The Journal of Clinical Endocrinology & Metabolism Vol. 93, No. 11_Supplement_1 s51-s56
Copyright © 2008 by The Endocrine Society
Is Obesity Our Genetic Legacy?
Alexandra I. F. Blakemore and
Philippe Froguel
Section of Genomic Medicine (A.I.F.B., P.F.), Hammersmith Hospital, Imperial College London, London W12 0NN, United Kingdom; and Centre National de la Recherche Scientifique 8090-Institute of Biology (P.F.), Pasteur Institute, BP 245-59019 Lille, France
Address all correspondence and requests for reprints to: Professor Philippe Froguel, Section of Genomic Medicine, Hammersmith Hospital Campus, Imperial College London, Du Cane Road, East Acton, London W12 0NN, United Kingdom. E-mail: p.froguel{at}imperial.ac.uk.
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Abstract
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Context: To design rational management regimes and identify novel therapeutic targets, it is essential to understand the biological drivers of the current epidemic of obesity. This review describes our current knowledge of genetic factors in obesity, drawing functional parallels in the underlying neuroendocrine mechanisms and suggesting promising new directions for research.
Evidence Acquisition: Published literature, addressing both the current knowledge of genetics of monogenic and syndromic forms of extreme obesity, and the emerging literature on genetic factors associated with more common forms of obesity are analyzed.
Evidence Synthesis: The current genetic evidence in obesity underlines the importance of neuroendocrine mechanisms of appetite regulation. Monogenic forms of disease explain 6% of children with extreme obesity, having hyperphagia associated with defects in the leptin-melanocortin pathway, as a central feature. Candidate gene association studies indicate that more subtle variations of the same genes also contribute to common forms of obesity. Well-powered genome-wide association studies recently identified FTO as a strong contributor to both childhood and adult obesity, demonstrating the power of such hypothesis-free analysis to provide new insights into the underlying pathogenic mechanisms of a common complex disease.
Conclusions: Although there has been some very heartening recent progress in elucidating genetic mechanisms underlying obesity, we are still a long way from explaining the high heritability of adiposity. Investigations of different forms of variation, such as copy number polymorphism, may extend our understanding of this condition.
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Introduction
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As obesity becomes ever more widespread and severe in westernized populations, presenting a growing burden for health care provision (1), the imperative to identify drivers for our burgeoning adiposity becomes increasingly urgent. The future does not look optimistic. The U.S. Center for Disease Control and Prevention reports that in 2007, not only had not one U.S. state reached the A Healthy People 2010 target to reduce the proportion of obese adults to 15%, but also in contrast, self-reported adult obesity had increased by 1.7% since 2005 (2). These trends are mirrored globally. In a recent report, the absolute numbers of obese individuals were projected to total 2.16 billion overweight and 1.12 billion obese by 2030 (3).
It is abundantly clear that despite intensive efforts to reduce adiposity by various programs of dietary restraint, exercise regimens, public health education, and drug therapies, there is currently no effective, long-term therapy for morbid obesity, other than bariatric surgery. Elucidation of the genetic contribution to the etiology of the condition, and definition of subtypes of obesity amenable to different approaches to management, may be our best hope of developing a nonsurgical therapy for this chronic disabling, disfiguring and often life-threatening condition.
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But Surely It Is All Caused by the Environment?
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Over the past three decades, there have been substantial changes in the human environment, including increased access to highly palatable, calorie-dense foodstuffs and decreased need for physical activity in daily lives. We may be the first generation of humans to live in an environment of such long-term gustatory abundance and leisure, and these conditions present a significant challenge to our metabolic regulatory systems, with 25.6% of U.S. adults being obese in 2007 (1), and the number of "super obese" individuals, with body mass index (BMI) greater than 50 kg/m2, increasing 6-fold in the last decade. The consequences of obesity for the individual concerned are severe and wide ranging, including social stigmatization and financial detriment (4, 5, 6), as well as increased risk of diabetes, cardiovascular disease, osteoarthritis, respiratory disease, and a range of cancers (7). In addition, obesity is associated with an increased incidence of psychiatric disease (8, 9) and with decreased cognitive function (10, 11), although the mechanisms underlying these phenomena remain to be elucidated (12). It is clear that this escalating epidemic is related to the recent environmental changes, but the relationship is not a simple one. Not all people are affected equally by our unhealthy lifestyles; some are protected from the deleterious effects of the obesogenic environment, whereas others carry gene variants rendering them particularly sensitive to it.
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So What Is the Evidence that Genes Are Involved at All?
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In fact, it is very robust, with twin studies giving heritability estimates of around 0.7 for BMI in adults and children (13), and comparable levels for other measures of adiposity: skinfold thickness, waist circumference, and total and regional fat distribution (14, 15, 16, 17, 18). This means that around 70% of the individual variation in adiposity between people is apparently due to genetic factors. People at high genetic risk for obesity are more susceptible to the effects of an unhealthy environment. Thus, as expounded by Wardle et al. (13), "Targeting the family may be vital for obesity prevention in the earliest years, but longer-term weight control will require a combination of individual engagement and society-wide efforts to modify the environment, especially for children at high genetic risk."
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Can’t Obese People Lose Weight if They Just Eat Less and Exercise More?
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Well clearly this is at least partly true, but we may be substantially overestimating our powers of self-determination with reference to certain aspects of behavior. Long term, almost no one can maintain significant weight loss after dieting (19) because eating behavior is under neuroendocrine control, and intake cannot be permanently repressed by conscious effort. The study of ob/ob and db/db strains of mice that spontaneously become obese because of hyperphagia, as well as suffering infertility and immunological deficit, highlights the role of leptin in control of food intake (20). Because these mice are not subject to the type of social effects commonly thought to be associated with obesity in humans (poor education, dysfunctional family situations, social exclusion, childhood sexual abuse, emotional stress, fast food outlets, or excessive use of television and computer games), they represented the first proof that it was possible to have a purely biologically based appetite dysregulation. The cloning of the leptin and leptin receptor genes was a real breakthrough in the understanding of appetite control and was swiftly followed by identification of the first examples of human monogenic obesity (21, 22). Individuals with severe defects in the leptin or leptin receptor genes are uncommon, but other monogenic forms of obesity caused by defects involving the hypothalamic leptin-melanocortin pathway are observed at a higher frequency: 1.8% of obese adults and up to 6% of early-onset severely obese children have dominant monogenic obesity caused by mutations in the gene encoding the melanocortin-4 receptor (23, 24), and other rare recessive mutations in the proopiomelanocortin and prohormone convertase 1 genes also result in hyperphagia and severe early-onset obesity (25, 26). Acting downstream of the leptin-melanocortin pathway, mutations in the neurotrophic tyrosine kinase receptor type 2 gene, which encodes the receptor for brain-derived neurotrophic factor (BDNF), also result in monogenic early-onset obesity (27). Individually, most mutations in the leptin-melanocortin and related pathways are uncommon, but each has a strong effect, leading inexorably to the phenotype of extreme obesity.
Other rare causes of severe obesity have also helped to pinpoint genes or genomic regions important for the maintenance of body weight. These have also tended to have a neuroendocrine basis, mediated largely through appetite dysregulation. The best-known example of this is Prader-Willi syndrome, in which the absence of the paternally inherited copy of a region on the long arm of chromosome 15 leads to insatiable hunger, obsessive food-seeking behavior, and consequent severe obesity, along with learning disability and dysmorphic features. The precise mechanism underlying the hyperphagia in humans remains to be determined, but recent analysis of a murine model of Prader-Willi syndrome has narrowed down the genomic region of interest. Mice with a deletion of the small nucleolar RNA cluster, Snord116, exhibit a defect in meal termination mechanisms, characterized by extended feeding duration and hyperghrelinemia (28). Some Prader-Willi-like patients have had a defect involving haploinsufficiency for the single-minded homolog 1 gene on chromosome 6, which encodes a transcription factor essential for formation of the hypothalamic paraventricular nucleus, and which was also identified as a candidate gene for childhood obesity in studies (29, 30, 31).
In another microdeletion syndrome, Wilms’ tumor, aniridia, genitourinary abnormalities, and mental retardation (WAGR) (a deletion of a region of chromosome 11p13, including the Wilms’ tumor suppressor and PAX6 genes, and characterized by WAGR), only around 50% of patients become obese. The explanation for this is found in the size of each patient’s mutation; in cases in which the deletion also included the adjacent BDNF gene, there was haploinsufficiency for BDNF (32), which acts downstream of the leptin-melanocortin pathway (33). Gray et al. (34) had already provided evidence that disruption of BDNF causes human obesity, and the WAGR data support this. Animal studies further support these data. Heterozygous Bdnf knockout mice exhibit hyperphagia and obesity, which is reversible by intracerebroventricular infusion of BDNF protein (35).
Another knockout mouse model has increased our understanding of appetite dysregulation in Bardet-Biedl syndrome, a ciliopathy with complex genetic etiology involving at least 12 genes, some of which may interact (36). The protein products of two of the homologous mouse genes, Bbs2 and Bbs4, are required for the correct localization of somatostatin receptor type 3 and melanin-concentrating hormone receptor 1 in central neurons, providing a potential molecular mechanism for the hyperphagia in Bardet-Biedl syndrome (37).
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What about More Common Forms of Obesity?
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It is clear from the study of rare obesity syndromes that the majority of molecular defects discovered so far are neuroendocrine in nature, with profound effects on feeding behavior resulting in severe early-onset obesity. The situation with common forms of obesity may differ. Most fat children go on to become fat adults, but many more people only become obese in adult life, particularly in middle age. Although subtle variants in the genes discussed previously are obvious candidates for contribution to common obesity, distinct genetic mechanisms may also be in play in adult-onset disease. In addition, different factors are likely to be involved in extreme adult obesity than in more common forms.
As with other complex diseases, a large number of candidate gene association studies, of variable power, have been performed in obesity and related phenotypes (reviewed in Ref. 38). By far the most strongly replicated candidate gene from these analyses is melanocortin 4 receptor, but other replicated associations include those with adipokine and adipokine receptor genes (including those encoding leptin and its receptor, adiponectin, resistin, TNF-
, and IL-6). In contrast to studies of rare childhood obesity syndromes, genes concerned with energy utilization have also been implicated in common obesity, with replicated associations with the genes encoding β-adrenergic receptors 2 and 3, hormone-sensitive lipase, and mitochondrial uncoupling proteins 1, 2, and 3 (38). Underlining the central role of behavioral stimuli in obesity, alleles of genes encoding dopamine, serotonin, and cannabinoid receptors (DRD2, HTR2C, and CBI) (38, 39, 40, 41) are also reported to be associated with feeding behavior and related traits.
The last 2 yr have seen a revolution in our approach to the study of complex disease as well-powered, hypothesis-free genome-wide association (GWA) studies have led to the identification of new candidate genes in various disorders, including type 2 diabetes and obesity. In the course of these studies, a new gene for obesity, FTO, was also identified simultaneously by three separate groups (42, 43, 44). This association has subsequently been confirmed by a number of GWA or candidate gene association analyses (45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61). The contribution of the FTO variant is fairly modest, with adult homozygotes for the risk allele having only a 2- to 3-kg increase in weight (43), but the obesity high-risk allele is common in Caucasian populations. Its effects begin early in life. Higher fat mass is observable from the age of 2 wk (61), and carriage of the allele is associated with higher BMI and reduced satiety in children (62). However, the most significantly associated single nucleotide polymorphism (SNP) is intronic, and the molecular mechanisms underlying the association remain unclear. The gene encodes a 2-oxoglutarate-dependent nucleic acid demethylase (63); the gene is widely expressed but at particularly high levels in the hypothalamus. There are contradictory reports of up-regulation and down-regulation in response to feeding and fasting between rats and mice (64, 65). In studies of humans with different genotypes, other workers report effects on insulin sensitivity in the brain (66) and on peripheral lipolysis (67). A third possibility is that the observed effect attributed to FTO is, in fact, a result of a ciliopathy resulting from dysregulation of an adjacent gene, FTM (68). Further work is required to determine which mechanisms are producing the major effect.
In addition to the studies reported previously, there are reports of association with the genes encoding b-catenin-like protein 1 (69), insulin-induced gene 2 (70) myotubularin-related protein-9 (71), ganglioside induced differentiation associated protein 1, and somastatin-receptor-2 (72), but these await independent replication by other researchers.
In general, the yield from GWA studies of obesity has been low so far, and some findings await independent replication. Most current GWA studies have only moderate power to detect common variants associated with a binary trait with a relative risk of around 1.2 or above, and it has been estimated that studies of 50,000 subjects or above are necessary to provide 90% power to detect variants with genetic effects of around that magnitude (73). Currently, the only feasible approach to increasing power is through large-scale metaanalyses, and we anticipate that such investigations will increase the yield of obesity associated loci.
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So What Have We Learned So Far?
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All of the genes currently known to cause monogenic or syndromic obesity are expressed in the brain and appear to exert their effects by modulation of feeding behavior. Common SNPs in several of these genes are associated with common obesity and with mild abnormalities in food intake behavior. The evidence for involvement of other mechanisms, such as altered energy utilization, is much less compelling. In this respect there is little evidence so far for the existence of "thrifty genes" (74), so that an alternative hypothesis proposed by Speakman (75), that accumulation of genetic factors predisposing to obesity results largely from genetic drift after the relaxation of selection resulting from lack of predation, is gaining additional credibility.
Our efforts to identify genetic factors in obesity have yielded some notable successes, but we are still a long way from explaining the high heritability of the condition. Most genetic association studies have been predicated on the idea that common genetic variants in relevant genes alter their function in relatively subtle ways, having a cumulative effect on risk of obesity. This is the "common variant-common disease hypothesis." However, there is an alternative possibility: that there exist in the population a large number of more deleterious variations, each one being individually quite rare (76, 77), although initial such studies of well-known candidate genes have not shown variation in coding sequences that would account for a significant fraction of obesity (78). Extensive resequencing will be required to identify such variants. Alternatively, the missing heritability may be accounted for by other genetic factors. One possibility is that a recently appreciated form of genetic polymorphism, genomic copy number variation, might make a major contribution to interindividual phenotypical differences (79). Copy number variation is widespread in the genome, including many genes and regulatory regions, and it has been estimated to account for around 18% of variation in gene expression between normal individuals (80, 81), but is nontrivial to genotype in the large-scale studies required to firmly establish potential associations with obesity. Other genetic effects, including epigenetic modifications, may also contribute to phenotypical variability. Our knowledge of genetic factors predisposing to obesity has increased rapidly over recent years, and the pace of this should accelerate as technologies for genome resequencing, detection of structural variants, and ultra high-throughput SNP genotyping continue to mature.
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Footnotes
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Disclosure Statement: The authors have nothing to disclose.
Abbreviations: BDNF, Brain-derived neurotrophic factor; BMI, body mass index; GWA, genome-wide association; SNP, single nucleotide polymorphism; WAGR, Wilms’ tumor, aniridia, genitourinary abnormalities, and mental retardation.
Received July 31, 2008.
Accepted September 15, 2008.
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Abstract
Introduction
