16    Obesity

Some hae meat and cannae eat

Some would eat that want it

But we hae meat and we can eat

Sae let the Lord be thankit.

—Robert Burns (1759–1796), “The Selkirk Grace”

At the tail of the eighteenth century, when Rabbie Burns wrote “The Selkirk Grace,” food was not to be taken for granted. Even in wealthy Edinburgh where Burns lived there were frequent riots in protest at the price of grain. At the University of Edinburgh, where I work, the Anatomical Museum displays the skeleton of a leader of those riots: “Bowed Joseph,” barely four feet tall, had the curved spine and deformed limbs characteristic of rickets, once a common disease of undernutrition, but he had a powerful voice, and charisma. As told by Sir Walter Scott, Joseph could summon a mob of up to ten thousand “town rats” by the beat of his drum, “all alike ready to execute his commands, or to disperse at his bidding.”¹ In 1780, returning drunk from Leith Races, he fell to his death from a stagecoach.

In the early nineteenth century, most people in Western Europe could afford only the cheapest foods: cereals, root vegetables, and pulses. Livestock products provided less than 15% of calorie intake, and little sugar, green vegetables, or fresh fruit was eaten. Through the nineteenth and twentieth centuries, the productivity of agriculture increased and drove down the real price of food. At the same time, with the spread of industrialization and trade, real incomes grew. The cost of moving food from rural areas into cities also fell, and when refrigeration was introduced in the 1870s, cheaper foods could be imported from distant agricultural economies. At first, people ate more bread and potatoes, but increasingly they ate more sugar, oils and fats, fruit and vegetables, much more meat and dairy products, and fewer starchy staples. In Northern Europe, the proportion of calories derived from livestock rose from less than 15% in the early nineteenth century to more than 30% in the 1960s, and this pattern was repeated across the world as countries developed.²

As countries get richer and the cost of food falls, and as life expectancy increases and reproduction rates fall, there will be more obesity:³ obesity develops slowly, so its prevalence increases with age. As we age, we all produce less growth hormone, and in consequence we lose muscle mass and increase fat mass. When everyone has enough to eat, more are bound to become obese; those predisposed to obesity become victims of enough food to realize that predisposition.

Obesity is not an aesthetic judgment; worldwide; back in 2002, still rising rapidly, it was the sixth most important risk factor contributing to the overall disease burden. In developed countries, it was the fifth leading cause of loss of healthy life, behind tobacco, high blood pressure, alcohol, and high cholesterol. In the United Kingdom, obesity contributes to about 30,000 deaths every year, and about ten times that many in the United States, where it is now the main preventable cause of illness and premature death.⁴

Between 1971 and 2000, the prevalence of obesity in the United States increased from 14.5% to 30.9% of adults. This accompanied an increase in energy intake: according to food surveys, women increased their calorie consumption by 22% (from 1,542 to 1,877 calories per day) but men by only 7% (from 2,450 to 2,618 kilocalories). This mainly reflected increased consumption of carbohydrates, especially pasta, breads, and cereal-based snacks. The percentage of calories from fat decreased while protein consumption remained about the same.^5,6

The cause of obesity might seem obvious. Although the world population is rising, food production is rising faster, and more people have the opportunity to become obese. We eat more energy-dense foods, and are less physically active due to the increasingly sedentary nature of work and increasing urbanization. Where our fathers toiled and sweated, we tweet and snack; where they trekked and climbed, we use cars and escalators.

This might be partly true, but it’s dangerous to mistake a plausible explanation for a valid one. Scientists are professional skeptics. Skepticism isn’t about making fun of nonsense like homeopathy—that’s the job of every thinking person. It is about questioning not things we can see to be nonsense but things we take for granted. If people eat too much and take no exercise they are likely to become obese, but are we really eating more and exercising less? And if we are, is this really why more of us are obese?

The message from the United States seemed to be that obesity was due to overconsumption of carbohydrates, but most countries have seen an increase in obesity despite different consumption patterns. In Canada, the prevalence of obesity almost tripled between 1985 and 2000,⁷ and there, energy intake increased by 18% between 1991 and 2002, but, unlike in the US, it was fat consumption that increased most.⁸ In Australia, in the twenty years to 2000, the daily average calorie intake grew by only 87 calories yet obesity rates doubled.⁹ In the UK, even while obesity rates rose, calorie intake declined, as did the percentage of fat in the diet^10,11 (figure 16.1).

Figure 16.1

Trends in food intake. Data collected by an annual survey of food purchases in the United Kingdom. From 1940 to 1973, the data did not include alcoholic drinks, soft drinks, confectionery, or eating out. From 1973 to 1991, the reported intakes were adjusted. From 1992 onward the data included alcoholic drinks, soft drinks, and confectionery, and from 1994 they also included eating out. The data (https://www.gov.uk/government/collections/family-food-statistics/) were published on March 9, 2017, by the Department for Environment, Food, and Rural Affairs in the UK. Data were collected annually for a sample of households using self-reported diaries of all purchases over a two-week period. Where possible, quantities were recorded in the diaries, but otherwise they were estimated. Energy and nutrient intakes were calculated using standard nutrient composition data for each of 500 food types.

So, depending on which data you choose to use, you can tell any story you like. The problem might be that these data are not perfect, especially data about diets that depend on people answering questionnaires. Those who respond to food surveys may not always confess their taste for “junk food,” and there seems to be consistent underreporting of intake. Similar problems affect all surveys that rely on people being willing to disclose things they would rather deny to themselves. Nevertheless, it seems unlikely that the reported decline in food consumption hides an increase that is masked by increasing underreporting.

If we can’t rely on people to tell the truth and we can’t keep them in laboratories for years while we control their diets, what can we do? We have data on total food production. In the United States, the total food supply in 2000 provided 3,800 calories per person per day, 500 more than in 1970. But of those calories, the US Department of Agriculture estimated that about 1,100 were lost to waste, spoilage, and other causes, including cooking.¹² That’s a big uncertainty, and if we waste more food now than we used to then the data will be very misleading. Comparing countries, we find little relationship between obesity and food supply. Those with low food production have low rates of obesity, but if we compare only industrialized countries there’s a rather weak correlation. It is hard to be sure that we are eating more now than people did fifty years ago or that people are less active now, and hard to see any one globally applicable explanation of the rising obesity rates. There are differences between men and women, rich and poor, city dwellers and country folk, and these differences vary from region to region.

Obesity is perhaps best defined as an excessive enlargement of the body’s adipose tissue. We might think of fat as an ugly nuisance, but it is a very important organ: it gives heat insulation and it stores energy for times of shortage; it allows us to eat intermittently, sometimes to indulge our appetite, sometimes to skip a meal for other, competing rewards. In white adipose tissue, specialized cells called adipocytes store fat in semiliquid form. This fat can be converted into energy in a way that is regulated by hormones.

Obesity is conventionally defined as a body mass index (BMI) of more than 30. BMI is a crude index, calculated as the ratio between body weight (in kilograms) and the square of height (in meters), but family doctors and outpatient clinics routinely monitor BMI in large numbers of patients, making data easy to collect frequently and on a large scale. For adults, a BMI of less than 18.5 marks you as underweight, above 25 as overweight, and above 30 as obese. For any one person, this may be misleading—athletes with a large muscle mass can have a high BMI despite a very low fat mass. Men with a “healthy” BMI typically have 15% to17% body fat, while women have between 18% and 22%. Typically, elite male athletes have just 6% to 12% body fat, and some have much less.

Most people have about 30 billion adipocytes, and these expand or contract according to the supply of energy. This storage system is flexible, but it can be overwhelmed, and different people have different capacities to store fat safely. When the capacity to store fat safely is exceeded, lipid can accumulate in the heart, skeletal muscle, pancreas, liver, and kidney. This increases the risks of many diseases, including heart failure and type 2 diabetes.

How fat you are depends mostly on your genes, genes that determine your metabolic rate and general body composition;¹³ how fat your parents are is a good predictor of how fat you will be. The obesity epidemic has been blamed on lifestyle changes—the “obesogenic environment”—but exactly who becomes obese is largely determined by genetics. This confuses many people—if body weight is governed by our genes, how can we be getting fatter when they haven’t changed? Understanding this requires understanding how genes interact with the environment.

Heritability is defined technically as the proportion of total phenotypic variability caused by genetic variance in a population. In this case, we are concerned with understanding how much of the variability in body weight in a population is due to the genetic differences between individuals. This can be addressed by looking at family pedigrees—how similar closely related people are in BMI—and especially by studying identical twins and nonidentical twins. The presumption is that twins are reared in the same environment; identical twins are usually much more similar in BMI than nonidentical twins who have some differences in their genes.

Such studies all show that human obesity has a strong heritable component.¹⁴ Exactly how strong the link is between BMI and genes depends on sex, on the environment, and on when in life BMI is measured. In children, the link is strong: about 80% of variation in BMI appears to be due to heritable differences, with the family environment having surprisingly little effect. In a few individuals, obesity can be attributed to a defect in a single gene, but these cases of monogenetic obesity are very rare. Generally, the variability of body weight reflects differences in many genes, each with small effects on different physiological processes, including metabolic regulation, appetite, food preference, and fat storage.

Counterintuitively, the apparent heritability of BMI has increased as the obesity epidemic has unfolded. When food is in limited supply, individual differences in BMI mainly reflect environmental factors—variations in access to food. When food is cheap and abundant, genetic differences between individuals reveal themselves, and, because our genes encode a predisposition to weight gain that depends on the environment, these differences are magnified.

Why so many appear to be predisposed to gain weight has long been the subject of speculation about evolutionary mechanisms. The “thrifty phenotype” hypothesis proposed that obesogenic energy-efficient genes favoring fat storage emerged by natural selection in populations repeatedly exposed to famine.¹⁵ By contrast, the “drifty phenotype” hypothesis proposed that when early hominids began to make tools, use fire, and band together they became less subject to predation, so genes that favored a lean phenotype became less subject to selection pressure.¹⁶ This relaxation of selection pressure would result in the persistence of minor mutations, producing a diversity of human phenotypes including some prone to obesity. A third view acknowledges that genetic susceptibility to obesity is not the same across ethnic groups.¹⁷ Its adherents propose that descendants of early humans who remained in Africa or migrated to tropical or subtropical environments maintained heat adaptation genes, while the descendants of those who migrated to colder regions acquired genes for cold adaptation, equipping them with a higher metabolic rate and greater resistance to obesity. Perhaps all are true, to some extent for some populations, perhaps none are: it matters that we differ more than why we differ.

The heritable differences in BMI have many components: differences in how much we eat depend on differences in appetite, but the amount of weight gain that results from overfeeding also has a strong genetic component, as does the impact of specific diets and that of exercise. However, the search for the genes responsible has (so far) found associations that account for only about a fifth of the variation between individuals.¹⁸ This has focused attention on other heritable mechanisms, and particularly on the consequences of events in uterine and early postnatal life. Stress and poor nutrition during gestation and in early life have lifelong “programming” effects on physiology. If you were born with a low body weight, either because your mother was stressed during pregnancy or because of inadequate nutrition, you are more likely to become obese. Apparently, your physiology develops in anticipation of a world where food is scarce and must be consumed whenever possible.

This hypothesis was proposed to explain the findings of a now famous study. Toward the end of the Second World War, a blockade by the German army led to a famine in the west of the Netherlands. The Hunger Winter of 1944–45 killed more than 20,000 people. In 1976, a study of 300,000 recruits in the Dutch army showed that the sons of women who had become pregnant toward the end of the famine were more likely to be obese than men born before or after. The authors proposed that early nutritional deprivation had affected the development of the hypothalamic regions that regulate food intake and growth.¹⁹ Subsequent studies in animals showed that the offspring of mothers who had been underfed while pregnant grew up to be hyperphagic: they ate bigger meals and preferred high-fat food. These changes were accompanied by changes in the hypothalamus, especially in the expression levels of neuropeptides that regulate food intake.^20,21

Environmental challenges, however severe, cannot change our genes: the DNA sequence of an individual is fixed. However, how genes are expressed can be influenced by epigenetic modifications—gene sequences can be “silenced” by processes such as DNA methylation and histone modification. The children conceived toward the end of the Hunger Winter showed differences in the prevalence of methyl groups on the gene that encodes IGF2, a hormone that regulates fetal growth. Children whose mothers had gone hungry in early pregnancy had fewer methyl tags than siblings born earlier or later, and similar effects were found in mice whose mothers had been fed a low-fat diet while pregnant. These “programming effects” can have a big influence on disease susceptibility in later life, affecting the risks for heart disease, obesity, and diabetes.

The father’s experiences also matter. Male rats on a high-fat diet become obese and develop impaired glucose tolerance and insulin sensitivity—signs of diabetes.²² Surprisingly, their daughters are also affected: even on a normal diet they have impaired glucose tolerance and insulin sensitivity. Thus, parents “experiences can affect their children’s health. There is also evidence that some of these effects can be passed from generation to generation. One theory is that programming “adapts” a newborn to the world it is born into, by modifying its physiology as appropriate for an environment that is placid or stressful, lush or barren.

How fat you are also depends on your gut microbiota.²³ We are not alone, even in our own bodies: each of us shares our body with tens of trillions of microorganisms in our gut. These live on the nutrients we ingest, and their composition varies according to our diet and antibiotic exposure. There is a huge diversity of species, and they have many beneficial effects—they help in digesting nutrients and protect against some pathogens—but they have also been associated with inflammatory bowel diseases, irritable bowel syndrome, colorectal cancer, allergic disease, and obesity.

Identical (monozygotic) twins generally have a similar body weight and a similar gut microbiome (the composition of the whole population of microorganisms: which species are present, and in what proportions). But some identical twins differ substantially in body weight, and in 2014 a study published in Science suggested that such discordance might be due to a discordance in their gut microbiome.²⁴ That the leaner of a pair of twins has a different gut microbiome than an obese brother or sister is not surprising, and it might reflect no more than that some microorganisms thrive better than others in the guts of obese individuals. But this study took samples of the microbiota and introduced them into the guts of germ-free mice. Remarkably, mice given samples from the obese twins gained, on average, about 10% in fat mass, while mice given samples from the lean twins maintained a normal weight. In humans, fecal-matter transplants to alter gut flora are an effective treatment for recurrent, refractory Clostridium dificile infection, and some reports suggest that such transplants might also be an effective treatment for some cases of diabetes and obesity.^25,26

How many calories a person needs depends on many things. An individual’s energy expenditure can be measured by giving a dose of “doubly-labeled water,” enriched with the isotopes ²H and ¹⁸O. Oxygen leaves the body either as exhaled carbon dioxide or in water (in urine, sweat, and breath), whereas hydrogen can leave the body only in water. So, by comparing the ratios of these isotopes in blood, urine, or saliva it is possible to calculate how much oxygen has been converted to carbon dioxide. This is a measure of the average metabolic rate, and is equivalent to daily energy requirements. People vary in their energy requirements according to their age, gender, and level of physical activity, but also according to their different genetic constitutions and their physiological status—pregnant and lactating women need much higher energy intakes.

We use energy in all our physical activity—climbing stairs, walking, even fidgeting. We use energy in eating and digesting food, and for raw foods this can be a considerable proportion of their energy content. We use energy in maintaining our body temperature, even if most of us who live in cold climates have centrally heated homes, sleep in warm beds, and stay mainly indoors. Nonexercise activity thermogenesis represents these common daily activities, and can result in up to 2,000 calories of expenditure per day above the basal metabolic rate.^27–30

Are people less active today? We don’t have objective data from fifty years ago. Fewer people have manual jobs, people walk less, and the most popular leisure pursuits are screen time and computer games. But more people consciously exercise, and more cycle. More than 45 million Americans belong to health clubs, up from 23 million in 1993. Does it make a difference how much we exercise? It takes a lot of effort to burn off excess weight, but we don’t even lose the weight that we expect to for the exercise that we do take. In studies lasting more than 25 weeks the average weight loss is only about a third of that predicted from caloric expenditure. The Dose Response to Exercise in Women study examined the benefits of regular exercise for overweight postmenopausal women with elevated blood pressure.³¹ Three groups of women took supervised exercise for six months, at 50%, 100%, and 150% of recommended intensity, and a control group had no supervised exercise. More than 400 women took part, and most, even in the control group, lost weight. However, the women who exercised hardest did not lose more than control subjects, and about a quarter of them gained weight. The difference between actual and predicted weight loss in response to exercise has been termed “compensation.”

If we increase our food intake, exactly how much weight we put on varies from one person to the next, but typically we defend our body weight by increasing energy expenditure after eating more than usual. Conversely, if we exercise intensely, we compensate by reducing our energy expenditure between bouts of exercise or by eating more.³² That’s nothing new; as a child I was sent out on a Sunday morning for a long walk or to play football to build up an appetite before dinner.

There is little value in general recommendations about calorie intake; a recommended value that is enough for all will be too much for some and not enough for others. Health Canada produces detailed recommendations by weight, gender, and activity level.³³ They estimate that a woman aged 31 to 50 needs between 1,800 and 2,250 calories each day depending on her level of physical activity, while men of that age need between 2,350 and 2,900 per day. Remember that, in the United States, the estimated food supply in 2000 provided 3,800 calories per person per day, of which about 1,100 were wasted. This leaves 2,700 calories per day—not very different from Health Canada’s advice on the intake required for a healthy body weight. The image of the obese individual as scoffing beefburgers and doughnuts washed down with sugary drinks is misleading. There are some like this, just as some are emaciated by self-denial, or by diets for which our digestive systems are poorly adapted. But the diets of most overweight people differ little from those of most people of normal weight.³⁴

The physicians who must deal with the problems arising from obesity have little to offer. People on a strict calorie-controlled diet lose weight, but when the control stops, most regain the weight that they lost and often gain more. Exercise is hard for the obese, hard on the knees and joints, humiliating in public, and depressingly ineffective.

Obesity is not a lifestyle choice, nor a moral failing or a weakness of will, but a multifactorial disease, a disease that is often a dysfunction in the hypothalamus. This can reflect a dysfunctional responsiveness to hormonal and neural signals from peripheral tissues, dysfunctional production of those signals, or dysfunctions in the signaling within the hypothalamus from diverse populations of neuropeptide-secreting neurons that regulate appetite, food choice, energy expenditure, and glucose homeostasis.

It doesn’t do much good to berate the obese for their lack of willpower. There’s something offensive about the disdain of the affluent lean for their overweight neighbors, a disdain sometimes expressed by politicians for whom words come to mouth faster than facts to brain. Who knows what stress your neighbors encounter in their daily lives, the legacies of their genes or their birth environment, and what struggles they endure to restrain their weight?

Living in Edinburgh, you don’t escape Robert Burns—the passionate poet of the common man, songster and seducer, full of wit and anger. His “Address to the Rigidly Righteous” is an attack on conventional, unthinking morality and the dogmatic beliefs of those who believe they can easily identify causes of human behavior.

Who made the heart, ’tis He alone

Decidedly can try us;

He knows each chord, its various tone,

Each spring, its various bias:

Then at the balance let’s be mute,

We never can adjust it;

What’s done we partly may compute,

But know not what’s resisted.

Notes

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22.  Ng SF, Lin RC, Laybutt DR, Barres R, Owens JA, Morris MJ (2010) Chronic high-fat diet in fathers programs β-cell dysfunction in female rat offspring. Nature 467:963–966.

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24.  Ridaura VK, Faith JJ, Rey FE, Cheng J, Duncan AE, Kau AL, Griffin NW et al. (2013) Gut microbiota from twins discordant for obesity modulate metabolism in mice. Science 341(6150):1241214. doi: 10.1126/science.1241214.

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26.  Marotz CA, Zarrinpar A (2016) Treating obesity and metabolic syndrome with fecal microbiota transplantation. Yale Journal of Biology and Medicine 89:383–388.

27.  Villablanca PA, Alegria JR, Mookadam F, Holmes DR Jr, Wright RS, Levine JA (2015) Nonexercise activity thermogenesis in obesity management. Mayo Clinic Proceedings 90:509–519.

28.  Johnson F, Mavrogianni A, Ucci M, Vidal-Puig A, Wardle J (2011) Could increased time spent in a thermal comfort zone contribute to population increases in obesity? Obesity Reviews 12:543–551.

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