Past, present and future strategies to study the genetics of body weight regulation.

Genetic advances have made remarkable progress towards our understanding of body weight regulation. Much of our current knowledge has come from the cloning and characterisation of the genes responsible for obesity syndromes in the mouse, and the identification of homologous mutations causing rare forms of obesity in humans. Gene targeting experiments in mice have been instrumental in confirming the importance of many genes in the aetiology of obesity, and the existence of a fundamental physiological pathway that controls energy balance is becoming clear. The genetic determinants that underlie common forms of human obesity are largely polygenic, with most genes producing small effects. Thus, elucidating the many genetic determinants of obesity is a current challenge for modern geneticists. Despite the inherent difficulties, progress has been made through linkage/association studies and a genetic map of quantitative trait loci for human obesity is beginning to emerge. Obesity research is now very much in a transition period. Not so long ago, access to high throughput screening, as well as microarray and proteomic techniques, was prohibitively expensive and available only to the few. In recent years, these technologies have become more accessible to the larger scientific community and, in this paper, we will discuss how such technological advances are likely to drive the next wave of progress in obesity research. For example, large-scale mutagenesis screens in rodents coupled with high throughput screening are likely to emerge as important technologies for identifying genes previously unexpected to be involved in body weight regulation. Furthermore, applications of microarray and proteomic techniques will further refine our understanding of currently known peptides as well as identify novel pathways and molecules which are involved in energy homeostasis.     

Human obesity: toward functional genomics

Genetic and environmental aspects are recognized in the obesity field and attempts to elucidate multiple genes and gene/environment interactions are necessary. In rare cases of monogenic obesities, genetic tools have proved extremely powerful for identifying the genes responsible and for defining new syndromes. Abnormalities of genes involved in the leptin/melanocortin axis have been described. In common obesity, most studies include the search for genotype/phenotype associations without taking into account the influence of environment (diet, sedentary lifestyle) in the relationship. Many genes and candidate regions have been proposed to be involved in the determinism of human obesity. Among the limitations to this integrated approach, one can cite the difficulty of having large enough samples as well as biocomputing tools that are still in their infancy for accessing the question of multiple interactions with no "a priori hypotheses". This picture will probably change rapidly in the future. The purpose of this paper is to present some examples of the knowledge acquired in the field of obesity genetics and the new ongoing tools and developments that aim at studying the contribution of genes to obesity and their response to environmental changes. The capacity for studying multiple genes at once at the DNA or RNA levels is rapidly growing. Finally, tremendous progress in biocomputing will allow the integration of information from different sources (i.e. environment, phenotype, genotype, gene expression) and thus improve our ability to deal with complexity. Examples of these approaches exist in humans and in animal models.     

The role of stearoyl-CoA desaturase in the control of metabolism

Since obesity is becoming increasingly prevalent worldwide, much effort is being devoted to understanding its pathogenesis and treatment. In recent years, several candidate genes have been proposed as therapeutic targets. However, stearoyl-CoA desaturase 1 (SCD1) is of special significance, because it is the major gene target of leptin-a central mediator of energy homeostasis. There is evidence that SCD1 deficiency activates metabolic pathways that promote beta-oxidation and decrease lipogenesis in liver and skeletal muscles. One mechanism is via increased activation of AMP-activated protein kinase. SCD1 mutation results also in global changes in expression of genes involved in lipid metabolism. SCD1 deficient mice have increased energy expenditure, reduced body adiposity, and are resistant to diet-induced obesity. In this review, we examine data from our laboratory and others suggesting that SCD1 is an important component in the regulation of body metabolism.     

Gene-diet interactions in childhood obesity

Childhood overweight and obesity have reached epidemic proportions worldwide, and the increase in weight-associated co-morbidities including premature type 2 diabetes mellitus (T2DM) and atherosclerotic cardiovascular disease will soon become major healthcare and economic problems. A number of studies now indicate that the childhood obesity epidemic which has emerged during the past 30 years is a complex multi-factorial disease resulting from interaction of susceptibility genes with an obesogenic environment. This review will focus on gene-diet interactions suspected of having a prominent role in promoting childhood obesity. In particular, the specific genes that will be presented (FTO, MC4R, and NPC1) have recently been associated with childhood obesity through a genome-wide association study (GWAS) and were shown to interact with nutritional components to increase weight gain. Although a fourth gene (APOA2) has not yet been associated with childhood obesity, this review will also present information on what now represents the best characterized gene-diet interaction in promoting weight gain.     

Shared genetic risk factors for obstructive sleep apnea and obesity.

Both obesity and obstructive sleep apnea (OSA) are complex disorders with multiple risk factors, which interact in a complicated fashion to determine the overall phenotype. In addition to environmental risk factors, each disorder has a strong genetic basis that is likely due to the summation of small to moderate effects from a large number of genetic loci. Obesity is a strong risk factor for sleep apnea, and there are some data to suggest sleep apnea may influence obesity. It is therefore not surprising that many susceptibility genes for obesity and OSA should be shared. Current research suggests that approximately half of the genetic variance in the apnea hypopnea index is shared with obesity phenotypes. Genetic polymorphisms that increase weight will also be risk factors for apnea. In addition, given the interrelated pathways regulating both weight and other intermediate phenotypes for sleep apnea such as ventilatory control, upper airway muscle function, and sleep characteristics, it is likely that there are genes with pleiotropic effects independently impacting obesity and OSA traits. Other genetic loci likely interact with obesity to influence development of OSA in a gene-by-environment type of effect. Conversely, environmental stressors such as intermittent hypoxia and sleep fragmentation produced by OSA may interact with obesity susceptibility genes to modulate the importance that these loci have on defining obesity-related traits.     

Progress in the genetics of common obesity: size matters

PURPOSE OF REVIEW: Over the past two decades serious efforts has been invested in the search for genes that predispose to common obesity, but progress has been slow and success limited. Genome-wide association, however, has revived optimism. Here we review recent advances in the field of obesity genetics and discuss the most important findings of candidate gene, genome-wide linkage studies and genome-wide association studies. We conclude by speculating about the way forward in the near future. RECENT FINDINGS: Although large-scale candidate gene studies have placed MC4R more firmly on the human obesity map, the major breakthrough in obesity genetics was the discovery of FTO through genome-wide association. Variants located in the first intron of FTO were unequivocally associated with a 1.67-fold increased risk for obesity and a 0.40-0.66 kg/m2 increase in body mass index. SUMMARY: Genome-wide association promises to enhance greatly our understanding of the genetic basis of common obesity, although candidate gene studies will remain a valuable approach because they allow more detailed analyses of biologically relevant candidates. A key factor contributing to continued success lies in large-scale data integration through international collaboration, which will provide the sample sizes required to identify genetic association with conclusive evidence.     

Obesity and hypertension: two epidemics or one?

The association between obesity and hypertension is well documented, although the exact nature of this relation remains unclear. Sympathetic nervous and renin-angiotensin-aldosterone system activation appear to play an important role in the sodium and water retention, rightward shift in the pressure-natriuresis, and blood pressure elevation observed in obese individuals. Visceral obesity and the ectopic deposition of adipose tissue may be important in the activation of these systems and in the target organ damage that ensues. Weight loss is critical in the effective management of obesity hypertension and the accompanying target organ damage, although recidivism rates are high. However, prevention of weight gain should be the major priority for combating hypertension and its consequences in the future. The present review will provide an overview of our understanding of the etiology, pathophysiology, and treatment of obesity hypertension. Our focus is on the state of knowledge in humans. The potential role of abdominal obesity is considered throughout our review. We refer to relevant animal literature for supportive evidence and where little or no data in humans are available.     

The genetics of childhood obesity and interaction with dietary macronutrients

The genes contributing to childhood obesity are categorized into three different types based on distinct genetic and phenotypic characteristics. These types of childhood obesity are represented by rare monogenic forms of syndromic or non-syndromic childhood obesity, and common polygenic childhood obesity. In some cases, genetic susceptibility to these forms of childhood obesity may result from different variations of the same gene. Although the prevalence for rare monogenic forms of childhood obesity has not increased in recent times, the prevalence of common childhood obesity has increased in the United States and developing countries throughout the world during the past few decades. A number of recent genome-wide association studies and mouse model studies have established the identification of susceptibility genes contributing to common childhood obesity. Accumulating evidence suggests that this type of childhood obesity represents a complex metabolic disease resulting from an interaction with environmental factors, including dietary macronutrients. The objective of this article is to provide a review on the origins, mechanisms, and health consequences of obesity susceptibility genes and interaction with dietary macronutrients that predispose to childhood obesity. It is proposed that increased knowledge of these obesity susceptibility genes and interaction with dietary macronutrients will provide valuable insight for individual, family, and community preventative lifestyle intervention, and eventually targeted nutritional and medicinal therapies.     

Genetic aspects of susceptibility to obesity and related dyslipidemias

Obesity has a multifactorial origin. However, although environmental variables undoubtedly play a role in the development of obesity, it is now clear that genetic variation is also involved in the determination of an individual's susceptibility to body fat accumulation. In addition, it is also widely accepted that obesity is not a single homogeneous phenotype. It is also heterogeneous regarding its causes and metabolic complications. The regional distribution of body fat appears to be an important correlate of the metabolic complications that have been related to obesity. Due to their higher accumulation of abdominal fat, men are generally more at risk for the metabolic complications of obesity than women whereas some obese women, with large gluteal-femoral adipose depots may have a cosmetic problem which may not necessarily require medical intervention. Several studies have been conducted to understand the mechanisms by which abdominal obesity is related to diabetes, hypertension and cardiovascular disease. It appears that the increased risk of abdominal obesity is the result of complex hormonal and metabolic interactions. Studies in genetic epidemiology have shown that both total body fatness and the regional distribution of body fat have a significant genetic component. Standardized intervention studies using an identical twin design have shown that individuals that have the same genetic background tend to show similar changes in body fat and in plasma lipoprotein levels when exposed to standardized caloric excess or energy restriction. Finally, although abdominal obesity is a significant risk factor for cardiovascular disease, not every abdominal obese subject will experience metabolic complications, suggesting that some obese individuals may be more susceptible than others. Variation in several genes relevant to lipid and lipoprotein metabolism may alter the relation of abdominal obesity to dyslipoproteinemias. Abdominal obesity should therefore be considered as a factor that exacerbates an individual's susceptibility to cardiovascular disease.     

What obesity research tells us about epigenetic mechanisms

The pathophysiology of obesity is extremely complex and is associated with extensive gene expression changes in tissues throughout the body. This situation, combined with the fact that all gene expression changes are thought to have associated epigenetic changes, means that the links between obesity and epigenetics will undoubtedly be vast. Much progress in identifying epigenetic changes induced by (or inducing) obesity has already been made, with candidate and genome-wide approaches. These discoveries will aid the clinician through increasing our understanding of the inheritance, development and treatment of obesity. However, they are also of great value for epigenetic researchers, as they have revealed mechanisms of environmental interactions with epigenetics that can produce or perpetuate a disease state. Here, we will review the evidence for four mechanisms through which epigenetics contributes to obesity: as downstream effectors of environmental signals; through abnormal global epigenetic state driving obesogenic expression patterns; through facilitating developmental programming and through transgenerational epigenetic inheritance.     

Hepatic Gene Expression Profiling Reveals Key Pathways Involved in Leptin-Mediated Weight Loss in ob/ob Mice

Background

Leptin, a cytokine-like protein, plays an important role in the regulation of body weight through inhibition of food intake and stimulation of energy expenditure. Leptin circulates in blood and acts on the brain, which sends downstream signals to regulate body weight. Leptin therapy has been successful in treating leptin deficient obese patients. However, high levels of leptin have been observed in more common forms of obesity indicating a state of leptin resistance which limits the application of leptin in the treatment of obesity. If the central effect of leptin could be by-passed and genes which respond to leptin treatment could be regulated directly, new therapeutic targets for the treatment of obesity may be possible. The purpose of this study was to identify genes and subsequent pathways correlated with leptin-mediated weight loss.

Methodology/Principal Findings

We utilized microarray technology to compare hepatic gene expression changes after two types of leptin administration: one involving a direct stimulatory effect when administered peripherally (subcutaneous: SQ) and another that is indirect, involving a hypothalamic relay that suppresses food intake when leptin is administered centrally (intracerebroventricular: ICV). We identified 214 genes that correlate with leptin mediated weight loss. Several biological processes such as mitochondrial metabolic pathways, lipid metabolic and catabolic processes, lipid biosynthetic processes, carboxylic acid metabolic processes, iron ion binding and glutathione S-transferases were downregulated after leptin administration. In contrast, genes involved in the immune system inflammatory response and lysosomal activity were found to be upregulated. Among the cellular compartments mitochondrion (32 genes), endoplasmic reticulum (22 genes) and vacuole (8 genes) were significantly over represented.

Conclusions/Significance

In this study we have identified key molecular pathways and downstream genes which respond to leptin treatment and are involved in leptin-mediated weight loss. Many of these genes have previously been shown to be associated with obesity; however, we have also identified a number of other novel target genes. Further investigation will be required to assess the possible use of these genes and their associated protein products as therapeutic targets for the treatment of obesity.     

Investigation of Obesity Candidate Genes On Porcine Fat Deposition Quantitative Trait Loci Regions

Objectives: To investigate possible obesity candidate genes in regions of porcine quantitative trait loci (QTL) for fat deposition and obesity‐related phenotypes. Research Methods and Procedures: Chromosome mapping and QTL analyses of obesity candidate genes were performed using DNA panels from a reference pig family. Statistical association analyses of these genes were performed for fat deposition phenotypes in several other commercial pig populations. Results: Eight candidate genes were mapped to QTL regions of pig chromosomes in this study. These candidate genes also served as anchor loci to determine homologous human chromosomal locations of pig fat deposition QTL. Preliminary analyses of relationships among polymorphisms of individual candidate genes and a variety of phenotypic measurements in a large number of pigs were performed. On the basis of available data, gene‐gene interactions were also studied. Discussion: Comparative analysis of obesity‐related genes in the pig is not only important for development of marker‐assisted selection on growth and fat deposition traits in the pig but also provides for an understanding of their genetic roles in the development of human obesity.     

Nutrigenomics: integrating genomic approaches into nutrition research

It has been suggested that the supermarket of today will be the pharmacy of tomorrow. Such statements have been derived from recognition of our increasing ability to optimize nutrition, and maintain a state of good health through longer periods of life. The new field of nutrigenomics, which focuses on the interaction between bioactive dietary components and the genome, recognizes that current nutritional guidelines may be ideal for only a relatively small proportion of the population. There is good evidence that nutrition has significant influences on the expression of genes, and, likewise, genetic variation can have a significant effect on food intake, metabolic response to food, individual nutrient requirements, food safety, and the efficacy of disease-protective dietary factors. For example, a significant number of human studies in various areas are increasing the evidence for interactions between single nucleotide polymorphisms (SNPs) in various genes and the metabolic response to diet, including the risk of obesity. Many of the same genetic polymorphisms and dietary patterns that influence obesity or cardiovascular disease also affect cancer, since overweight individuals are at increased risk of cancer development. The control of food intake is profoundly affected by polymorphisms either in genes encoding taste receptors or in genes encoding a number of peripheral signaling peptides such as insulin, leptin, ghrelin, cholecystokinin, and corresponding receptors. Total dietary intake, and the satiety value of various foods, will profoundly influence the effects of these genes. Identifying key SNPs that are likely to influence the health of an individual provides an approach to understanding and, ultimately, to optimizing nutrition at the population or individual level. Traditional methods for identification of SNPs may involve consideration of individual variants, using methodologies such as restriction fragment length polymorphisms or quantitative real-time PCR assays. New developments allow identification of up to 500,000 SNPs in an individual, and with increasingly lowered pricings these developments may explode the population-level potential for dietary optimization based on nutrigenomic approaches.     

Amino acid biosynthesis in plants: Approaching an understanding at the molecular level

Summary The genes encoding GS and EPSP synthase have already been cloned. Clones containing portions of the genes encoding aspartate amino transferase and asparagine synthetase tentatively have been identified by this and other laboratories. It is certain that many other genes encoding other important enzymes involved in amino acid biosynthesis will also be identified in the near future. It is evident that new techniques for the separation of proteins will greatly aid in identifying low abundance genes more rapidly and efficiently. Micro techniques need to be further developed and the necessary equipment made available to laboratories. Hopefully the cost of the required equipment will decrease and commercial enterprises will offer more contract services for work requiring the more expensive equipment. Graduate training in advanced techniques of separating proteins at high resolutions should be encour-aged expanded so that our future scientists are well versed in protein biochemistry as well as in techniques of molecular biology.     

Commingling analysis of obesity in twins

Evidence is presented for multiple components in the distribution of human fatness across several large twin samples, after removing age effects and allowing for residual skewness in component distributions. The upper component distributions corresponded to overweight or obesity in samples of middle-aged or older individuals. A bivariate analysis demonstrated that, while monozygotic co-twins appeared to be drawn from the same component distributions (normal or overweight), the twin correlations varied across components, with the lowest correlation in the overweight group. While these analyses cannot provide a definitive test of competing genetic and environmental hypotheses, this approach is useful for generating hypotheses about the causes of obesity. When combined with other published literature, our results suggest that the genetic background largely determines the propensity to become obese. Whether a predisposed person becomes obese and the extent of obesity depend on environmental exposures that are largely independent of early family experience. Both genes and environment appear to be important in obesity, but it appears that some genotypes may be much more sensitive to the environment than are others.     

Characterization of epistasis influencing complex spontaneous obesity in the BSB model

There is growing awareness that complex interactions among multiple genes and environmental factors play an important role in controlling obesity traits. The BSB mouse, which is produced by the backcross of (lean C57BL/6J x lean Mus spretus) x C57BL/6J, provides an excellent model of epistatic obesity. To evaluate potential epistatic interactions among six chromosomal regions previously determined to influence obesity phenotypes, we performed novel Bayesian analyses on the basis of both epistatic and nonepistatic models for four obesity traits: percentage of body fat, adiposity index, total fat mass, and body weight, and also for plasma total cholesterol. The epistatic analysis detected at least one more QTL than the nonepistatic analysis did for all obesity traits. These obesity traits were variously influenced by QTL on chromosomes 2, 7, 12, 15, and 16. Interaction between genes on chromosomes 2 and 12 was present for all obesity traits, accounting for 3-4.8% of the phenotypic variation. Chromosome 12 was found to have weak main effects on all obesity traits. Several different epistatic interactions were also detected for percentage of body fat, adiposity index, and total fat mass. Chromosomes 6 and 12 have not only main effects but also strong epistatic effects on plasma total cholesterol. Our results emphasize the importance of modeling epistasis for discovery of obesity genes.     

MicroRNAs 33, 122, and 208: a potential novel targets in the treatment of obesity,diabetes, and heart-related diseases

Despite decades of research, obesity and diabetes remain major health problems in the USA and worldwide. Among the many complications associated with diabetes is an increased risk of cardiovascular diseases, including myocardial infarction and heart failure. Recently, microRNAs have emerged as important players in heart disease and energy regulation. However, little work has investigated the role of microRNAs in cardiac energy regulation. Both human and animal studies have reported a significant increase in circulating free fatty acids and triacylglycerol, increased cardiac reliance on fatty acid oxidation, and subsequent decrease in glucose oxidation which all contributes to insulin resistance and lipotoxicity seen in obesity and diabetes. Importantly, MED13 was initially identified as a negative regulator of lipid accumulation in Drosophilia. Various metabolic genes were downregulated in MED13 transgenic heart, including sterol regulatory element-binding protein. Moreover, miR-33 and miR-122 have recently revealed as key regulators of lipid metabolism. In this review, we will focus on the role of microRNAs in regulation of cardiac and total body energy metabolism. We will also discuss the pharmacological and non-pharmacological interventions that target microRNAs for the treatment of obesity and diabetes.