Mutations in ligands and receptors of the leptin-melanocortin pathway that lead to obesity

Obesity is associated with increased morbidity and mortality from cardiovascular disease, diabetes mellitus and certain cancers. The prevalence of obesity is increasing rapidly throughout the world and is now recognized as a major global public-health concern. Although the increased prevalence of obesity is undoubtedly driven by environmental factors, the evidence that inherited factors profoundly influence human fat mass is equally compelling. Twin and adoption studies indicate that up to 70% of the interindividual variance in fat mass is determined by genetic factors. Genetic strategies can, therefore, provide a useful tool with which to dissect the complex (and often heterogeneous) molecular and physiologic mechanisms involved in the regulation of body weight. In this Review, we have focused our attention on monogenic disorders, which primarily result in severe, early-onset obesity. The study of these genetic disorders has provided a framework for our understanding of the mechanisms involved in the regulation of body weight in humans and how these mechanisms are disrupted in obesity. The genes affected in these monogenic disorders all encode ligands and receptors of the highly conserved leptin-melanocortin pathway, which is critical for the regulation of food intake and body weight.     

Genetics of human obesity

Obesity is a multifactorial condition. Environmental risk factors related to a sedentary life-style and unlimited access to food apply constant pressure in subjects with a genetic predisposition to gain weight. The fact that genetic defects can result in human obesity has been unequivocally established over the past 3 years with the identification of the genetic defects responsible for different monogenic forms of human obesity: the leptin, leptin receptor, pro-opiomelanocortin, pro-hormone convertase-1 and melanocortin-4 receptor genes. The common forms of obesity are, however, polygenic. The examination of specific genes for involvement in the susceptibility to common obesity has not yet yielded convincing results. Approaches involving the candidate genes and the positional cloning of major obesity-linked regions (state-of-the-art future prospects) will be discussed.     

Genetics of obesity and overgrowth syndromes

Childhood overweight and obesity is highly prevalent within society. In the majority of individuals, weight gain is the result of exposure to an 'obesogenic' environment, superimposed on a background of genetic susceptibility brought about by evolutionary adaptation. These individuals tend to be tall in childhood with a normal final adult height, as opposed to those who have an underlying monogenic cause where short stature is more common (although not universal). Identifying genetic causes of weight gain, or tall stature and overgrowth, within this setting can be extremely problematic and yet it is imperative that clinicians remain alert, as identification of a genetic diagnosis has major implications for the individual, family and potential offspring. Alongside this, the recognition of new genetic mutations in this area is furthering our knowledge on the important mechanisms that regulate childhood growth and body composition. This review describes the genetic syndromes associated with obesity and overgrowth.     

中国人单基因突变糖尿病及肥胖病的研究

对糖尿病和肥胖病病因学研究的不断发展使许多单基因糖尿病和肥胖病被发现。对中国人已开展的青少年发病型成人糖尿病、线粒体糖尿病、黑皮素4受体(MC4R)及部分伴糖尿病的遗传综合征的研究提示,单基因肥胖病及糖尿病存在种族、遗传和临床特点的异质性。对这些特殊类型糖尿病和肥胖病的深入认识将有助于对疾病的病因细致分类和个体化治疗的指导。     

The leptin melanocortin pathway and the control of body weight: lessons from human and murine genetics

The recent rapid increase in the prevalence of obesity across the world is undoubtedly due to changes in diet and lifestyle. However, it is also indisputable that different people react differently to this change in environment and this variation in response is likely to be genetically determined. While for the majority of people this effect is presumed to be polygenic in origin, there is now strong evidence for a small number of genes having a large effect in some families with severe obesity. Studies of these families, coupled with parallel studies in murine models, have provided novel insights into the molecules involved in the regulation of appetite, energy expenditure and nutrient partitioning. We review here the lessons we have learnt from mouse models of obesity, both naturally occurring and artificially generated through targeted gene deletions, and more importantly from human monogenic syndromes of obesity. These have illuminated the critical role in which the central leptin melanocortin pathway plays in the control of mammalian food intake and body weight.     

Genetics of human obesity: lessons from mouse models and candidate genes

Obesity is a common disorder with potentially serious negative implications on health and quality of life and a rising prevalence worldwide, warranting effective treatments. The disorder runs in families, and important knowledge is expected to follow the identification of human obesity genes. Although statistical analysis of inheritance of obesity in humans suggests a large genetic component in obesity, up to 80%, few actual obesity genes have been identified so far. However, a number of obesity causing genes have successfully been cloned from rodents with monogenic forms of obesity, and it is probable that new knowledge in the field of human obesity will result from these findings.     

What have rare genetic syndromes taught us about the pathophysiology of the common forms of obesity?

Obesity is a central feature for several congenital syndromes, including Prader-Willi, Angelman, Bardet-Biedl, Cohen, Alström andBörjeson-Forssman-Lehmann syndromes, and Albright's hereditary osteodystrophy. Although a role for the central nervous system, including the hypothalamus-pituitary axis, has been suggested for the etiology of obesity in these syndromes, the pathophysiologic pathways are as yet not well defined, and in many cases may identify currently unknown mechanisms. Nevertheless, many of the causative genes and unusual mechanisms, including parental imprinting of genes and complex patterns of inheritance, have been identified. We review the latest advances in understanding congenital syndromes in which obesity is purely genetic, drawing on comparisons to genetic studies of obesity in the human population as well as to those in experimental and agricultural animal models. An understanding of the genetic basis for these syndromes will provide a more comprehensive picture of the mechanisms that control food intake and energy balance in humans.     

Genetics of obesity in humans

Considerable attention has focused on deciphering the hypothalamic pathways that mediate the behavioral and metabolic effects of leptin. We and others have identified several single gene defects that disrupt the molecules in the leptin-melanocortin pathway causing severe obesity in humans. In this review, we consider these human monogenic obesity syndromes and discuss how far the characterization of these patients has informed our understanding of the physiological role of leptin and the melanocortins in the regulation of human body weight and neuroendocrine function.     

Transgenic animal models for the study of adipose tissue biology

The traditional view of adipose tissue as a passive energy reservoir has changed. Adipose tissue is a complex, highly active metabolic and endocrine organ. With obesity as an increasingly important public health threat, a major development in the understanding of adipose tissue biology has come with observations in different biological spheres including whole-body physiology and application of transgenic animal models. Scientific progress has been made with the identification of several genes in spontaneous monogenic animal models of obesity, and in understanding the molecular mechanisms underlying phenotypes of altered body weight, adiposity and fat distribution by creating transgenic and knockout animal models. Mouse phenotypes resulting from inactivation or overexpression of molecules responsible for the regulation of adipose tissue metabolism have led to novel concepts in the understanding of adipocyte biology and development of obesity. This review presents an overview of transgenic animal models for the study of adipose tissue biology.     

The Genetics of Obesity

Obesity is a result of excess body fat accumulation. This excess is associated with adverse health effects such as CVD, type 2 diabetes, and cancer. The development of obesity has an evident environmental contribution, but as shown by heritability estimates of 40% to 70%, a genetic susceptibility component is also needed. Progress in understanding the etiology has been slow, with findings largely restricted to monogenic, severe forms of obesity. However, technological and analytical advances have enabled detection of more than 20 obesity susceptibility loci. These contain genes suggested to be involved in the regulation of food intake through action in the central nervous system as well as in adipocyte function. These results provide plausible biological pathways that may, in the future, be targeted as part of treatment or prevention strategies. Although the proportion of heritability explained by these genes is small, their detection heralds a new phase in understanding the etiology of common obesity.     

Prader-Willi-Labhart syndrome: relations with the hypothalamus and chromosome 15

The Prader-Willi syndrome is a human disease whose physiological causes have not yet been elucidated. However, clinical and biological parameters suggest that it is an hypothalamic disorder. This syndrome is the most common form of human congenital obesity. In many cases, the genetic alteration has been identified as a microdeletion in the chromosomal region 15q11-q13. Consequently, one can presume that obesity in patients with Prader-Willi syndrome is the result of some hypothalamic deficiency involving the products of one or several genes found in this region of chromosome 15. Several DNA markers belonging to this genomic region have been isolated. If these are fragments of expressed genes, it may be possible to examine the possible association of their products with the hypothalamus and the disease. Such studies may provide new insights into the role of the hypothalamus in the pathophysiology of obesity.     

Lessons in obesity from transgenic animals

Many genetic manipulations have created models of obesity, leanness or resistance to dietary obesity in mice, often providing insights into molecular mechanisms that affect energy balance, and new targets for anti-obesity drugs. Since many genes can affect energy balance in mice, polymorphisms in many genes may also contribute to obesity in humans, and there may be many causes of primary leptin resistance. Secondary leptin resistance (due to high leptin levels) can be investigated by combining the ob mutation with other obesity genes. Some transgenic mice have failed to display the expected phenotype, or have even been obese when leanness was expected. Compensatory changes in the expression of other genes during development, or opposing influences of the gene on energy balance, especially in global knockout mice, may offer explanations for such findings. Obesity has been separated from insulin resistance in some transgenic strains, providing new insights into the mechanisms that usually link these phenotypes. It has also been shown that in some transgenic mice, obesity develops without hyperphagia, or leanness without hypophagia, demonstrating that generalised physiological explanations for obesity in individual humans may be inappropriate. Possibly the most important transgenic model of obesity so far created is the Type 1 11beta-hydroxysteroid dehydrogenase over-expressing mouse, since this models the metabolic syndrome in humans. The perspectives into obesity offered by transgenic mouse models should assist clinical researchers in the design and interpretation of their studies in human obesity.     

Genes involved in animal models of obesity and anorexia

Pathological deviations in bodyweight is a major increasing health problem in industrialized societies. It is currently unclear what genetic mechanisms are involved in the long-term control of human body-weight and to what extent these genes are involved in pathological deviations of bodyweight control such as anorexia and obesity. Major support for the concept of genetic control of bodyweight has recently emerged from different animal models. A number of new genes have been found during recent years that, when mutated, have a negative effect on bodyweight in animals and sometimes also in man. Although available evidence points toward a multifactorial nature of weight disorders in most human subjects, the single genes isolated in animal models may become powerful tools to elucidate the genetics also in man. In addition, these genes may serve to promote the development of targeted small-drug pharmaceuticals aimed at novel biochemical pathways. Finally, the uncovering of several quantitative trait loci (QTL) influencing body mass, body fat or fat topography in the mouse and rat has now also made it possible to perform studies of polygenically caused obesity in rodents. The role of the Genome Project in developing a complete gene map will greatly facilitate transforming these OTLs to actual molecules involved in the biology of bodyweight.     

Genetic obesities

Obesity has become an increasingly prevalent public health problem and results of the complex interaction of genetic and environmental factors. The study of rare syndromic forms of obesity enables progress in identifying molecular and physiological mechanisms, underlying the development of adiposity, food intake and energy expenditure. The identified role of the hypothalamic leptin-melanocortin pathway as major in monogenic forms of obesity, has led to the recognition of new genes controlling energy homeostasis and new pharmacological targets.     

Genetic and hereditary aspects of childhood obesity

Genetic factors are involved in the regulation of body weight and in determining individual responses to environmental factors such as diet and exercise. The identification and characterization of monogenic obesity syndromes have led to an improved understanding of the precise nature of the inherited component of severe obesity and has had undoubted medical benefits, whilst helping to dispel the notion that obesity represents an individual defect in behaviour with no biological basis. For individuals at highest risk of the complications of severe obesity, such findings provide a starting point for providing more rational mechanism-based therapies, as has successfully been achieved for one disorder, congenital leptin deficiency.     

Eating behaviour in contrasting adiposity phenotypes: Monogenic obesity and congenital generalized lipodystrophy

Most known types of nonsyndromic monogenic obesity are caused by rare mutations in genes of the leptin‐melanocortin pathway controlling appetite and adiposity. In contrast, congenital generalized lipodystrophy represents the most extreme form of leanness in humans caused by recessive mutations in four genes involved in phospholipid/triglyceride synthesis and lipid droplet/caveolae structure. In this disease, the inability to store triglyceride in adipocytes results in hypoleptinemia and ectopic hepatic and muscle fat accumulation leading to fatty liver, hypertriglyceridemia and severe insulin resistance. As a result of hypoleptinemia, patients with lipodystrophy show alterations in eating behaviour characterized by constant increased energy intake. As it occurs in obesity caused by genetic leptin deficiency, exogenous leptin rapidly reduces hunger scores in patients with congenital generalized lipodystrophy, with additional beneficial effects on glucose homeostasis and metabolic profile normalization. The melanocortin‐4 receptor agonist setmelanotide has been used in the treatment of monogenic obesities. There is only one report on the effect of setmelanotide in a patient with partial lipodystrophy resulting in mild reductions in hunger scores, with no improvements in metabolic status. The assessment of contrasting phenotypes of obesity/leanness represents an adequate strategy to understand the pathophysiology and altered eating behaviour associated with adipose tissue excessive accumulation/paucity.     

Genetic factors in the pathogenesis of CPPD crystal deposition disease

Crystal deposition is a very complex process ruled by numerous factors. A small but important proportion of cases of chondrocalcinosis are monogenic, and many of the genes involved have been identified. These genetic findings strongly point to control of the level of extracellular inorganic pyrophosphate as the primary mechanism for their association with either calcium pyrophosphate dihydrate or hydroxyapatite deposition. However, effects on extracellular inorganic pyrophosphate levels do not explain the mechanism of association in all of these monogenic diseases. Further, there are likely to be several as yet unidentified genes that are important in this common condition. This review highlights what genetic studies have demonstrated about the processes involved in these diverse but related disorders.     

Genetics of Severe Obesity

Purpose of Review

This review aims to present current information on genes underlying severe obesity, with the main emphasis on the three genes LEP, LEPR and MC4R.

Recent Findings

There is a substantial amount of evidence that variants in at least ten different genes are the cause of severe monogenic obesity. The majority of these are involved in the leptin-melanocortin signalling pathway. Due to the frequency of some of the identified variants, it is clear that monogenic variants also make a significant contribution to common obesity.

Summary

The artificial distinction between rare monogenic obesity and common polygenic obesity is now obsolete with the identification of MC4R variants of strong effect in the general population.

     

Genomic epidemiology of blood pressure salt sensitivity

High blood pressure (BP) is a complex trait determined by genetic and environmental factors, as well as their interactions. Over the past few decades, there has been substantial progress elucidating the genetic determinants underlying BP response to sodium intake, or BP salt sensitivity. Research of monogenic BP disorders has highlighted the importance of renal salt handling in BP regulation, implicating genes and biological pathways subsequently identified in candidate gene studies of salt sensitivity. Despite these advancements, certain candidate gene findings await replication evidence, and some biological pathways warrant further investigation. Furthermore, results from genome-wide association studies (GWASs) and sequencing work have yet to be reported. GWAS will be valuable for uncovering novel mechanisms underlying salt sensitivity, whereas future sequencing efforts promise the discovery of functional variants related to this complex trait. Delineating the genetic architecture of salt sensitivity will be critical to understanding how genes and dietary sodium interact to influence BP.