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Overview
Signal Transduction Education  
Active Learning Projects - Obesity Project - Team 1    
 
Obesity
Team 1   Team 2   Team 3   Team 4   Team 5   Instructions du Projet
 
1. Regulation of food intake and obesity
2. Messengers involved in the homeostatic regulation of food intake
3. Messengers involved in the hedonic regulation of food intake
4. Signalling mechanisms in the arcuate nucleus and the regulation of food intake
5. Treatment of obesity
Instructions du Projet

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Homer-donut

1. Regulation of food intake and obesity

Summary:
Introduction
Homeostatic and hedonic regulation
Obesity
Searching for genes that predispose to obesity

Auteurs:
Laetitia Bourgeade, Mamadou Bamba Gaye, Laura Guerenne, Marianne Guerine.

Introduction

reddot Why do we eat? Because we get terribly hungry if we don’t eat and refusal to nourish ourselves would ultimately lead to our demise. Indeed, but we also eat because it is nice to eat. Food constitutes an important source of pleasure. We like to eat and we like to eat together. Shared meals make an important contribution to the social cohesion of communities as witnessed by the importance of gastronomic cultures and its symbolic role in certain religions (communion).

Homeostatic and hedonic regulation

reddot If we consider ourselves an organism assembled from billions of nano-machines, than, from a technical point of view, we eat in order to provide the organism with the necessary elements that allows it to function. We need elements to replace failing parts (maintenance), to replace broken parts (repair), to expand the organism (growth) and we need fuel to drive these nano-machines. In case the organism is homeothermic (constant temperature or “warm-blooded”), it will also need fuel to maintain its temperature (either by heating or cooling).

Figure 1 Use of nutrients; maintenance, repair, growth, fuel and storage

reddot Organisms differ from the machines around us in that the elements necessary for the making of structural components (maintenance, repair and growth) are also used as fuel (and the other way round). In other words, what is eaten can serve different purposes. Metabolic pathways decide about the whereabouts of nutrients: used as fuel, as structural components or stowed away in a storage compartment. The good news is that this versatility makes organisms very robust, allowing them to adapt to changes in environment (changes in supply of food). The bad news is that by omitting fat from diet, it not necessarily follows that organism are not going to get fat (which some people erroneously think). However, certain elements are not interchangeable. They constitute the so-called essential dietary requirements of which linoleic acid (essential fatty acid), vitamins, a number of essential amino acids and minerals are important examples.

Vitamins
The name is derived from » vital amines«, referring to organic compounds that contain a basic nitrogen atom (N), or amine, and are essential for life. The name was coined by Casimir Funk and Frederick Hopkins around 1912 (“vitamin hypothesis of deficiency”), when describing a substance rich in sulfur and nitrogen (thiol and amine), derived from the husk of rice and able to prevent beri-beri (“I cannot, I cannot”). This is a disease first described in south-east Asia, occurring in inmates of prisons and asylums as well members of the army and navy, with symptoms such as general lethargy, neuropathy, paralysis and cardiovascular trouble, hence its name. We now know that the symptoms are due to a lack of vitamin B1 (a component also known as thiamine) in people whose diet consists mainly of polished-rice (white or uncured rice). Naturally, general starvation may also cause beri-beri and in the well-fed world the symptoms are sometimes manifest in alcoholics (due to an inappropriate diet).

reddot Maintenance and the fuel needed to make the nano-machines work take the major part of the daily ingested food. Repair and growth take only a minor part. In the resting state, the heart, brain and liver are the most demanding organs. It has been postulated that the computing power of the human brain (clock time of one kiloHertz) is limited by the brain’s energy supply. Although this makes humans relative poor performers, compared to modern day computers with a clock time of several gigaHertz, it renders them (us) less vulnerable to transient nutrient shortage (Attwell D, Gibb A. Neuroenergetics and the kinetic design of excitatory synapses. Nat Rev Neurosci 2005;6:841-849). With increasing locomotor activity (physical action or work), skeletal muscles will take the lead by far (increased metabolic rate of 2000 kcal/day (resting) to 6000 (etape du tour de france).

Energy
The nutritional value of food is described in different ways, for instance by its content of vitamins, protein, sugar, fat, fibre or minerals, but also by the amount of energy it stores (and is liberated in the form of heat when you burn it). The energetic content is expressed in kilocalories (kCal) or kilojoules (kJ). Certain ingredients of food are rich in energy (like fat), others are poor (like water). “Life style journals” in particular, have a tendency to reduce the nutritional value of food to its caloric value. The general wisdom is that if you take in too much energy (too many kCal or kJ), compared to your expenditure, you gain weight. As a logical consequence, in order to stay slim you either reduce food intake or you increase energy expenditure. As both are difficult to achieve, a whole cult of “low caloric food” has been developed of which the efficacy remains questionable (as one probably eats more in order to reach the same satiety signal). From a biologist point of view, we see no interest in this caloric approach to nutrition because it is not precise; bodies store fat not energy and it is fat that causes the trouble not the energy it harbours (see metabolic syndrome below). Moreover, fat is used for many purposes not just fuel to be burned in order to “liberate its energy” (see below “fat is necessary”).

reddot Numerous nano-machines that constitute the organism act as sensors that verify the presence or absence of the necessary elements. In case of shortage, these sensors will drive the organism towards an energy-saving and food-searching behavior (appetite signal, leading to orexic behaviour). In times of opulence, (satiety signal, leading to anorexic behavior), their will be room for other activities (like reproduction). If all works well, which it does generally speaking, a fine-tuned equilibrium is maintained in which “supply” and “expenditure” are matched (homeostasis). Incorrect set-point values of nutrient sensors or incorrect interpretation of the sensors’ signals may lead to a disequilibrium between supply and expenditure. As we will discuss below, such disequilibrium may lead to an excess of food intake (causing obesity, see below) or a shortage (as in anorexia). Team 2 will tell us more about homeostatic regulation of food intake. For those who seek molecular detail, some of the signal transduction pathways involved in anorexic and orexic behaviour are discussed by team 4.

Homeostasis
From Greek: óμος, hómos, "similar"; and ιστημι, histemi, "standing still"; concept developed by Walter Bradford Cannon (made popular in the book “The wisdom of the body” published in 1932) referring to the property of a system (either open or closed) to regulate its internal environment and tending to maintain a stable, constant condition. Typically used to refer to a living organism. Multiple dynamic equilibrium adjustment and regulation mechanisms make homeostasis possible. Source; Wikepedia

reddot In order to assure a constant supply of elements (to maintain, repair and fuel the organism) several types of reserves have been created. The organism itself stocks a limited amount of glycogen (sugar chains) both in the liver (70 gr) and in muscles (~300 gr). Sheer unlimited amounts (kg) of fat are stored in adipose tissue, which localizes beneath the skin, around internal organs (so-called visceral fat that surrounds the kidneys and the gut momentum) and in the bone marrow. Although muscles are not created as reserves, they can nevertheless be used as a source of elements in case of famine (leading to muscle wasting). Reserves are also created outside the organism. Much of our agricultural and economic endeavor is guided by the need to assure a constant supply of food. Although many consider the highly industrialized society, resulting from this endeavor, stress-full, this is only a mild-stress compared to the mental havoc caused by not knowing if tomorrow is going to provide you enough food for survival. It may not come as a surprise that in many cultures body corpulence acts as a sign of well-being as it reflects unlimited access to food and thus certain affluence. It is only recently that the Western world has started to stigmatize overweight.

Figure 2 Food as a source of pleasure

Hedonic regulation

reddot The homeostatic regulation described above is only half the story. Food is also a source of pleasure; food has “hedonic valence” (figure 2). Just the smell of food or the sight of it can make you hungry (if you are not saturated). Having eaten one sweet increases the desire to take a second one. But getting a severe gastritis after having consumed (infected) raw tartar may reduce your appetite for a second steak. Some foods are less pleasant than others and producers of sweets, biscuits and instant meals know all too well what kind of odour and taste procures the highest pleasure (so customers keep coming back for more). What this means is that the choice and quantity of food we take is not only determined by the need for maintenance, repair, growth and fuel, it is also determined by the mental reward (pleasure) it procures. Yes, we eat also in order to please our brain and sharing this experience may make, for some, the reward signal even stronger. Although hedonic and homeostatic regulation of food intake are studied as two different entities, in everyday life they seem inseparable. We are unable to tell whether appetite is a consequence of the need for pleasure or a lack of elements that maintain/fuel the organism. Like with nutrient sensors, the hedonic reward-sensors in the brain may also have inappropriate set-points. This may leave us with a constant sentiment of hunger (a craving for food), or the other way round, providing us with a sense of disgust as in anorexia. Team 3. will tell you more about hedonic valence of food.

Obesity

reddot Obesity (from latin obesitas = fatness) is defined as the condition where excessive accumulation of body fat becomes a severe nuisance to our health (and quality of life) and reduces life expectancy. The world health organization (WHO) has recognized it as a disease since 1997, in other words, obesity is a recent illness. Some describe it as the first non-infectious epidemic of mankind (see figure 4 and 5).

reddot The diagnosis of obesity is principally based on estimation of the body mass index (BMI) which compares weight and height using the following formula:

BMI = weight (kg)/height (m) x height (m) or kg/m²

(BMI = weight (lb)/ height (in) x height (in) x 703, for US/customary and imperial)

reddot Someone is declared obese when his/her BMI equals or exceeds 30 kg/m2 (cut-off point) (figure 3)

reddot The WHO made several subcategories (see table 1 below) to facilitate the screen for health risk because the prevalence of co-morbidities, such as hyperinsulinemia, hyperlipidemia and hypertension (we return to this), tends to increase with increasing BMI.

BMI WHO classification of BMI
< 16,5 = underweight
16,5 - 18,5 = meager
18,5 – 25 = normal
25 - 30 = overweight
30 - 35 = moderate obese or obese I
35 – 40 = severe obese or obese II
40 - 50 = morbid obese or obese III
> 50 = super obese

Table 1


Figure 3 Where do you stand with respect to BMI?

  1. World Health Organization; Report of a WHO consultation on obesity. Obesity: preventing and managing the global epidemic; WHO 1998
  2. Criteria for definition of overweight in transition: background and recommendations for the US. Kuczmarski RJ, Flegal KM. Am J Clin Nutr 2000;72:1074-1081

reddot The earth is populated by roughly six billion people of which 800 million are undernourished and 1 billion are obese, and numbers are rising. In France, the number of obese augments with 6% each year and 15% of the children are overweight (and will drift into the obese category with increasing age). Obesity is the consequence of a severely disturbed equilibrium between “supply” and “expenditure”. With respect to the cause, a global spread of a sedentary life style and an easy access to (fast) food are often-quoted suspects: one speaks of a global “obesogenic lifestyle”. However, until today formal proof is lacking that children with overweight are physically less active and there is no firm evidence that overweight is caused by fast-food habits. In short, the underlying mechanisms of obesity, except for one or two examples of genetic disorders, are not known.


Figure 4 Worldwide distribution of obesity in 2005

Figure 5 Distribution of obesity in France
Eating too much, a lack of will?
People who are slim and healthy and sporty and clever and successful as well as esteemed, have a tendency to say that they have achieved all this through an act of will. Naturally they would say that, because it adds another layer of supremacy to their (already) hegemonic position. It is the logic that firmly positions people amongst the “winners” and distinguishes them from the “losers”. Identifying winners (good) and losers (bad) is an essential part of human identity. From this it follows that those who have severe overweight, suffer from continuous health trouble, have a sedentary lifestyle, failed at school and have a low income naturally lack will power. Since a lack of will is generally considered “bad”, those who are slim and healthy and sporty and clever and successful as well as esteemed, reserve themselves the right to condemn those who are not all this, in particular when it comes to sharing healthcare costs. Some medics go as far as stating that “corpulent people are economically damaging for society” (Haslam DW, James WPT. Obesity. The Lancet 2005 ;366 :1197-1209). As a consequence of this, even children under six years qualify their high-BMI-index schoolmates as lazy, stupid, ugly, cheaters or liars.

It is generally believed that with increasing knowledge of how the human body functions, as an assembly of interacting nano-machines, the human condition shall, sooner or later, be controlled so that, with the appropriate will and medication, we can live healthy and happily until, say, 85 and then die peacefully without having been a socio-economic burden to mankind. In these web pages, made by 3rd year students at the University of Bordeaux, we take no moral position with respect to overweight; we neither condemn nor praise. What we try to show is that appetite, or lack of it, is controlled by complex neuronal circuits employing complex signalling mechanisms and that anomalies in these mechanisms may lead to altered nutritional behavior. The observations that a mouse can be protected against overweight through the loss of a tyrosine phosphatase (PTP1B), but gets hopelessly obese when you remove its leptin receptor (Ob), are two striking examples of how signalling processes control nutritional behavior without any known implication of will or environment. Moreover, recent studies show that mice lacking the Fto gene, waste energy. These mice eat more, move less yet do not store fat excessively! We have still a lot to learn about what determines fat storage and nutritional behaviour in humans and caution is the keyword when it comes to moral judgments.

The business of body measurements (antropometrics)

reddot The concept of BMI was not developed in a quest to understand the health risks of body fat. Adolphe Quetelet, an astronomer living in the 19th century, wished to know if mathematical laws of probability, which he applied on celestial events, would also govern human life. The rationale behind it was that by gathering information on a large sample of subjects, one might be able to extract certain trends and applying these one might predict human behavior or determine someone’s “normality”. Quetelet started measuring weights and heights, amongst other details, of French and Scottish army conscripts and found, after charting his data, a “normal distribution” i.e. a bell shaped curve of which the peak reflects the average weight or height. He then found that for the average conscript, its weight was proportional to his height squared (weight / height x height or kg/m2). This became known as the Quetelet Index. In other words, knowing someone’s height could predict its mass, and the other way round (if we deal with “average” persons). Quetelet may have gone as far as proposing that with such measurements one could find parameters to filter out criminals, troublemakers, racial impure people and other types of deviants. Height/weight calculations gained much interest when actuaries of life insurance companies attempted to correlate physiognomy (outer appearance) with life expectancy and discovered a negative correlation between overweight and longevity (the higher the Quetelet index, the shorter the lifespan). One of the leading companies in these studies was the Metropolitan Life Insurance and the new height/weight tables obtained from these studies were named after it. The idea of “desirable body weights” (giving rise to lowest mortality rate) had penetrated society around 1960. The Quetelet index was replaced by the Body Mass Index (BMI) in 1980 when governmental health authorities started to join forces with the provision of dietary guidelines. In 1985 BMI became the official international standard for measuring obesity, and the National Institutes of Health dubbed men with a 27.8+ BMI and women with a 27.3+ BMI as “obese”. This was later, upgraded to 30+ BMI (to reduce the number of ill) and people with a BMI in between 25 and 30 were labeled overweight.

Health is, in part, a code word for a positive range of qualities that any given society wishes to see in citizens: from beauty to loyalty to responsibility to fecundity to efficiency.
adapted from: Gilman S. The art of medicine. The Lancet 2008;371:1499
  1. Fat politics: the real story behind America’s Obesity Epidemic, Olivier JE, Oxford University Press, 2005
  2. Monster’s Blog; Melanie Lazarus
  3. Harrison GG, Height-weight tables. Ann Intern Med 1985; 103:489-94
  4. Pai MP, Paloucek FP, The origin of the "Ideal" body weight equations. Ann Pharmacol 2000; 34:1066-69

Consequences of obesity (co-morbidity)

reddot The cut-off point of the BMI index is arbitrary, whether one is declared healthy or ill is largely based on statistical analysis; it is determined by calculating how far someone deviates from the norm (the desirable body weight). But there is more to it. Obesity (BMI >30) at an early age is estimated to reduce life expectancy with seven years and overweight (BMI in between 25-30) is estimated to reduce life expectancy with two to five years. The reduced life expectancy associated with obesity (see figure 6) is in part explained by the occurrence of other illnesses (co-morbidities) of which cardiovascular diseases (such as hypertension, elevated LDL-cholesterol and triglyceride levels (hyperlipidemia)), type II diabetes (insulin is released, even in excess, but body cells do not respond), respiratory difficulty and cancer are the most frequent ones. Reduced life expectancy may thus be the consequence of cardiac arrest, hemorrhagic stroke (cerebral bleeding), thrombosis (blood clots in lung or brain), renal failure, respiratory failure (airflow obstruction), cancer or prolonged coma. These are “normal” causes of death but the difference is that they occur (on average) at a later age with non-obese people. Overweight is also associated with sleep apnea (frequent pauses in breathing, leading to bad night rest), osteoarthritis (erosion of joints) and sometimes with depression (figure 7).

Figure 6 BMI and the relative risk of early death. Note that according to this parameter, both skinny
and fat people have an increased change of early death.

reddot Collectively, the above described illnesses are now thought to be the consequence of a “metabolic syndrome” caused by fat-storing cells, so-called adipocytes. These cells release, in excess, non-esterified fatty acids (free fatty acids) and inflammatory mediators (such as IL-6 and TNF-α) into the blood and they fail to produce adiponectin. An excess of free fatty acids has been shown to block the action of insulin and thus may explain the development of type II diabetes (resistance to insulin). Metabolic syndrome may also increase the incidence of cancer. Much is still to be learned.

Obesity and cancer
A prospective cohort study has been performed in 1.2 million UK women aged 50-64 and followed up for, on average, 5.4 years for cancer incidence and 7.0 years for cancer mortality. During the follow-up 45 037 developed cancer and 17 203 died from this disease. Increased body mass index (BMI) was associated with an increased incidence of (highest) endometrical cancer (uterus), adenocarcinoma of the oesophagus, kidney cancer, leukaemia, multiple myeloma, pancreatic cancer and non-Hodgkin’s lymphoma. An increased incidence of breast cancer was observed in post-menopausal women and of colorectal cancer in premenopausal women.
Reeves GK et al Cancer incidence and mortality in relation to BMI in the million women study: cohort study. BMJ 2007;335:1134-1145.


Figure 7 Morbidities associated with obesity. These are of course not unique
to obese persons, but their incidence is higher and they occur at a younger age.

reddot To give an impression what the relative risk factor actually means, the following table shows you the outcome of the multicentre follow-up study (named “EPIC”) published in the N Engl J Med (Pischon et al. 2008, reference below). In this study, information, such as gender, age, weight, height, waist- and hip-circumference, smoking or not, was collected in a group of 380 000 participants. About 9.7 years later, the same group was investigated (by interview, medical record analysis and questionnaires) and it was found that 14 723 had died. How death distributed amongst the different BMI categories of participating men is shown in table 2. Participants with a “desirable” weight were given a relative risk factor of 1.0 with which the other categories were compared. What it shows is that proportionally more participants had died in the higher index categories (relative risks of early death are growing from BMI 28 upwards). NB, it is not clear to us how the adjusted risk is calculated but it must comprise an age correction because logically, the risk factor increases with age (the older you get the bigger the change that you die in 10 years time).

Men BMI
  21-23.5 23.5-25 25-26.5 26.5-28 28-30 30-35 >35
Person x years 176 701 188 823 215 370 186 758 177 458 157 899 24 794
N° of death 1071 1144 1209 1118 1212 1256 380
Adjusted risk 1.03 1.0 (reference) 0.91 0.96 1.08 1.24 1.94

Table 2 (adapted from Pischon et al, 2008)

Wrong fat and not-so wrong fat; indexing fat content by a waist-to-hip circumference ratio

reddot Weight for height indexes (BMI) have the limitation that they are based on measurements of body weight rather than body composition. Body weight does not give information about the specific components of body composition. For example, body builders may have a very high BMI (and be considered obese) because of excess muscle rather than fat. More recently, large surveys showed that fat storage in the buttocks and upper legs (gluteofemoral fat), has little impact on life expectancy, whereas storage in the belly (abdominal fat) has. The above described metabolic syndrome is typically detected in people with an excess of abdominal fat. The above described Europen study showed that the waist-to-hip ratio (cm/cm) might also be a good parameter to measure life expectancy According to this study, considered at risk are men with a waist-to-hip ratio above 1.0 and women with a ratio above 0.86 (see figure 8).

  1. Despres J-P, Lemieux I. Abdominal obesity and metabolic syndrome. Nature 2006;444:881-887
  2. Pischon T et al. General and abdominal adiposity and risk of death in Europe. New Engl J of Med 2008;359:2105-2120
  3. Haslam DW, Jmaes WPT. Obesity. The Lancet 2005;366:1197-1209


Figure 8 (a) “Wrong” fat, abdominal, and “not so wrong” fat, gluteofemoral. (b) The waist-to-hip ratio provides information about the distribution of fat. (c) An increased waist-to-hip ratio correlates with an increased risk factor (for early death). Note that a slim waist (low index) increases life expectancy
(compared to persons with a desirable BMI).

Fat is an essential component of our body
Despite all these fat-frightening stories, our body needs fat. In fact the very existence of living organisms, made up of cells, has been made possible by the formation of a privileged space surrounded by a bilayer of fat (a lipid bilayer or plasma membrane). The proper functioning of this fatty bilayer requires a good deal of cholesterol (another modern-day villain). Fat-derived molecules play an important role in the communication between cells. Well known examples are our sex hormones. Nerves, including those in our brain, need fatty-sheets in order to isolate and rapidly propagate their electronic messages (action potentials). Subcutaneous (beneath the skin) fat protects against physical insult, like an under-pad for carpet, it also protects against cold. Fat surrounding internal organs makes them more shock proof. Finally, fat is both an efficient and readily accessible mode of nutrient storage, acting as a buffer during the days when food is hard to get by.

How to deal with obesity

reddot Given the persistence of increasing numbers of overweight and obese people, it follows that obesity is hard to deal with. Team 6 will discuss surgery and medication that is used to treat morbid obesity. The other, not so severe, cases of obesity and overweight have to content with governmental “life style” guidelines that can be summarized as “eat less, eat healthy and exercise more”. There is no proper medication to prevent or cure obesity. Trying to be less fat has become an obsession for a good deal of people, but paradoxically, inappropriate dieting and medication may do them more harm than their actual overweight. Here is a job for science students.

Searching for genes that predispose to obesity

reddot In the age of molecular biology it may not come as a surprise that numerous scientists try to connect obesity with genetic traits such as gene polymorphisms (slight modifications in the nucleotide sequence of genes), gene deletions (genes are lacking) or chromosomal translocations (genes are broken or moved to other areas of the genome resulting in loss of function or aberrant expression). Basically two approaches are employed. In the first genetic anomalies are searched in the genome of severe or morbid obese persons. These studies can either be focused on genes that were revealed to be involved in obesity in mice or they can be whole genome screens (with no particular gene in mind). A variant to this approach are searches for obesity genes in patients with syndromes leading to a broad range of anomalies amongst which obesity (referred to as syndromic obesity), mental retardation, dysmorphism and organ-specific abnormalities. In these cases, often as not, chromosomal abnormalities are already indentified (know location) but the genes involved still need to be discovered (positional cloning). Examples are Prader-Willi (lack of paternal 15q11.2-q12 chromosome segment), Bardet-Biedl (associated with different chromosomal locations) and Alström syndrome. In the second approach, whole genome polymorphism screens are employed on a large group of people which are genetically not too divergent and have grown up with relative small variations in environment (for instance living in isolation on an island). The results of these screens are compared with antropometric data of the same population in the hope to find an association between a high body mass index (or waist-to-hip ratio) and single nucleotide polymorphisms of certain genes. Both approaches have revealed genes that are associated with body weight.

reddot A distinction is made between monogenic obesity, stemming from a single dysfunctional gene leading to an obesity in which environmental factors play a minor role, and polygenic obesity, in which numerous genes make minor contributions in determining body weight (trough fat storage) and where environmental conditions play an important role. Amongst environmental conditions we cite: type and abundance of food, exercise (sport, manual work etc), gut microbiota, peer pressure, viruses, medical treatment (“obesogenic medication”) or hormones. What this means is that carriers of mutations of these genes, in contrast to the above described monogenic obesity, are not necessarily obese. As one may imagine, this makes the search for targets for medical intervention not particular easy.

reddot In monogenic obesity, mutations have been found in genes coding for leptin and its receptor, the melanocortin- 4 receptor (MC4-R), POMC, SIM1 and PC1 (see table 3). All these play a role in the establishment of a satiety signal leading to anorexic behaviour. Loss of their function may thus be expected to lead to increased appetite. We return to these proteins in the pages of team 2 and team 4. Other examples are TrkB, carboxypeptidase E and TUB of which the role in the regulation of food intake remains to be discovered. These mutations are found in a total number of 200 cases of morbid obesity (a tiny fraction of the 1 billion or so obese persons). In patients with Prader-Willi syndrome, the ghrelin gene is a potential candidate. Ghrelin is released by the stomach and has an orexic effect, it provokes appetite, so here a gain of function is to be expected.

Gene Transmission Obesity Associated phenotype
Leptin Recessive Severe/morbid right from birth Lack of gonadotrophins
(LH, FSH) leading to
hypogonadism
Leptin receptor Recessive Severe/morbid right from birth Lack of gonadotrophins
(no pubertal development),
low growth hormone
and thyrotropin
Pro-opiomelanocortine (POMC) Recessive Severe showing after first months Adrenal insufficiency, red hair
Proconvertase 1 (PC1) Recessive Moderate, showing after first months Lack of gonadotrophins,
partial ACTH deficiency,
high pro-insulinemia
Melanocortin-4 receptor (MC4R) Dominante Early, variable levels of obesity Sometimes excessive
growth in childhood

Table 3 genes whose sole mutations are associated with early onset obesity

Prader-Willi syndrome
One of the disorders of this syndrome is a low muscle tonus and little motor activity. As a consequence motor milestones are delayed and the average age of sitting is 12 months and walking 2 years. The situation improves with aging but adults remain hypotonic. This and the subsequent reduced muscle bulk may contribute to a disproportional gain of body fat (reduced expenditure). Significant obesity generally begins when hyperphagia, another characteristic of the syndrome, has its onset (between 1 and 6 years). Food seeking behavior, with hoarding of or foraging for food, eating of unappealing substances such as garbage or pet food, stealing of food or stealing money to buy food are common.


Figure 9 The 8 year old Eugenia Martinez Vellejo was paraded around
on fairs as “la monstrua” (the monster), so nicknamed because of her obesity.
She was most likely affected by the Prader-Willi syndrome. Painting by
Juan Carreño de Miranda (1680) and exhibited at the Prado, Madrid, Spain.

reddot Common obesity is polygenic and about sixty genomic regions are involved in the regulation the distribution and the quantity of fat-mass, energetic expenditure and regulation of circulating insulin and leptin concentrations (satiety hormones) (see figure 9). These regions vary between different populations.


Figure 10 Regions of the genome linked to obesity-related phenotypes in six different populations
from Mutch DM, Clément K. Unraveling the genetics of human obesity. PLosGenet 2006;2(12):e188

reddot Precise examples of genes involved in are still few. We cite: GAD2 (glutamic acid decarboxylase), ENPP1 (ectonucleotide pyrophosphatases/phosphodiesterase 1), SCL6A14 (solute carrier protein, a neurotransmitter transporter) and FTO (fat mass and obesity associated gene). As the role in their regulation of food intake is not clear, these are referred to as “gene candidates”.

Energy expenditure without locomotor activity, the other side of the coin

reddot We have mainly focused on the regulation of food intake as an essential factor in the acquisition of fat, but recent research has shown that there is another side of the coin and that is energy expenditure independent of locomotor activity (exercise or work). In modern ecological terms, there are sustainable humans who use their food really efficiently (but tend to get fat) and there are those who waste in the form of excessive thermogenesis (heat production) (and tend to stay slim). Evidence is now being provided that indeed some people can eat carelessly and do not accumulate fat, whilst others gain weight by just looking at food.

reddot Matters are far from clear but the picture that emerges is that certain mitochondria, localized in (brown) adipose tissue, do not use fuel (glucose or fatty acids) to make ATP. They uncouple metabolic pathways (glycolysis and citric acid cycle) from oxidative phosphorylation (used in the generation of ATP) and as a consequence only heat is produced (and the metabolic end-products H20 and CO2). It is a bit like trying to charge a battery with a dynamo on a bicycle but failing to connect the wires. You get really hot but in vain. The thus generated heat will leave the body through conduction, convection, radiation and evaporation of sweat. All rather inefficient but studies with mice show that it may keep you slim (see textbox below about Fto). Incidentally, new born babies, lacking locomoter activity and with low muscle tonus, use the same mechanism to stay warm, as do hibernating bears.

Fto
The abbreviation of the gene fto stands for » fatso « which means “a fat person”. This has nothing to do with fat storage, the gene was named so because of its enormous size (250 kb). The fto gene was discovered as a gene candidate for the fused toe (Ft) phenotype of mice in which a large region (serveral hundred kb) of chromosome 8 is lacking (Cloning of Fatso ( Fto ), a novel gene deleted by the Fused toes ( Ft ) mouse mutation. Peters T, Ausmeier K, Ruther U. Mammalian Genome 1999;10:983-986). In fact the scientist searched for genes involved in limb and craniofacial development as well as the control of programmed cells death and left-right body asymmetry. It has now been shown that the Ft deletion comprises genes of the Iroquois B (IrxB) cluster and of Fts, Ftm, and Fto. Only later when the link was made with obesity did the name become derogatory and Fto has been rebaptized “fat mass and obesity associated gene”.

Fto and obesity
Fto came to light as an obesity-causing gene candidate in a big genomic screen (>4000 participants) held at the isle of Sardinia (Italy). Genome wide screening for single nucleotide polymorphisms (SNP) revealed that participants that had replaced an A (adenine) for a G (guanine) in both their Fto genes (one paternal, one maternal) were heavier than those carrying the common “A” allele. Participants with A/A genes had an average BMI of 26.4, those carrying A/G had 26.9 but those carrying G/G had 27.9. They also showed an increased hip circumference. The code name for the G variant of Fto is rs9930506.
Scuteri, A, Sanna S, Chen W-M, Uda M, Albai G et al. Genome-wide association scan shows genetic variants in the FTO gene are associated with obesity-related traits. PLoS genetics 2007;3(7):e115

Loss of Fto leads to energy waisting
Fto codes for oxoglutarate-dependent nucleic acid demethylase but what precisely Fto does to reduce fat storage in humans is not yet clear. Some hints are given by mice lacking the gene (fto-/-). They are protected against an excess of fat storage, despite decreased spontaneous locomotor activity and relative hyperphagia, because of increased energy expenditure. In other words, these mice eat more, move less but nevertheless remain lean ! Energy expenditure is still poorly studied, but from this study and others the message emerges that some people convert a larger part of their food into heat, they are simply less efficient and thus remain lean.
Fischer J, Koch L, Emmerling C, Vierkotten J, Peters T, Brüning JC, Rüther U. Inactivation of the Fto gene protects from obesity. Nature 2009;458:894-898).

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