CHAPTER 10. The interplay of genes, lifestyle, and obesity Paul W. Franks CHAPTER 10 CHAPTER This chapter reviews the evi- long term [1]. Success in pharmaco- marketed for treatment of diabetes: dence supporting a joint effect of therapeutics for weight loss has also (i) metformin, which reduces hepatic genes and lifestyle factors in obesi- been meagre, and in some instances gluconeogenesis (the production of ty, focusing mainly on evidence from disastrous. A handful of anti-obesity glucose in the liver); (ii) sodium-glu- epidemiological studies and clinical medications have been approved cose linked transporter 2 (SGLT2) trials research. by the European Medicines Agency inhibitors, such as empagliflozin, Obesity is the scourge of most (EMA) and the United States Food which reduce re-uptake of glucose contemporary societies; about 40% and Drug Administration (FDA). One in the kidneys and are diuretic; and of adults worldwide are overweight of the most successful of these is (iii) glucagon-like peptide-1 (GLP-1) and 13% are obese (http://www.who. the lipase inhibitor orlistat. Howev- agonists, such as exenatide, which int/mediacentre/factsheets/fs311/ er, because orlistat diminishes in- diminish appetite by delaying gastric en/). Much of the burden that obesity testinal fat absorption, a frequent emptying. However, because all of conveys arises from the life-threat- side-effect of the drug is fatty stool, these drugs can cause side-effects ening diseases it causes, although which many patients cannot toler- and they are not all reimbursable by there are also direct consequences, ate. Other weight-loss drugs, such health insurance providers for treat- because quality of life is often dimin- as rimonabant, are approved for use ment of obesity, they are rarely used ished in people with morbid obesity in the European Union but are not primarily for weight reduction. as a result of social stigma and other widely prescribed because of safety The third weapon in the anti-obe- societal challenges. concerns and limited effectiveness. sity arsenal is bariatric surgery. Un- Although intensive lifestyle mod- Many other weight-loss drugs have like drugs and lifestyle intervention, ification leads to short-term weight been brought to market in the past which perturb the disease process, loss in most people, weight regain few decades, only to be withdrawn surgery can permanently alter the typically begins within a year of in- because of serious side-effects, in- disease trajectory. Therefore, long- tensive intervention, and only a small cluding death [2]. There are other term weight loss through surgery minority of the target populations are drugs that do achieve safe weight is generally sustained to a much able to maintain reduced weight in the loss, primarily those approved and greater degree than weight loss from Chapter 10. The interplay of genes, lifestyle, and obesity 79 lifestyle intervention or drug therapy. factors modulate a person’s response morphological features. Studies in However, like drug therapies, bariat- to weight-loss therapies might help adults have reported somewhat low- ric surgery is expensive – although to predict the response to different er heritability estimates for obesity. it is cost-effective for diabetes treat- types of intervention, by guiding One of the most eloquent adult ment compared with drug therapy therapeutic choices in ways that are twin studies assessed the heritability [3] – and is not risk-free; serious ad- more precise and effective than con- of body mass index (BMI) in several verse events [4] include about 4 in ventional approaches, thereby avoid- hundred male and female Swedish 1000 patients dying within 60 days of ing unnecessary side-effects and twins; about half of them had been surgery [5]. Thus, although surgery reducing costs. reared together, and the remainder is appropriate for a small minority of had been reared apart, having been morbidly obese patients, it is no pan- Why might gene–lifestyle adopted into different families soon acea for the obesity epidemic. interactions be relevant in after birth [8]. The study showed that Of the three core prevention and obesity? the concordance of BMI in mono- treatment options for obesity, behav- zygotic (identical) twins was about ioural interventions that favourably Germline DNA variants are especial- 70% regardless of whether the twins affect chronic energy balance are by ly appealing biomarkers for targeting had been reared apart or together, far the most compelling, not least be- obesity interventions, because they whereas the concordance in dizygot- cause diet and exercise are generally are randomly assigned at meiosis ic (fraternal) twins was substantially safe, are relatively inexpensive, and and are stable throughout a person’s less, suggesting a strong genetic convey numerous additional benefits life, rendering their associations with component to obesity. Importantly, to health and well-being that drugs phenotypes fairly robust to confound- however, as discussed later in this and surgery do not. However, the ing and reverse causation. DNA vari- chapter, the genetic aberrations that considerable therapeutic idiosyncra- ants are also the starting point of a cause obesity do so through a range sies of lifestyle therapy cause wide process called the central dogma of of diverse mechanisms, including variability in its effectiveness at a molecular biology [6], downstream of those that affect appetite, satiation, population level. Some of this varia- which a complex molecular cascade and energy expenditure. bility is due to the extent to which the ensues that translates the effects of However, knowing that obesity is participant adheres to the interven- extrinsic environmental exposures highly heritable does not necessarily tion, and some is due to differences (of which diet and exercise are major mean that it is the consequence of in the participant’s biology, which components in obesity) to the clinical gene–lifestyle interactions. To deter- modulates the effects of lifestyle in- phenotypes that characterize health mine this, one could test whether the terventions on rates of weight loss and disease. That molecular cas- obesogenic effects of lifestyle expo- and weight regain. cade is made up of gene transcripts sures (in epidemiological studies) or The common outcome variable in and proteins, as well as epigenomic response to weight-perturbing inter- obesity research and clinical practice features (in the form of methylation ventions (in clinical trials) are heri- is weight change, because it can be marks, open chromatin, histone table. In studies of twins in the USA assessed easily and inexpensively. modifications, etc.), small circulating exposed to long-term overfeeding Changes in the amount and deposi- molecules (metabolites), and an ar- [9] or exercise [10] interventions, the tion of adipose tissue and ectopic fat ray of peptide hormones and other concordance in adaptive response are probably more clinically impor- biochemical components. to the interventions was significant- tant phenotypes, but they are more Studies in twins provided some ly higher within twin pairs compared difficult to quantify. Beyond this, of the earliest compelling evidence with the concordance between unre- weight change should be more than that obesity is under a high degree lated participants for a range of body merely aesthetic; thus, the many of genetic control. A study of chil- composition measures, including clinical sequelae of weight change dren and adolescents showed that waist circumference, body fat per- should also be tracked. Neverthe- 82–90% of the phenotypic variance centage, and fat-cell diameter (for less, whether the outcome of lifestyle was explained by additive genetic exercise response). intervention trials is weight or a relat- factors [7]. The study used objective Collectively, there is compelling ed metabolic outcome, the response assessments of body composition evidence supporting the view that to the intervention is generally highly (dual-energy X-ray absorptiometry body corpulence in the free-liv- heterogeneous. [DEXA] and hydrostatic weighing), ing state and change in body cor- Therefore, quantifying and under- enabling the careful distillation of pulence with diet or exercise are standing the ways in which genetic body corpulence into its constituent governed to a considerable extent 80 by genetic factors. These are so- ments in expensive follow-up studies hensive analysis of FTO variation called quantitative genetics studies. (such as clinical trials) to test wheth- and explored interactions with ob- Unlike the molecular genetics stud- er a gene–lifestyle interaction has jectively assessed physical activity ies of the modern era, quantitative the potential for clinical translation. (via accelerometry). The trial tested genetics provides a broad-strokes The FTO example cited above for genotype–treatment interactions genome-wide overview of genet- was the first of several encouraging on changes in obesity-related traits ic influence on a phenotype but illustrations of gene–lifestyle inter- in the Diabetes Prevention Program offers no insights into the specific actions in obesity. The role of FTO (DPP), a randomized controlled tri- molecular aberrations (e.g. single variation in obesity was first de- al (RCT) of intensive lifestyle mod- nucleotide polymorphisms [SNPs], scribed in three papers published in ification, metformin, and placebo insertions and deletions [indels], and close proximity in 2007. Two of the control interventions