, overall, a failure. The overwhelming majority of people who lose weight by dieting regain it in several years. Many have blamed this on patients' lack of will-power and discipline, but there is mounting evidence that biological mechanisms contribute substantially to relapse from weight loss during dietary therapy. These include a compensatory decrease in energy expenditure during dieting and compensatory adaptations that would be expected to increase appetite. 4. We live in an era of evidence-based medicine; the evidence does not support the efficacy of diet therapy for maintenance of weight loss in obesity. This has been true for decades, despite efforts to improve behavioural therapy. Despite what we want to happen, this will not likely improve, because the failure of diet therapy for the maintenance of weight loss in obesity is probably primarily biological, not behavioural. 5. In the third part of the article, I argue that drugs will increasingly dominate the treatment of obesity. We are in the midst of a revolution in understanding the biological regulation of appetite and metabolism that began with the pioneering discovery of leptin. In my judgement, this will lead inevitably to the development of safe, effective therapy for obesity. 6. This transformation from behavioural to pharmacological therapy proved true with hypertension and hypercholesterolaemia. Pharmacological therapy for hypertension and hypercholesterolaemia followed the discovery of the pathways regulating arterial pressure and cholesterol biosynthesis, respectively, and behavioural therapy for these diseases is now secondary. Despite the skepticism, I predict that the same transformation will occur in the treatment of obesity. This is not to argue against the need for environmental modification to slow the escalating epidemic of obesity, but it is to suggest that future effective treatment of common human obesity should recognize the limitations of dietary therapy for maintenance of weight loss and the promise of pharmacological therapy.

Epistasis among genes is a universal phenomenon in obesity:: evidence from rodent models

Identification of genes that cause spontaneous mendelian obesity in mice began a new age of obesity studies with the ability to discover mechanisms underlying the biological causes of obesity. Studies in humans quickly confirmed that orthologs of mouse obesity genes also cause monogenic (mendelian) forms of human obesity. However, the six genes that cause mendelian forms of human obesity (leptin, leptin receptor, proopiomelanocortin, prohormone convertase, melanocortin receptor-4, and peroxisome proliferator-activated receptor) each have insignificant effects on common human obesity.1 Common obesity is inherited as a polygenic (quantitative) trait influenced by many genetic and environmental variables. Thus, alleles of genes causing common forms of human obesity are unlikely to produce mendelian pedigrees showing segregation of mutations with obesity. Genes for common obesity will produce small increases in obesity risk ratios or will influence obesity by more complex routes, such as gene gene epistasis and gene environment interactions. The identification of genes underlying complex traits such as obesity, diabetes, and hypertension has been less successful than for simple mendelian traits. One of the reasons for this is the presence of epistasis that can mask the effects of one locus on another locus and reduce the power to identify either locus. Epistasis is generally defined as the interaction between two or more genes or their mRNA or protein products to influence a single trait. Non-additive genetic effects and interactions between genes contribute considerably to the phenotypic variance of body weight and

Studies of natural allele effects in mice can be used to identify genes causing common human obesity.

Although genes causing rare Mendelian forms of human obesity have provided much useful information about underlying causes of obesity, these genes do not explain significant proportions of common obesity. This review presents evidence that animal models can be used to uncover subtle genetic effects on obesity and can provide a powerful rigorous compliment to human association studies. We discuss the advantages of animal models of obesity, various approaches to discovering obesity genes, and the future of mapping and isolating naturally occurring alleles of obesity genes. We review evidence that it is important to map naturally occurring obesity genes using quantitative trait locus (QTL) mapping, instead of mutagenesis and knockout models because the latter do not allow study of interactions and because naturally occurring obesity alleles can interfere with cloning from mutagenesis projects. Because a substantial percentage of human obesity results from complex interactions, the underlying genes can only be identified by direct studies in humans, which are still very difficult, or by studies in mice that begin with QTL mapping. Finally, we emphasize that animal model studies can be used to prove that a specific gene, only associated with obesity in humans, can indeed be the underlying cause of obesity in mammals.

Obesity--a genetic disease of adipose tissue?

Although the rapid increase in the prevalence of obesity in many countries suggests that environmental factors (mainly overeating and physical inactivity) play the most important role in the development of overweight, it is very likely that genetic factors also contribute. It appears that one major gene in combination with one or several minor genes constitute the genetic components behind excess accumulation of body fat in most obese individuals. However, monogenic obesity has been described in a few families due to changes in leptin, leptin receptor, prohormone convertase, pro-opiomelanocortin or melanocortin-4 receptor. None of the monogenic variants is of great importance for common human obesity; the latter genes are unknown so far. Results from genomic scans suggest that major obesity genes are located on chromosomes 2, 10, 11 and 20. Studies of candidate genes indicate that the minor obesity genes control important functions of adipose tissue, and that structural variance in these genes may alter adipose tissue function in a way that promotes obesity. Such genes are beta 2- and beta 3-adrenoceptors, hormone-sensitive lipase, tumour necrosis factor alpha, uncoupling protein-1, low-density lipoprotein receptor, and peroxisome proliferator activator receptor gamma-2. Some of these genes may promote obesity by gene-gene interactions (for example beta 3-adrenoceptors and uncoupling protein-1) or gene-environment interactions (for example beta 2-adrenoceptors and physical activity). Some are important for obesity only among women (for example beta 2- and beta 3-adrenoceptors, low-density lipoprotein receptor and tumour necrosis factor alpha). Few 'non-adipose' genes have so far shown a firm association to common human obesity, which could suggest that the important genes for the development of excess body fat also control adipose tissue function.

The mahogany protein is a receptor involved in suppression of obesity.

Genetic studies have shown that mutations within the mahogany locus suppress the pleiotropic phenotypes, including obesity, of the agouti-lethal-yellow mutant. Here we identify the mahogany gene and its product; this study, to our knowledge, represents the first positional cloning of a suppressor gene in the mouse. Expression of the mahogany gene is broad; however, in situ hybridization analysis emphasizes the importance of its expression in the ventromedial hypothalamic nucleus, a region that is intimately involved in the regulation of body weight and feeding. We present new genetic studies that indicate that the mahogany locus does not suppress the obese phenotype of the melanocortin-4-receptor null allele or those of the monogenic obese models (Lep(db), tub and Cpe(fat)). However, mahogany can suppress diet-induced obesity, the mechanism of which is likely to have implications for therapeutic intervention in common human obesity. The amino-acid sequence of the mahogany protein suggests that it is a large, single-transmembrane-domain receptor-like molecule, with a short cytoplasmic tail containing a site that is conserved between Caenorhabditis elegans and mammals. We propose two potential, alternative modes of action for mahogany: one draws parallels with the mechanism of action of low-affinity proteoglycan receptors such as fibroblast growth factor and transforming growth factor-beta, and the other suggests that mahogany itself is a signalling receptor.