A crisis of fat? - Background information


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This guide provides background information on obesity, its causes, consequences and treatment, as well as providing an insight into the ethical, legal and social aspects associated with this disease.

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A crisis of fat? - Background information

  1. 1. Educators’ guide “A crisis of fat?” (Background information)AUTHOR FUNDED BY:
  2. 2. Table of contents1. Introduction 32. State of the art 3 2.1. What is obesity 3 2.1.1 How common is obesity and whom does it affect? 4 2.1.2. Is obesity the same as body fat? 6 2.2. Causes of obesity 7 2.2.1 Genes 7 2.2.2 Environment 10 2.2.3 Epigenetics: genes and environment working together 13 2.3. Physiological processes affecting energy balance and weight regulation 14 2.4. Consequences of obesity 17 2.5. Obesity treatment 20 2.5.1 Treatment approaches 203. Ethical, Legal and Social Aspects (ELSA) 23 3.1. Introduction 23 3.2. Is Obesity a health problem? 23 3.3. The causes of obesity 24 3.4. Treatment of Obesity 27 A crisis of fat? - 2 - Background information
  3. 3. 1. IntroductionThese teacher guidelines will give you information on the Xplore Health module “A crisis offat?”. It will first introduce the topic to enable you to prepare your lesson using the differentmultimedia tools that you will find on the website. The guidelines provide information on thestate of the art in this research field and on the ethical, legal and social aspects surroundingthis topic.2. State of the artA rising prevalence of obesity is seen around the world. Worried about the long-term threat tohealth from obesity, doctors and researchers are trying to understand what makes peoplebecome obese so that they can design treatments and prevention strategies.2.1. What is obesity?Obesity is defined according to body mass index (BMI), a simple measure that takes intoaccount a person’s height when understanding their weight. To calculate BMI (kg/m2), aperson’s weight in kilograms is divided by the square of their height in metres.The definitions of overweight and obesity for most people are:  Overweight: BMI greater than or equal to 25kg/m2  Obesity: BMI greater than or equal to 30kg/m2However, for people of Asian origin, lower cutoffs have been suggested due to their higherpercentage of body fat:  Overweight: BMI greater than or equal to 23kg/m2  Obesity: BMI greater than or equal to 25kg/m2Defining obesity and overweight in children is harder due to their changing body mass duringgrowth. Similar growth charts to those that define normal height and weight at different agesduring childhood have been produced to define obesity and overweight in children.  A crisis of fat? - 3 - Background information
  4. 4. 2.1.1 How common is obesity and whom does it affect?Key facts from the UN on obesity and overweight (fact sheet number 311, March2011):- Worldwide obesity has more than doubled since 1980- In 2008, 1.5 billion adults, 20 years and older, were overweight. Of these, over 200 million men and nearly 300 million women were obese.- 65% of the world’s population live in countries where overweight and obesity kills more people than underweight.- Nearly 43 million children under the age of five were overweight in 2010.Obesity and overweight are increasing in the UK and across the world. Currently, thecountries with the highest rate of obesity in adulthood include the USA (36% of men andwomen), Saudi Arabia (26% of men and 44% of women) and Egypt (18% of men, 40% ofwomen). In the UK, 26% of men and women are obese. Combined data on obesity andoverweight prevalence show several countries where less than 40% of the adult populationhave normal weight. A crisis of fat? - 4 - Background information
  5. 5. Data on the prevalence of obesity and overweight in children shows that these problems startin early life. In England, 23% of boys and 27% of girls are overweight and obese; in the USA,these figures are 35 and 36%. Of particular concern is not just the high prevalence of thesedisorders, but also the upward trend in obesity and overweight across the globe. Data fromcountries with rapidly enlarging populations and economies, such as India and China, show aprevalence of childhood overweight and obesity at 10-15%. These global trends are studiedclosely by international organisations, such as the International Obesity Task Force, whodescribe obesity as a ‘global epidemic’ and are concerned by the negative impact it is havingon health and disease and economic growth.Data on these trends is also collected on a local level, and collated into health profiles fordifferent regions by the Public Health Observatory. Recent data collected on the populationliving in Tower Hamlets, London shows that 26% of children in year 6 (aged 10-11) areobese, well above the national average of 19%. Adult obesity in Tower Hamlets is lessprevalent (19%), and this may suggest in increasing trend towards obesity from childhoodonwards. Most importantly, the association between obesity and other health conditions,such as cardiovascular disease, diabetes and stroke, is highlighted by high rates of theseconditions in Tower Hamlets, compared to the national average. Type 2 diabetes is stronglyassociated with obesity, and is found in 6% of the Tower Hamlets population (compared to5% in the UK), equating to approximately 14,000 people with the disease. The following mapshows how information about obesity (as well as other factors such as age, smoking anddeprivation) can be used to predict the risk of developing diabetes in the local population. A crisis of fat? - 5 - Background information
  6. 6. Fig. 1. Heat map showing the percentage of the adult population at high risk of diabetes in Tower Hamlets, London [From Noble et al, British Medical Journal 2012]2.1.2 Is obesity the same as body fat?All body fat stores contribute to body mass index, however research has shown that not allfat stores have the same impact on a person’s health. Visceral fat describes the fat locatedaround body organs such as the liver, kidneys and heart, and is thought to be metabolicallyactive and associated with insulin resistance (a precursor of type 2 diabetes), and high levelsof cholesterol. People with excess visceral fat also have an increased risk of heart diseaseand stroke.People with excess visceral fat tend to hold their extra weight around the middle of the body,causing a so-called ‘apple-shaped’ appearance. This is also sometimes known as centraladiposity or obesity, and can be defined by the ratio of a person’s waist to hip ratio. Men tendto have more visceral fat and be more centrally obese than pre-menopausal women (whotend to have more subcutaneous fat and be ‘pear-shaped’). People from different ethnicgroups also have a varying risk of increased visceral fat: people of Asian origin are A crisis of fat? - 6 - Background information
  7. 7. particularly at risk, and this may underlie their increased risk of disorders such as type 2diabetes. The lower BMI cutoffs for overweight and obesity in Asian people is to take intoaccount these differences.Body fat is difficult to measure, but can be measured using DEXA (dual energy X-rayabsorptiometry) as well as MRI and CT scans. Bioelectrical impedance analysis is a simple,non-invasive technique, often performed in pharmacies and gyms, but is rarely accurate.2.2. Causes of obesityObesity is a so-called ‘complex disease’ where it is known that several different factors play arole in causing the disease. These causes include a person’s environment (e.g. what theyeat and how much exercise they do) and their genes. A person’s genes and environment arethought to work together to predispose someone to obesity.2.2.1 GenesEvidence that a person’s genetic make-up plays a role in their risk of becoming obese comesfrom many different types of research study. Doctors working with obese patients in theirclinics often see that patients who are overweight and obese have family members who havethe same pattern of bodyweight. This can often imply a genetic link, but as patterns of eatingand exercise often also run in families, this does not make it easy for researchers to decidewhether a family is sharing similar obesity genes, or whether they are sharing similar‘obesogenic’ environments. Studies of twins have helped clear up this uncertainty.Monozygotic (identical) twins share the same genes but dizygotic twins do not, and neithertype of twins has the same environment. Estimates of how ‘heritable’ obesity is can becalculated from looking at the intra-pair correlation of weight: monozygotic twins have ahigher heritability of weight and obesity than dizygotic twins, suggesting a genetic influenceon weight (see below). Further evidence of the importance of genetics over environmentcomes from adoption studies, where twins and siblings were reared apart, as was sometimesnormal practice in the 1940s. Researchers found that a familial tendency towards obesitywas still apparent in twins and siblings reared separately, suggesting an overriding influenceon obesity from genetics, despite different environments. A crisis of fat? - 7 - Background information
  8. 8. Fig.2 Body Mass in twins [Borjeson, Acta Paediatr Scand, 1976]Finding obesity genesThe last few decades of genetic research have taken many approaches to discover genesthat could cause obesity. These genetic studies have taken two main approaches: (i)identification of common genetic variants (or single nucleotide polymorphisms) usinggenome-wide association studies (GWAS), and (ii) identification of rare gene defects (suchas mutations and deletions) with candidate gene studies. These two approaches highlight thecomplexity of understanding genetic factors in obesity as they study two very differentaspects of obesity: the common causes of obesity (using GWAS) and the rare causes ofobesity (using candidate gene studies). Identification of common genetic variants associatedwith obesity helps researchers to understand the risk to large numbers of people, but thesevariants are only associated with a small increase in risk (e.g. each copy of the FTO riskallele is associated with a 0.45kg/m2 increase in body mass index). In contrast, identificationof a rare variant may yield insight into some unusual forms of obesity, such as congenitalleptin deficiency, but these are unlikely to be present in the majority of people with obesity.Many people have questioned whether these recent genetic insights are worth theconsiderable financial investment put into them. Understanding common variants may enabledoctors to build up ‘risk profiles’ for patients to help inform them more accurately about theirown genetic risk of developing obesity. It may also be possible to use this genetic information A crisis of fat? - 8 - Background information
  9. 9. to tailor treatments and lifestyle interventions that are known to be more or less effective forcertain risk groups according to their genetic make-up. For those people with rare forms ofobesity, understanding the exact gene defect causing their condition may enable them to useprenatal screening in the future to prevent the same condition being present in offspring.Single gene defects may also be targeted by gene therapies or specific tailored treatments,such as the administration of leptin treatment to the few sufferers of congenital leptindeficiency. For any genetic researcher, the ‘translation’ of their genetic insights to clinicalpractice is important to justify their study. Genetic researchers also need to consider theethical aspects of their work and the potential for genetic information to be misused. Type of genetic variation Rare single gene variants Multiple common gene variants Effect on body weight Account for a lot of extra weight Account for a little bit of extra in very few people weight in a lot of people Examples Ob gene, MC4R gene FTO gene, TMEM18 gene Association with other Can be associated with rare One of many ‘normal’ varied clinical conditions diseases, e.g. congenital leptin human characteristics, but can deficiency, MC4R deficiency also associate with other common diseases, e.g. type 2 diabetes How are these found? Candidate gene studies, animal Genome-wide association studies studies, exome sequencing Potential relevance Prenatal genetic testing and Understanding risk of disease gene therapy and tailoring disease prevention strategies. A crisis of fat? - 9 - Background information
  10. 10. 2.2.2 EnvironmentThe environment can contribute significantly to a person’s weight, irrespective of their geneticmake-up. The environment is a loose definition that can take into account a range of factorsthat affect (a) energy intake, such as the quantity, cost and type of food that is available, theirappetite and behaviour towards food, and (b) energy expenditure, including physical activitylevels and patterns of sedentary behaviour.In simplistic terms, a balance exists between the energy intake and energy expenditure, suchthat if the former exceeds the latter, there will be net weight gain. For an ‘average’ person,the excess energy intake required to cause weight gain may be as little as 100 calories perday to cause a 5kg weight gain over a 1 year period. Although calculations such as this helpus to understand how small amounts of excess energy intake can influence a person’sweight, they do not take into account the range of other factors that affect propensity toweight gain. Energy intake Energy expenditure Food intake Basal metabolic rate (depends on body stores and contribution from fat/carbohydrates/protein) Individual behaviours – hunger and Thermogenesis, e.g. from food intake and appetite, habit, comfort muscle activity Societal and economic influences Physical activity (e.g. volitional exercise or e.g. cost and availability of food normal activities such as sitting, working, fidgeting, posture)Energy intakeOver the last century, improving economic circumstances in developed countries haveenabled the production of cheap, high-energy food that can be transported around the world.The increased accessibility of calorific food, and a food industry that promotes certain eatingpatterns, are thought to underlie the rapid increase in obesity amongst the world’ populationover the last few decades. In contrast, economic difficulties facing the world’s poorestnations, as well as famine cycles, prevent many populations from suffering the epidemics ofoverweight and obesity that much of the global population is experiencing. Migration patterns A crisis of fat? - 10 - Background information
  11. 11. of certain ethnic groups highlight the importance of the external environment andaccessibility to food, such as that seen when Asian people move from a rural to urbansettings in Asia, or to a more ‘Westernised’ country such as the UK. The focus on population-wide influences on energy intake, such as the role of the food industry, is key to preventionstrategies in obesity.Individual determinants of energy intake are also important to the development of overweightand obesity. A range of factors influences an individual’s energy intake, and this ranges fromhunger and appetite leading a person to eat, the satiety, satisfaction and comfort derivedfrom eating (whether as meals or snacks), as well as patterns of habitual eating. Theneurobehavioural mechanisms underlying all of these factors are increasingly understood,and explain the complex relationship between all of these factors, many of which arephysiologically and genetically regulated.Energy expenditureThe basal metabolic rate (BMR) of an individual accounts for 60-75% of their daily energyexpenditure. The BMR refers to the amount of energy the body requires to maintain normalbody functions in a normal environment, e.g. homeostatic cellular processes that keep thebody alive. The BMR itself is determined by a person’s body size and composition, and inparticular, their fat-free mass. The fat-free mass of a person is composed of their mostmetabolically active tissues, such as the heart, brain, kidneys and liver. Fat, or adiposetissue, contributes 20-30% of body weight, but only 3-5% of resting metabolic rate. It istherefore understandable that a person with excessive body fat content is relatively‘inefficient’ in their overall basal metabolic efficiency, with less calories used to keep theirbody fat stores in a metabolic equilibrium. This inefficiency is one reason in which overweightand obese people find it difficult to lose weight, as they have to increase their energyexpenditure significantly to overcome this net energy surplus.Thermogenesis, or heat production by the body, is another important determinant of energyexpenditure. The body produces heat in many different contexts: in response to foodconsumption, from muscle activity during exercise, during a stress response when hormonessuch as adrenaline are produced, and finally in low temperature conditions when the bodyshivers to produce heat. A crisis of fat? - 11 - Background information
  12. 12. The processes regulating basal metabolic rate and thermogenesis are not voluntary, andtherefore individuals have little ability to change these should they be trying to lose weight.However, it is hoped that research into these processes may yield some novel methods ofpharmacological treatment for obesity in the future.Physical activity is a significant component of energy expenditure, and one that is modifiablethrough individual behaviour such as exercise. Large studies show the benefits of regularphysical activity on weight and risk of diseases, including type 2 diabetes, cardiovasculardisease, stroke and premature death. Regular, intensive physical activity, and achieving anegative energy balance can be a successful means to weight loss, and in particular canresult in the loss of abdominal fat. However, an increase in physical activity may beinsufficient for an obese person to achieve significant weight loss; and only when this iscoupled with dietary change may the necessary weight loss ensue. UK recommendations onphysical activity (see below) are based on the knowledge that regular physical activity isrequired to maintain weight in normal, healthy people. Societal and behavioural factors alsoplay a significant role in activity levels, with increasing car use, and sedentary behaviour athome, playing an important role in the increasing rates of obesity and overweight.Children, aged 5-18 years Adults, aged 16-64 years Older adults, aged 65 +Moderate-vigorous physical 150 minutes of moderate Any amounts of physical activityactivity for at least 60minutes intensity activity (at least 10 will provide health benefitsper day minutes at a time), e.g. 30 minutes 5 days per weekVigorous intensity activities, Or, 75 minutes of vigorous Aim to be active daily, and ifsuch as those that strengthen activity per week possible, aim for the samemuscle and bone, at least 3 amount of physical activity asdays per week younger adults Obese adults should aim for 60- 90 minutes of moderate intensity physical activity on most days.Moderate physical activity means that you get warm, mildly out-of-breath, and mildly sweaty,and can include brisk walking, jogging, cycling, swimming, dancing or heavy housework or A crisis of fat? - 12 - Background information
  13. 13. DIY. Vigorous physical activity will include more intensive sports that result in being moreout-of-breath, sweaty or an increased heart rate.2.2.3 Epigenetics: genes and environment working togetherEpigenetics is an emerging area of science that is uncovering the link between our genesand the environment they function in. Humans, mammals, and many other species, have anepigenetic ‘landscape’ across the genome, composed of a range of different chemical andstructural modifications. This landscape varies according to the genetic architecture, formingcertain patterns in gene promoters, introns, exons and outside of genes. One commonlystudied epigenetic mark, DNA methylation, occurs predominantly at CpG dinucleotidesacross the genome and can affect the machinery of gene transcription and whether a genegets switched on or off (gene expression). Other epigenetic marks, such as histonemodifications, can affect the structure and function of proteins with wide-ranging downstreameffects. From these descriptions, it can be seen that epigenetic modifications interact with ourgenetic make-up very closely. To understand this better, some researchers have used ananalogy of an orchestra conductor (the epigenetic modification) in charge of many musicians(the DNA code) to create music (gene functioning).The environment in which an organism lives may also have a significant effect on itsepigenetic profile. In this context, the ‘environment’ of an organism might include certainnutritional deficiencies, a high calorie food intake, smoking, or exposure to drugs and toxins.These adverse environmental conditions can directly affect epigenetic marks withdownstream effects on gene expression and resulting in a change in phenotype, such asonset of disease. Mammalian epigenetic profiles are thought to have particular susceptibilityto changes in environment during development as their epigenetic marks are erased andreplaced when an embryo is formed. This area of research is called ‘fetal programming’, anddescribes how the maternal in utero environment may ‘programme’ an individual fetus todevelop obesity and type 2 diabetes in adulthood.Understanding the role of epigenetic processes in mediating gene-environment interactionsis giving exciting insight into the causes of complex diseases such as obesity and type 2diabetes. Researchers at the Blizard Institute, Queen Mary University, London (Finer,Rakyan, Hitman) have identified that the presence of a genetic polymorphism associatedwith increased risk of obesity at the FTO gene changes the epigenetic state of that generegion. A different methylation pattern in the FTO gene in people carrying the obesity risk A crisis of fat? - 13 - Background information
  14. 14. allele may affect how the gene works and could provide a route to understand themechanisms underlying obesity. Epigenetic changes have also been found in fetalprogramming studies such as the Dutch Winter Hunger Study that identifies higher rates oftype 2 diabetes in the adult offspring who were born to famine-exposed mothers during the1940s. Another study has shown that mothers in India who are deficient in vitamin B12 (dueto the lacto-vegetarian diet that many Hindu Indians follow) have children who are atincreased risk of obesity and type 2 diabetes by the age of 6 years. These findings arethought to underlie the concept of the ‘thrifty’ phenotype, in which there is an adaptationtowards an environment of nutritional deprivation, set down in early life. Other researchersthink that there may also be a ‘thrifty’ genotype in populations that have evolved to cope withnutritional deprivation. It is thought that the ‘mismatch’ between these thrifty developmentalorigins, and an actual environment of nutritional excess in later life, may be a high-risksituation for individuals to become obese and develop type 2 diabetes. Many researchershave suggested that this theory may explain the recent Asian epidemic of obesity and type 2diabetes as populations have changed rapidly over recent generations from living in ruralareas (with nutritional deprivation and high physical activity levels) to urban areas where foodis in excess and physical activity levels drop.2.3. Physiological processes affecting energy balance and weight regulationAs described above, obesity comprises a complex clinical condition, with numerousunderlying genetic and environmental triggers. These influences are now understood toaffect a wide range of physiological processes in the regulation of overall energy balance.Such processes include neurobehavioural pathways and gut-brain signaling pathways thatwork together to achieve homeostasis in the body. An expanding knowledge of thesecomplex pathways is yielding significant insights into the factors that control body weight,such as appetite, satiety and eating behaviours.The homeostatic control of energy balance (and therefore body weight) requires the brain toact as the chief regulator, coordinating metabolic signals from peripheral tissues, paracrineand endocrine hormone signaling, and feedback from the nervous system.Metabolic signals, e.g. glucose and free fatty acidsIngestion of food and the peripheral metabolic processes in the body is central to theproduction and utlisation of fuel for energy metabolism. Variation in levels of these A crisis of fat? - 14 - Background information
  15. 15. metabolites, such as after a meal, will set off a cascade of peripheral metabolic processesdesigned to achieve homeostasis. These processes include gluconeogenesis,glycogenolysis and glycolysis (to produce glucose for cellular processes) and glycogenesis(where glucose is in excess and is turned into fuel for storage). Like glucose, free fatty acids(from circulating trigylcerides) provide a rapid energy source for metabolism and cellularprocesses (from storage in adipose tissue) and can readily turn into fuel stores. Thesemetabolic signals, as well as others, are the trigger to more complex signaling within thebody that not only keeps body systems working efficiently, but is also responsive to states ofenergy influx, or extra requirement. The signaling that is required comes from a combinationof processes, driven mainly by hormonal and nervous systems.Hormonal signalsThese function on both a local (paracrine) and systemic (endocrine) level, and includenumerous peptide hormones with wide-ranging effects. Leptin is one such importanthormone, produced peripherally by adipose cells according to the current size of fat stores inthe body. It is the main message to the brain, via other circulating hormones such as insulin,on what is happening in the peripheries of the body and therefore how the brain shouldregulate overall energy balance (e.g. to try and achieve a negative energy balance if fatstores are excessive). It is thought that abnormalities in this process of leptin and insulinsignaling may predispose to obesity and may offer a therapeutic target in the future. Otherimportant signaling hormones include gut peptides, such as glucagon-like peptide 1 (GLP1)and cholecystekinin (CCK). These peptide hormones are produced in the gastrointestinaltract in response to food ingestion, and provide an efficient and responsive feedback systemto other hormones to regulate the metabolic environment (e.g. via insulin to normalise post-meal glucose levels) and to the brain to control appetite and induce a feeling of fullness aftera meal. In obesity and type 2 diabetes, this efficient gut peptide response to a meal can beblunted, and newer drug therapies are designed to restore the efficient functioning of thissystem. Other important hormone regulators of energy balance include the more commonly-known hormones produced in response to hypothalamic-pituitary signaling to peripheralendocrine organs such as the adrenal gland (corticosteroids and sex hormones) and thyroidgland (thyroxine) as well as the production of growth hormone by the pituitary itself. Theseendocrine hormones can affect the basal metabolic rate (e.g. thyroid and sex hormones),insulin sensitivity (corticosteroids), fat mass (growth hormone) as well as providing a complex A crisis of fat? - 15 - Background information
  16. 16. interaction between many of the circulating metabolic signals and paracrine signals alreadydiscussed.Nervous system signalsThe autonomic nervous system which includes both sympathetic and parasympatheticnerves, carries homeostatic feedback signals to and from the brain from peripheral tissues inthe body in relation to energy balance. Peripheral effects of these neural stimuli include theproduction of insulin and catecholamines (e.g. adrenaline and noradrenaline) that in turnregulate peripheral processes of energy balance. The vagus nerve carries important nervesignals back to the brain from mechanoreceptors in the stomach in response to their beingstretched by ingestion of a meal.Within the brain, several important structures receive the feedback signals outlined aboveand provide a responsive signal back to the peripheries. The key neuroanatomical regionsare in the hypothalamus and brainstem, and importantly, these areas lack an effective blood-brain-barrier, allowing easy recognition of signaling molecules and metabolites in thesystemic circulation. Within these brain regions, several specific neuropeptides communicateand coordinate the complex messaging that is required to achieve optimal energy balance.Important neuropeptides include neuropeptide-Y (NPY), alpha-melanocyte stimulatinghormone (a-MSH), amines (e.g. serotonin, acetylcholine, adrenaline, noradrenaline) andamino acids (e.g. glutamate and GABA).In addition to the hypothalamus and brainstem, other brain regions are emerging asimportant players in subtle neurobehavioural responses to food, such as reward behaviours,motivation, and the hedonistic aspects of food intake. These brain regions include thenucleus accumbens, and amygdala and contain many dopaminergic neurons. These brainregions interact closely with the cortical function of the brain, including that of taste and visualrecognition of food, and a conscious understanding of food, appetite and hunger.Understanding the complexities of these neurobehavioural mechanisms, and theirrelationship to the homeostatic control of energy balance is crucial to develop a deeperunderstanding of obesity. At the present time, many researchers are studying these brainprocesses to try and understand whether in some people they malfunction and predispose toobesity. Animal models, and studies of humans with rare monogenic forms of obesity isproviding significant insights, and this is being applied to larger studies of obesity to see if A crisis of fat? - 16 - Background information
  17. 17. they may have a role in common obesity. It is hoped that a detailed understanding of thispathophysiology will result in targeted therapies that treat the higher control of food intakeand appetite. 2.4. Consequences of obesityObesity and overweight predispose to a number of related ‘metabolic’ disorders that canincrease a person’s risk of morbidity and mortality. The risk of death is increased in peoplewith obesity mainly due to the excess risk of cardiovascular disease and cancer. Even whenadjusting for overall activity levels, smoking and other relevant factors, obesity is known to bean independent risk factor for premature death.Obesity-related complications relate to the complex pathophysiological problems associatedthe disorder, and are wide-ranging. In relation to the obesity itself, the onset of thesecomplications is often silent or delayed, but provides an important focus for intervention asthey underlie the morbidity and mortality of obesity. A crisis of fat? - 17 - Background information
  18. 18. Mechanisms Associated riskMetabolic disorders Adipocytes in excessive visceral fat Individuals with a BMI of Type 2 diabetes stores, are large in size and produce 25-29.9 are twice as likely excessive amounts of cytokines, such to develop type 2 High cholesterol and as IL-1, IL-6 and TNF-alpha. diabetes, and for a BMI of triglycerides Suppression of adiponectin production 30 or greater, the risk is (dyslipidaemia) reduces the body’s sensitivity to sixfold. Fatty liver disease insulin. The overall result of these Polycystic ovarian factors is to increase insulin syndrome resistance, one of the main features of type 2 diabetes. An increase in free fatty acids passing through the portal venous circulation also results in excessive production of certain lipid particles (e.g. VLDL) that further increases the production of insulin into the systemic circulation, compounding the effects of peripheral insulin resistance. Chronically high levels of insulin (due to insulin resistance), as well as changes to sex hormone metabolism can result in polycystic ovarian syndrome, which is manifest by chronic anovulation and raised androgen concentrations.Cardiovascular disease Adipocytes produce hormones, such The risk of high blood Hypertension as angiotensingen, that can increase pressure is 5 times higher blood pressure by direct effects on the in people who are obese. Ischaemic heart disease vascular endothelium. Obese people Strokes also have a raised total circulating blood volume and this raises the viscosity (thickness) of blood as well as increasing its clotting ability (via production of pro-thrombotic factors). These factors all increase the risk of hypertension, but also play a role in the development of atherosclerosis. A crisis of fat? - 18 - Background information
  19. 19. Mechanisms Associated risk The dyslipidaemia associated with obesity also predisposes to the development of atherosclerosis. When this pathological process affects coronary arteries, it can result in angina and heart attacks; in the cerebrovascular circulation, it results in TIAs and strokes.Cancer The excess risk of cancer in people At least 10% of cancer e.g breast, colon, who are obese is thought to be due to deaths are thought to be endometrial, kidney, many different factors, including the due to obesity prostate, oesophageal pro-inflammatory state, changes in cancers metabolism of sex hormones, and insulin resistance.Bone and joint disease Increased mechanical stress on joints arthritis from excessive body weight can cause arthritis. Arthritis is common in obesity, osteoporosis and is often manifest as back pain, disability knee and hip problems, and chronic disability. Reduced bone density can also occur, due to vitamin D deficiency and higher bone turnover due to sex steroid hormone imbalance. Reduced bone density, or osteoporosis, can lead to fractures and further disability.Respiratory disease These disorders result from the obstructive sleep apnoea restriction to breathing function due to excessive body fat, fatty tissue in the obesity hypoventilation neck and nasal polyps obstructing the syndrome upper airways, and hypothalamic disturbance of breathing patterns.Psychological problems Mood disturbances, such as Women in the US who are depression depression and anxiety, are more obese have a 37% common in people with obesity. This is increased risk of anxiety thought to be due to a range of factors, depression. A crisis of fat? - 19 - Background information
  20. 20. Mechanisms Associated risk including behavioural disturbances associated with trying to lose weight, dissatisfaction with body image, and social stigma.Pregnancy complications Obesity in pregnancy is increasingly common due to the increased prevalence of obesity in young people. Obesity in pregnancy puts both mother and baby at risk, due to higher rates of gestational diabetes, pre-eclampsia and fetal macrosomia.2.5. Obesity treatmentThe benefits of weight loss in obesity and overweight people are significant. TheCounterweight Programme has estimated that for an obese person with a BMI of >32.5kg/m2, the benefits of 10% weight loss include a 9-fold decrease in type 2 diabetes, 6-folddecrease in dyslipidaemia and hypertension and a 4-fold reduction in cardiovascular disease.The question is how to achieve this weight loss. The view held by many to just “eat less andexercise more” is correct in that these are the best strategies to achieve a negative energybalance, but is overly simplistic. The neurobehavioural mechanisms in energy regulation andthe knowledge that individuals with a high fat mass are ‘energy inefficient’, highlights thecomplexity of the underlying pathophysiological processes in obesity that are difficult toovercome to achieve weight loss.2.5.1 Treatment approachesLifestyle intervention, including diet and exerciseMany studies show the effectiveness of lifestyle interventions in both the prevention andtreatment of obesity. Lifestyle interventions can include a range of different approaches, buttheir cornerstone is to achieve a negative energy balance through dietary change andincreased physical activity. For those people who are able to adopt significant lifestyle A crisis of fat? - 20 - Background information
  21. 21. changes and maintain them in the long-term, the effects on obesity and the development ofobesity-related complications also last into the long-term. In contrast, ‘quick fix’ interventionssuch as crash diets, whilst they may achieve short-term weight loss, rarely produce medium-or long-term effects on body weight. An understanding of the neurobehavioural mechanismsthat control energy balance, as well as the role of higher brain functions, such as rewardbehaviour and motivation, that can malfunction in obesity give an insight into why a ‘lifestyleapproach’ to achieving weight loss is difficult.Drug treatmentsOver recent years, several different drug therapies have been trialled and used in thetreatment of obesity. Large clinical trials of some drugs have shown the beneficial effects onweight loss from drugs such as sibutramine and rimonabant that work mostly centrally onappetite and energy regulation. However, with increasing use in obese populations, side-effects of these drugs became apparent, including an increase in cardiovascular risk withsibutramine, or mood disturbance and suicide with rimonabant, and have led to thewithdrawal of both of these drugs. Pharmaceutical companies are continuing to work onthese types of compounds, trying to exploit their potential benefits in newer drugs without theassociated risk of side effects. The mainstay of drug therapy at the present time is orlistat, adrug that inhibits pancreatic and gastric lipases, preventing the breakdown of triglycerides inthe gut and therefore reducing their absorption and contribution to energy intake. Thebenefits of this drug are modest, achieving on average 2-3kg of weight loss over a 1 yearperiod of taking the drug. However, the concern raised by many patients who take this drugis that it causes gastro-intestinal side effects due to the rapid passage of high fat foodsthrough the GI tract, resulting in flatulence and diarrhoea. These side effects stop manypeople from taking the drug, but for those who can tolerate them, the drug can be helpful inthe management of obesity.Newer drug therapies available to treat obesity and type 2 diabetes include the GLP-1agonists, such as liraglutide and exenetide. This drugs work on gut peptide signalingcascade that is blunted in type 2 diabetes and obesity. As described earlier, these gutpeptides, such as GLP-1, are responsive to food intake in the stomach, producing a cascadeof effects to metabolise glucose and signal to the brain to reduce further food intake andappetite. The drugs used in this category mimic the natural GLP-1 response in normalindividuals. These drugs are relatively new, and their mechanisms of action are not fullyunderstood, but they seem to be effective in producing modest weight loss as well as A crisis of fat? - 21 - Background information
  22. 22. diabetes control over 1 year. Longer-term studies to test their efficacy in maintaining thisweight loss as well as reducing obesity-related complications are awaited. Furthermore,these long-term follow-up studies will also provide vital information about their safety andincidence of side effects.Bariatric (weight-loss) surgeryCurrently, bariatric surgery is the most successful means to achieve significant and long-termweight loss in obese individuals and prevent or treat obesity-related complications. Severaldifferent surgical approaches exist, including gastric banding and bypass operations. Theseoperations are thought to induce weight loss through a variety of different means, includingthe restriction of food into the stomach, promoting early satiety and reduced appetite, as wellas malabsorption from the gut and therefore reduced energy intake. Large studies show thatthese operations, and especially gastric bypass, can achieve significant weight loss of 10-30%, as well as a significant reduction in mortality of up to 40%. These beneficial effects arethought to outweigh the potential risks of performing surgery in obese individuals, andstudies also show that these operations are highly cost-effective as they reduce the expenseassociated with long-term treatment of obesity-related complications such as disability andtype 2 diabetes. At the present time, surgery is an option for individuals with a BMI>40kg/m2, or >35kg/m2 if associated with obesity-related complications such as type 2diabetes or obstructive sleep apnoea. In the UK, these criteria are suggested by the NationalInstitute of Clinical Excellence, based on extensive research and evaluation of their cost-effectiveness, however on a local level, access to these operations is sometimes restricteddue to short-term budgetary concerns of local health care organisations.Psychological therapiesThe neurobehavioural processes underlying obesity, including systems that promote ‘reward’and ‘motivation’ from eating can be targeted through specific psychological techniques suchas cognitive-behavioural therapy. This treatment approach can also be useful due to the highrates of psychological problems, such as depression and anxiety, in people with obesity.Most specialist obesity services offer tailored psychological support and treatment forpatients. In children with obesity, such approaches often include family-based interventions,understanding that the tendency towards obesity may be driven by familial eating patternsand behaviours at home. A crisis of fat? - 22 - Background information
  23. 23. Novel therapiesNewer drug therapies are hoped to provide safe and effective non-surgical treatments forobesity, and this is an area of rapid development by pharmaceutical companies. Withincreasing understanding of the pathophysiology of obesity, new therapeutic targets aresuggested, such as those that work on gut-brain signaling pathways and the more complexbehavioural aspects of food intake.3. Ethical, Legal and Social Aspects (ELSA)In this section you will find a number of opinions and incentives for discussion in class onethical, legal and social aspects (ELSA) related to “A crisis of fat?”:3.1. IntroductionObesity is a growing problem for global health, both in the developed world and in newlyindustrialising countries. How we think about, and tackle, obesity will have a significantimpact on rates of diabetes, heart disease, joint problems, and many other health conditions.Obesity is a complex social and medical problem, and public and professional attitudes toobesity contribute to this complexity.3.2. Is obesity a health problem?One initial reaction to the public health challenge of obesity is to argue that overweight orobesity are not health problems, except in the most extreme cases. Many people who wouldbe considered clinically obese do not consider themselves to be overweight (and manypeople who are not clinically obese consider themselves to be overweight – not simplypeople who suffer from anorexia nervosa or bulimia, but people who are in the normal rangeof “body-consciousness”).A commonsense view sees variation in human body size as to be expected, and thus normalrather than pathological. This is not to say that body size doesn’t attract judgement andcomment – it does. Societies have complex cultural attitudes to body size to do with howpeople understand beauty, fitness, care over personal appearance, signals of prosperity andso on.One of the most difficult challenges for health promotion is how to educate people aboutwhat, from a clinical point of view, obesity is (which may not match the commonsense A crisis of fat? - 23 - Background information
  24. 24. perception of being “heavy” or “fat” or “big-boned” or, for babies, “bonny”), without trading onor exaggerating the stigma which attaches to some forms of obesity. Attitudes to obesity arelinked quite strongly to social expectations and comparisons with near neighbours and familymembers: someone is not likely to consider themselves as overweight if they see themselvesas typical of their own family and friendship network.Apart from the extreme cases, people don’t often experience obesity directly, or, in the shortterm, experience health problems caused by obesity. Even where they do, they may considershortness of breath, for instance, as just a sign that they aren’t very fit, and this may notbother them, or indeed be a source of humour. In most cases, the consequences of obesitymaterialise over time, and people are either unaware of them, or discount their importancerather heavily. So, while tackling obesity is important both for population health and forindividual health, it can be hard to persuade people of this, without appearing to be moralisticor bullying. By the time a serious health consequence of obesity has materialised, it may betoo late to do much more than control the symptoms and repair the damage as best may be.3.3. The causes of obesityPersonal behaviourOne of the challenges of obesity from a health promotion point of view is that once theperson has accepted that obesity may be a health problem in general, and that it may be (orbecome) one for them personally, lay theories of the causes of obesity come into focus.People’s understanding of the behaviours which lead to obesity, or which can control ormove away from obesity, are complex, and may rest on mistaken or partial understandingsabout eating patterns, the nutritional contents of different kinds of food, the amount of foodthat constitutes a healthy intake, the efficacy of dieting in different ways, the role of exercise,and so on. In addition to their “health beliefs”, it is also well known that changing old habitsand acquiring new ones is hard, and the “cognitive biases” which make changing presentbehaviour to achieve long term but remote benefits are deeply entrenched in humanpsychology.On the other hand, it is also evident that there is a difference between how we judge our ownbehaviour and how we judge that of others. While some of the time we might be moreforgiving or tolerant of others behaviour, much of the time we are all too willing to believe thatothers’ behaviours are due to idleness, greed, fecklessness, or lack of willpower, whereas A crisis of fat? - 24 - Background information
  25. 25. our own behaviours are either rational, sensible and indeed no one’s business but our own orhard to change because of “real” difficulties which are “genuine” barriers to behaviour change(unlike those faced by the idle, feckless, etc. other person who is just weak-willed).Nowhere is this inconsistency in thinking about behaviour more obvious than in debatesabout personal responsibility for ill health (or obesity as a precursor to ill health). Becauseobesity is often attributed to moral failings like greed or irresponsibility, a common view isthat the obese person should not receive the same level of help and support than someonewhose diabetes or heart disease is caused by some factor we are more willing to considerindependent of personal conduct. And even within obesity, someone whose overweight isattributed to a “hormone problem” may receive more sympathy than someone whoseoverweight is attributed to a lack of self-control.Not only do these debates influence the public attitude to treatment of obesity itself, they areeven more influential in debates about the treatment of the health consequences of obesity(heart disease, diabetes and so on) where a persistent theme seems to be that “self-incurred” health problems should be a lower priority than “no-fault” health problems.Genetics and physiologyFrom the ethical point of view the main issue raised by the genetics and physiology ofobesity is in informing public attitudes to obesity and the perceived contribution of personalbehaviour. The genetics and physiology of obesity are intricate, and there is not likely to be asimple genetic test, or set of tests, which could act as a screening test for the risk of obesity,or obesity-related illness.The main contribution of genetics and physiology to the clinical medicine of obesity is likely tobe in understanding causal pathways which can lead to medical treatments (consideredbelow). To the extent that genetics and physiology provide a partial explanation of why somepeople are obese, and others are not, these partial explanations fit into the debates we havejust reviewed about the role of personal responsibility. In many ways, these will simply benew versions of the older explanations of the type “I am not fat, I just have an underactivethyroid” (meaning – I am overweight, but it’s not my fault) or “My family are all big-boned”(meaning, I am overweight, but I was born this way, this is my natural shape). A crisis of fat? - 25 - Background information
  26. 26. Structural explanationsAlthough the personal behaviour and personal responsibility accounts of obesity are probablydominant, there has been a growing interest in public debates about food in the ethics of thefood industry, and in the role of the government in shaping the environment.The role of the food industry has increasingly been criticised. Concerns are raised about thesalt and sugar contents of common foodstuffs; while the added salt content of processedfoods has long been a concern, recent interest has broadened to encompass concern aboutthe added sugar content of processed foods. Not only are consumers unaware of the saltand sugar contents of what they eat (notwithstanding more explicit food labelling), they arealso unaware of the way salt and sugar influence the desire to eat more of the same, thusinducing over-eating.Criticism has been levelled at portion sizes in fast-food outlets, at the marketing of highenergy foods to children (including in some countries sponsorship of school activities andsporting events to underscore an apparent link between consumption of high energy foodswith active lifestyles), and so on. Both incomplete or misleading information, and pro-consumption “nudges” which increase consumption and divert from healthier options areincreasingly widely criticised.Another problem concerns the way food is retailed; while the widespread availability ofsupermarkets and chains of small shops has made a big difference to the convenience ofurban life and in many rural communities as well, the marketing practices of the chains havebeen criticised for undermining the diversity of products available, presenting relativelyunhealthy (high fat, high energy processed foods) in more convenient and lower cost formsthan fresh foods, and the discounting of bulk purchases in ways that induce higher rates ofconsumption (notoriously in the case of alcohol, but also for sweets and biscuits, carbonateddrinks, and so on). If the marketing practices and dominant market position of the highstreetretailers make healthy eating more difficult and more expensive, then there is a clear case forgovernment intervention through fiscal policy, product regulation, and licensing, as well asthe currently popular “nudges”, “responsibility deals” and voluntary agreements with the foodindustry. A crisis of fat? - 26 - Background information
  27. 27. 3.4. Treatment of obesityThe main approaches to obesity include education and information; behaviour change;medication; and surgery.Education and information involve identifying (possibly through screening programmes, morelikely through discussion at routine medical appointments, and possibly through referral tospecialist weight-loss services) people who are obese or at risk of becoming obese, andeducating them about the dangers of obesity and about what can be done to overcomeobesity.This educational approach has certain hazards: it can enhance stigma; it may focus more onthe “worried well” than on the “genuinely” obese; it may not translate into actual behaviourchange. However, most governments and health services are now taking a more activeapproach to raising public and individual awareness of the problems of, and caused by,obesity.Mere education and information alone may influence some people to change their behaviourby taking up more intense physical activity, dieting, and deliberate attempts to eat a morevaried diet or a diet which has a higher proportion of fresh foods or lower fat or lower energycontent. However, many people will require further advice or assistance. Some private sectorinitiatives, such as “Weightwatchers”-style programmes seem to have some success, andpublic sector initiatives involving “prescriptions for exercise”, cognitive behaviour therapy,and other means have also been tried with some success. Unfortunately the evidence basefor interventions to reduce obesity involving personal behaviour change is not particularlyreliable, and further controlled trials are certainly needed.Another strategy for personal behaviour change, involving “nudges” which “change thedefaults” for personal behaviour without needing direct and deliberate action on the part ofthe consumer him or herself, is also receiving a lot of attention now. Some critics of this styleof intervention worry that because “nudges” don’t involve autonomous choice, they are unfairor manipulative. But the natural response to that is to point to the widespread use of thesetypes of behaviour modifying strategy by supermarkets and other retailers in encouragingpeople to buy more, or certain kinds of, products already. To harness these techniques topromote health would at least (a) have some chance of success and (b) advance apersonally and publicly beneficial, rather than a purely commercial, goal. A crisis of fat? - 27 - Background information
  28. 28. A different set of criticisms looks at the activity patterns of modern life, which encouragesedentary work and long-distance commuting in cars or vehicles which don’t involve exercise(but may involve boredom and boredom-induced comfort eating and drinking). The role ofgovernment in providing open spaces for exercise (especially in schools, but for thecommunity at large) and in regulating transportation to make cycling and walking easier,safer and more attractive, is important, and increasingly recognised.All of these structural issues are currently the topic of much discussion in the West. Howeverit is clear that they are now, and will continue to be, just as important in the newlyindustrialising countries, which are beginning to go through the “demographic transition”, andwhere regulation of the food and drinks industries may be limited or only nascent.Medical TreatmentOver the years many different medical treatment strategies have been tried to treat obesitydirectly, or to modify behaviour. Medicines which boost the consumption of energy by thebody (such as amphetamines) were popular at one time; there was a vogue for appetitesuppressants. Recent approaches which involve persuading the brain that the stomach isfull, when a smaller amount of food has actually been consumed, have been heavily investedin by the pharmaceutical industry. So too have drugs which inhibit the uptake of fats orenergy from food consumed.Aside from the medical question of how far these drug-based approaches are successful inpractice, and what side effects they have, the ethical questions here are challenging. First, itis questionable whether a medical treatment which permits the consumer to eat largeamounts of food without putting on weight is morally acceptable: it may encourage waste orgreed, and it entrenches a high consumption habit which will probably persist once themedical treatment is discontinued. Second, there is a challenge along the lines that it ismorally preferable to change one’s behaviour through one’s own efforts, rather than throughtaking a pill.This type of criticism is of long-standing; similar debates arise in psychiatry about the relativeethical standing of drug-based treatments for depression or low mood and cognitivebehavioural or psychotherapeutic interventions. It might reasonably be argued that wheresomeone cannot successfully change their diet or activity patterns, then a pill might be justthe intervention they need. And it may also be that the pill gets them started and makes A crisis of fat? - 28 - Background information
  29. 29. behaviour change easier, and thus more sustainable. Outside careful clinical trials we aresimply speculating and moralising.Surgical treatmentIn extreme cases, surgery to reduce the digestive tract so as to reduce appetite and theability to consume large quantities of food and drink has a good track record. But it is unlikelyto be a useful tool in large scale public health, dealing with mild to moderate obesity. And italso has to overcome public scepticism about how far obesity is the fault of the obeseperson. A standard complaint that surgery for obesity is a poor use of public (or insurance)money has more to do with the view that the obese person is at fault than it has to do withobjective evidence about cost-effectiveness of the surgery, or the relative ineffectiveness ofother interventions in the most obese patient.Authors:The State of the Art document was drafted by Sarah Finer, Specialist Registrar & ClinicalResearch Fellow in Diabetes & Endocrinology, Queen Mary University, London. The ELSAdocument was drafted by Richard Ashcroft, Professor of Bioethics at Queen Mary,University of London. A crisis of fat? - 29 - Background information
  30. 30. DEVELOPED BY: A crisis of fat? - 30 - Background information