The Causes of Obesity

Abstract

Obesity rates are rising in all parts of the world. It is generally believed that this is because of the rapid change in food availability and the removal of the obligatory need to do physical work. This chapter will discuss the powerful evidence that while these changes in lifestyle facilitate the development of obesity, on their own they cannot be the causes of obesity. They provide the necessary circumstances for the multiple genes selected over millions of years to improve the survival of the species, by causing excess deposition of stored energy as fat. There are single gene mutations that lead to severe obesity, such as a mutation in the leptin gene or the melanocortin 4 receptor gene or combinations of gene polymorphisms that interact to give different degrees of overweight. There are also multiple mechanisms described where environmental situations epigenetically imprint genes to lead to obesity. We also have two negative feedback systems to prevent obesity in genetically lean individuals. Finally, the body defends weight vigorously by increasing hunger and reducing energy expenditure when someone loses weight. This would not occur if obesity was only due to lifestyle changes.

1. Introduction

The world is undergoing an epidemic of obesity. The reason for this is the major change that has occurred in the last 50 years in the availability of food and in the removal of the obligatory need to undertake activities in our daily lives to find food. However, not everyone develops obesity when placed in an obesogenic environment. This chapter will discuss the evidence that all of obesity is genetic or epigenetic.

2. Evidence that all of obesity is genetic

There are three lines of evidence that obesity is strongly genetic.

1. Twin studies, adoption studies and epigenetic studies.

2. The existence of two negative feedback systems that prevent obesity in genetically lean individuals who find themselves in an obesogenic environment.

3. The fact that weight is vigorously defended by the body at the genetically determined level.

2.1 Twin studies

It is generally known that identical twins are very similar in body weight (Figure 1). It is also agreed that fraternal twins have some similarity in weight but not as much as identical twins. This was clearly shown in a study in which the correlation coefficient of identical twins was 0.7 while in fraternal twins, it was ~0.3. Interestingly in this study they also recruited twins that had been separated at birth. They found that the correlation coefficients were the same as in those who had been raised together [1].

Figure 1.

Identical twins [photo from National Geographic magazine December 26, 2011].

When 12 pairs of identical twins were force-fed by 1000 calories extra per day for 100 days, some put on weight while others did not. There was a range of weight gain. However, the twins largely tracked together such that if one twin did not put on much weight, neither did his twin [2].

2.2 Adoption study

In an adoption study from Denmark, 540 individuals who had been adopted as babies were recruited and divided into four weight categories: thin, median weight, overweight and obese. The authors were then able to track down the biological parents of these individuals. They asked the question, is there a similarity in weight category between the adopted individuals and their biological mothers? The answer was yes with a p value of <0.0001, and the biological father, yes with a p value of <0.02. It is likely that the lower significance level for similarity in weight category with the biological fathers was that among adopted individuals, one could never be certain of who the father was. They then asked the question: is there any relationship between the adopted individuals and their adoptive parents, the ones that they had lived with all their lives and whose lifestyle they shared with, and the ones with whom they also shared gut bacteria? There was no correlation at all. They concluded that: “genetic influences have an important role in determining human fatness in adults, whereas the family environment alone has no apparent effect” [3].

2.3 Epigenetic studies

2.3.1 Preconception

In a study conducted in mice, the authors divided a colony of mice into two groups. One group continued on their low-fat mouse chow while the other group was exposed to a high-energy diet for approximately 6 weeks. At the end of this period of time, eggs and sperm were collected and in vitro fertilisation was done. The embryos were then implanted in mouse mothers. They went to all this trouble to eliminate confounding factors as much as possible. Offspring from eggs and sperm taken from the mice that had been exposed to the high-energy diet became overweight [4]. This epigenetic imprinting of eggs and sperm by a high-energy diet may explain the recent explosion in the prevalence of obesity around the World. It is urgent that all Governments encourage their young people to have a healthy low energy diet for about 6 months before attempting to achieve pregnancy.

2.3.2 In utero

During the Second World War, occupied Holland went through a severe famine. A study investigating the body weights of military recruits some 20 years post World War 2 revealed that while those babies who were in the second or third trimester or just born at the start of the famine, remained lean, those who were in the first trimester grew up to develop obesity [5]. This suggests that early in embryogenesis when the baby is wiring his brain, it can prepare itself to be born into a harsh environment if it can sense that mum does not have enough to eat! This situation may now exist in those parts of the war-torn world that also have food deficiency. In the developed world it occurs only when a pregnant woman has severe hyperemesis gravidarum in the first trimester of her pregnancy. Feeding these women intravenously may be important to avoid this epigenetic mechanism leading to obesity.

2.3.3 Postnatal

In another rodent study, increasing food intake in young breast-feeding pups by reducing the litter size resulted in epigenetic imprinting of the Melanocortin system, leading to obesity [6].

2.4 Known obesity genes

Several single gene mutations have been shown to lead to severe obesity. These include inactivating-mutations in the leptin gene [7], the leptin receptor [8], the melanocortin 4 receptor gene [9], mutations on POMC gene [10], brain-derived neurotrophic factor [11] and prohormone convertase-1 genes [12]. Multiple polymorphisms of low penetrance such as The FTO gene could add up to produce obesity [13]. There are also syndromic gene defects that lead to obesity including Prader-Willi Syndrome [14], fragile X syndrome [15] and Bardet-Biedl syndrome [16]. The genes on chromosome 15 that cause Prader-Willi Syndrome are necessary for the correct wiring at the base of the brain. The hypothalamus is at the base of the brain, and because it is necessary for normal regulation of body weight [17], malfunction of the hypothalamus can sometimes lead to obesity. Further proof that there is abnormal function of the hypothalamus is that children with Prader-Willi Syndrome often also have difficulties in controlling their body temperature. They also have growth hormone deficiency requiring growth hormone treatment and hypogonadism requiring sex hormone treatment. Milder degrees of overweight can be caused by one or more of the 500 genes that have been linked to obesity, each gene having a small effect, but when combined with other obesity genes, the effects can be magnified [18].

2.5 Negative feedback systems

There are two negative feedback systems that prevent obesity in mammals. Firstly, there is the hormone leptin, originally described in mice and then found in humans. Leptin is a very powerful inhibitor of hunger. We know that a deficiency of leptin results in very severe obesity [19]. There is also evidence that the level of leptin is proportional to the fat content in the body [20]. Thus, if an individual who is genetically lean puts himself in an obesogenic environment, as he puts on fat, he makes more and more leptin, which then suppresses hunger, thus limiting weight gain.

Recently, a second negative feedback system has been described in rodents [21]. It appears that in mammals, the osteocytes found in bones can detect overweight accurately and can send a signal to the brain to reduce energy intake. To show this, rats and mice had a small bag containing saline implanted into the peritoneal cavity. After recovery, it was shown that these rodents accurately reduced their fat content to match the weight of the implanted fluid [21]. When mice in which osteocytes were genetically deleted were studied the same way, they did not adjust their fat content. The signal to the brain from osteocytes is not known yet, but it is not leptin.

2.6 The body defends weight vigorously

There is evidence that the body defends weight very vigorously, something that would not happen if weight were not genetically determined. To understand how this happens, I need to discuss how weight is regulated.

Weight is controlled by the brain. The hypothalamus is where the machinery is situated. In the arcuate nucleus of the hypothalamus there exist the primary neurons that regulate eating (Figure 2). There are the Neuropeptide Y (NPY) nerves that also produce Agouti-related peptide (AgRP). When these nerves fire, we feel hungry. They do this by projecting their electrical signals to the lateral hypothalamus. In the same Arcuate nucleus are also found POMC neurones that express Pro-opiomelanocortin (POMC) from which is cleaved αMSH, which binds to the melanocortin 4 receptor (MC4R) to suppress hunger. These nerve cells also express Cocaine and Amphetamine regulated Transcript (CART), which also suppresses hunger. These POMC nerve cells project to the paraventricular nucleus of the hypothalamus.

Figure 2.

Regulation of body weight.

These first-order neurones receive input from other areas of the brain including from pleasure pathways and from nerves coming from the nucleus of the tractus solitarius in the brainstem that receives signals from stretch receptors in the stomach via the Vagus nerve.

The other input is from multiple circulating hormones which are made in the gut, pancreas and fat. Ghrelin which is made in the stomach stimulates hunger while the gut hormones including Cholecystokinin (CCK), Oxyntomodulin, Glucagon-like Peptide-1 (GLP-1), Protein YY (PYY) and Uroguanilin and the pancreatic hormones insulin, amylin and pancreatic polypeptide and the fat hormone leptin all inhibit hunger. Following just 5% weight loss [22], the levels of these circulating hormones change in a direction that makes the individual hungrier [23, 24, 25]. These changes in hunger-controlling hormones are long-lasting [26, 27] and are probably life-long. In addition, there is evidence for a reduction in energy expenditure of up to 300 calories (or ~ 1200 kj) per day following weight loss [28], and studies have shown that this is mainly due to a reduction in spontaneous movement [29] rather than metabolic rate which hardly changed at all. The reduction in energy expenditure has also been shown to be long-lasting [30].

3. Non-genetic causes that can modulate body weight

There are other factors that can influence body weight, but that on their own cannot cause obesity because of the negative feedback mechanisms that our bodies have. These include

1. The built environment [31]

2. Viruses [32]

3. Medications including corticosteroids, antipsychotics and insulin [33, 34, 35]

4. Gut bacteria [36]

5. Sleep deprivation [37]

6. Stress [38]

7. Menopause [39]

1. The built environment is necessary to develop obesity because no matter how hungry an individual is, if there is no abundance of food, and there is a need to be very active to find food, the genes cannot cause obesity. So, the built environment is necessary but not causative in the development of obesity. Our hunter-gatherer ancestors, who lived before the development of agriculture ten thousand years ago, would have already accumulated many of the obesity genes, but obesity was uncommon because food was not in abundance.

2. Some viruses have been linked to weight gain. There are three adenoviruses (Ad 36, Ad 37 and Ad 5) that have been reported to be linked to obesity. They have been found to act on adipocytes to stimulate the collection of fat by activating enzymes that cause the accumulation of triglycerides and also activate transcription factors that cause the differentiation of preadipocytes and into mature adipocytes [40] much like PPARγ does.

3. Some medications can cause weight gain. Corticosteroids have been shown to stimulate hunger by inhibiting the hunger-suppressing action of leptin [41]. Antipsychotic agents such as olanzepine stimulate hunger and cause weight gain. Finally, insulin has been shown to cause weight gain [42] by reducing glycosuria and possibly through an action on the liver. The deletion of SOCS 3 in the liver makes the liver very sensitive to insulin [43]. The only phenotype these mice have is obesity and fatty liver. This suggests that somehow, the action of insulin on the liver promotes weight gain. When insulin enters the brain, however, it inhibits food intake [44]. So insulin encourages weight gain when working on the body and weight loss when acting on the brain. This is likely the reason why Determir insulin is the only insulin that is weight-neutral [45]. It has been made long-acting by adding a fatty acid chain, called Myristic acid, to the protein insulin molecule. This fatty acid molecule makes insulin enter the brain more easily so peripherally administered insulin also goes into the brain negating the peripheral effect of insulin to encourage weight gain.

4. Gut bacteria can influence body weight probably by assisting or inhibiting the absorption of nutrients [46]. Croversy and colleagues [47] reviewed the literature and concluded that individuals with obesity have a greater Firmicutes/Bacteroidetes ratio. They also reported that some bacteria have a positive and others, a negative correlation with obesity. It is highly likely that gut bacteria can modulate weight, but because of the negative feedback systems that we have, will, on their own, not cause obesity.

5. Sleep deprivation Has been found to reduce leptin and increase Ghrelin, which can lead to weight gain [48].

6. Stress causes the release of cortisol, and as mentioned above, corticosteroids inhibit the action of leptin. Some people eat less when stressed. This is because stress causes the cells in the hypothalamus and pituitary gland to upregulate the production of Proopiomelanocortin (POMC). A fragment of this large protein is adrenocorticotropic hormone (ACTH) which stimulates cortisol production. Another fragment is αMSH which inhibits hunger very powerfully by activating the melanocortin 4 receptor (MC4R). So, some individuals respond to αMSH and eat less while others respond to cortisol-inhibiting leptin action and eat more. Why one individual responds to one factor while another responds to another factor is not known for certain, but the difference may be the capacity to release cortisol [49]. Poor cortisol releasers eat less while robust cortisol releasers eat more.

7. Menopause is associated with weight gain. The average is around 2–3 kg, but some women gain a lot more. The cause was found in a rat study to be a transient increase in hunger which rapidly stops, plus a profound reduction in spontaneous activity which is persistent and only reversed by the administration of oestrogen [50]. The reduction of spontaneous activity was confirmed in a human study [51].

To conclude, there are many environmental factors that can influence body weight. In addition, irrespective of what the genes do, one cannot develop obesity unless there is an adequate amount of food available. This is best understood by using an analogy.

You put two pots outside, one holding 5 litres and the other holding 50 litres (Figure 3).

Figure 3.

Pots in the rain’ an analogy of the interaction of genes and environment in the development of obesity.

It rains overnight, and by the next morning, both pots are full. When you see the full 50-litre pot, you ask: “Is this pot holding 50 litres of water because it rained last night?” The answer is yes, of course. If it had not rained during the night, the pot would have been empty. This is the equivalent of seeing a very obese individual and asking: “Is this individual severely obese because of the overabundance of high-energy food?” The answer is, again Yes! If abundant food was not available, he would not be obese. However, the pot is holding 50 litres because it was made a large pot. Similarly, our severely obese individual is the weight he is because he was made this way by his genes.

It is very important for the whole world to understand that all obesity has a genetic basis. This is because there is evidence that many people with obesity are discriminated against in all fields of life, [52] and even among health professionals [53] because of the belief that they have themselves to blame. The discrimination will only end when it is widely accepted that all of obesity is genetic.