Field of Science

Focus on Obesity

Okay, last night, I saw a programme, called the Half ton mum (oh my f#cking god I linked to the daily mail... how much lower can this blog get?)
It was about an extremely fat woman, although she wasn't half a ton (more like 70 stone..... The combined weight of me and my family isn't that much)

but anyway, this documentary left me with the indelible question in my mind. How can someone let themselves get so fat that they cannot walk? or in her case, it got to the point where she literally couldn't move. She had weeping sores (which she never saw) and if she tried to roll over or move her legs, her skin would rip apart. And I'm not even going to start on the bedsores.
She had been stuck in her house for the past five years. I tend to go a bit crazy if I've been in the house for five days, so I cannot imagine the hell this woman was exposed to.
Not to mention that this documentary was helpfully followed by another, called "half ton man" this was about a man, who was actually half a ton in size.

Why Do People Become Obese ?
There is a very simple answer to this question. They eat a lot. According to a nutritional biochemist I know, An average human male has a recommended daily allowance of 2500 calories per day, and the average female requires 2100 on average.
However, these are rough estimates, and they depend on your activity level.

If i was stuck at a desk all day, I only need 1300 calories to survive. If I live an active athletic life, I may need as much as 3500, so actually following recommended daily caloric intake may not be the best guide. You can calculate your recommended daily caloric intake at this website (although I cannot vouch for whether it's trustworthy or not , because I never use it to look at how much I need to eat)

What I do is similar to what most people do. I trust my brain to tell me how much I'm supposed to eat. When most people eat, they become full after they've fulfilled their calorie needs, and stop eating. Some people don't eat much, and some people eat more, but their weight stays stable, because they fulfil their particular requirements.

This is what happens in animals, which is why you don't see fat foxes toddling around city streets, event though there is an abundance of food waste in the city. The same goes for rats.
However, these days there are a lot more people who seem to be ignoring their brain, or at least have stopped being able to tell (by natural means) when they have fulfilled their daily caloric requirement. these people eat more and more calories, and become overweight, then fat, then obese and (if they haven't died of a heart attack, diabetes or cancer by now) then super-obese.

The question we should be really asking is why are these people eating more, and putting on more weight?

Why Do People Over-Eat ?
Scientists have been trying to solve this particular problem for a while, and there are two factors which are believed to contribute to obesity:

A genetic malfunction in the bodily systems which allow for the brain to regulate it's food intake.
An environmentally induced malfunction in the body systems which control food intake.

The only way to discern how these factors are effected, the bodily systems involved with the regulation of food intake needed to be analysed and understood.

Since the late 19th century it has been believed that obesity was related to a problem in the hypothalamus. In those days, they didn't have the high fat food that we do today and so obesity was a much rarer condition. In Clinical literature of this time traced a correlation between obesity and tumours within the hypothalamus. Frolich and Babinski claimed that obesity was due to a malfunction in the pituitary gland (which was right next to the hypothalamus) while Erdhiem, on of their contemporaries believed it to have been due to a problem in the hypothalamus. [1] However, neither of these two groups were really sure about their theories. In order to test these theories, they had to use animal models. (I am not going to go into my opinions or the ethics of using animals for experimental use in this post. but I promise I will dedicate a post to this topic at a later date)

These models could not simply be animals that had been force fed food to make them fat. they had to have some sort of imbalance in their metabolism in order to make them want to become fat.

One of the first attempts to do this was in 1913, where Camus and Roussy performed a hypophysectomy on a dog (they lifted out it's hypothalamus) and showed that this did not in fact cause obesity unless the dog received brain damage at the same time. [1] The problem with this experiment was that it lacked repeatability, and therefore credibility.

It was only in 1939 when the role of the hypothalamus in the regulation of food intake could be confirmed, in an experiment performed by S.W. Ranson. In this experiment, an electrode was used to damage some sections of a rat hypothalamus, without touching the pituitary. This caused the experimental animals to become obese, proving that it was the hypothalamus, and not the pituitary which controlled obesity.

This is not to say that obesity is caused by damage to the hypothalamus, even 50 years ago, when they were doing these experiments they did not believe that. It was proposed by GC Kennedy in 1953 that in humans and animals, food intake is controlled by the adipostat mechanism [2].

Adipostat Mechanism
Adipo (meaning Fat) Stat (meaning stability)

Kennedy observed that rats keep their weight within certain limits. And they can do this even if you give them more exercise, or less exercise. they manipulate their food intake so that their body fat index remains constant [2]. This only fails to occur when rats have damage to their hypothalamus. Kennedy came to the conclusion that in order for this to occur, the brain must be able to detect the body fat levels of the mouse via the hypothalamus. In order to do this, the fat cells (when you get fat, the excess fat deposits in special cells called Adipocytes) themselves must be secreting a messenger molecule to tell the brain how fat the mouse has gotten. This is the Adipostat response.

Kennedy suggested that obesity was not caused by damage to the hypothalamus , but in fact was due to a fault in this adipostat response.

Obese Mice
Not long after the proposal of the adipostatic response, a new strain of mouse was found in laboratories, which grew incredibly fat. These were named the obese or ob/ob mice. These mice eat a lot of food, and they tend to eat until they literally cannot move. If you try to restrict their food for their own welfare, they will become incredibly aggressive. In fact , they behaved a lot like mice whom had experimental destruction of parts of their hypothalamus, except that these mice had perfectly healthy brains. So if the problem wasn't in the hypothalamus, these mice must have had a problem in their fat cells, in that they weren't secreting the messenger molecule telling the mouse's brain how fat the mouse had become.
How did the researchers test this?

Parabiotic Experiments
In hypothalamically damaged mice, there had been experiments in which the blood of these mice was shared with that of normal mice (there is not usually much problem with rejection in inbred laboratory mice)

These mice stayed fat, and the normal mice became thinner. This was because in the fat mice, the fat cells were producing messenger like mad, but since the hypothalamus was damaged, the fat mouse's brain could not detect the messenger. However, the normal mouse still had an intact hypothalamus, which reacted to the hormone stimulus, telling the mouse that it had too much fat. And so the normal mouse stopped eating, and became thinner.

However, when a normal mouse was strapped to the ob/ob mouse, it was the obese mouse which reduced it's food intake. So it had a functional hypothalamus, but the fat cells within the obese mouse did not function.

The molecular messenger however evaded identification for nearly 30 years, until in 1994. This peptide molecule was named leptin (from the greek Leptos meaning "thin") The ob/ob mouse strain was caused by a deficiency in the leptin producing genes.

By 1997, these genes were isolated, and moreover it was found that some human children also had a leptin deficiency[3], similar to that seen in ob/ob mice. These children exhibited rapid weight gain, and extreme hyperphagia (one child was observed to eat 3000 one sitting)

However, these children were treated with injections of leptin, and they were "cured" of their obesity. Leptin made them reduce their food intake, and they slimmed down to a healthy bodyweight.

Can we not cure all forms of obesity using Leptin treatment?
In theory, if we give leptin shots to all fat people, they should end up losing the weight that they've gained. However, this does not work in reality for two reasons:
Leptin Deficiency is not the cause of all obesity. in fact, only about ten people in the world have been reported to have this disease
Leptin was trialled as an anti-obesity drug. A clinical trial was done to investigate whether leptin could inhibit food intake in obese people [4]. What was found was quite disheartening to the drug company. the Leptin had no effect. Why? Because many people who become obese are resistant to the effects of leptin[5].

So while we are no closer to finding the cure for obesity, we do at least have a clue as to one of the factors which determines obesity. In the same way that in type 2 diabetes , you can become resistant to the effects of insulin, if you become too fat, you become resistant to the effects of leptin. This can go some way as to explaining how an ordinary fat person can progress to hyper-obesity without getting proper signals to the brain.

What causes Leptin Resistance?
In short, no-one knows for sure . A lot of scientists are trying to solve this problem at the moment. It is thought that Leptin resistance must originate in the hypothalamus. So how do researchers investigate this?

This is investigated through the use of diet induced obese mice. These mice are fed on a high fat diet, until they become quite fat. They aren't the perfect models of leptin resistance, because they don't become as fat as the Leptin deficient obese mouse strains I mentioned earlier. this means that these mice are still not completely resistant to leptin.

Their leptin resistance was measured through looking at how much P-STAT3 (a downstream signalling molecule affected by how successful leptin binding is) is expressed in different parts of the Hypothalamus [5].

What they found was that leptin resistance was confined to a specific part of the hypothalamus, known as the Arcuate Nucleus. Cells within this part of the brain stop responding to leptin. But nobody knows why these cells stop responding to leptin. However, it is significant that leptin signalling in the arcuate nucleus is down-regulated ,as opposed to other leptin receptors in the brain. for a start, Leptin has more than just one function it also acts on the reproductive system, and helps regulate gonadotrophin secretion in the pituitary. A lack of leptin can stop puberty (because the body needs fat for certain aspects of reproduction and puberty. Similar effects can be seen in anorexic children, who suffer from a leptin deficiency simply because they don't have enough fat cells.)

However, in induced leptin resistance, the cells in the arcuate nucleus ( the part of the brain which helps to regulate appetite) are more highly affected than other cells in the brain. This suggests that the downstream signals (rather than a specific receptor-receptor interaction) causes leptin resistance [5].

Arcuate Nucleus
What is the arcuate nucleus? and how does it help control your food intake?

The Arcuate nucleus consists of a bundle of neurones at the base of the hypothalamus, which is situated near to the 3rd ventricle of the brain (ventricles are filled with cerebro-spinal fluid which keeps brain cells alive)

The arcuate nucleus is made up of two types of neuroens. the first type are identified by their expression of neuropeptide Y (NPY) and agouti related peptide (AgRP), and the second type are identified pro-opiomelanocortin (POMC) and Cocaine and Amphetamine regulated transcript (CART). These neurones have opposing functions, with the 1st type stimulates feeding, the second type inhibits feeding.

Each of these neurones responds to specific appetite hormone signals, and in response can communicate to other parts of the brain, and with the gut to change feeding habits.

Through these different signals, it is able to "talk" to the stomach, the Duodenum, the jejunum, the ileum, the colon, the pancreas and the fat cells.

The arcuate nucleus is essentially the part of the brain which is supposed to tell you that you are full when you have had enough to eat.

How do my Organs tell my Brain that I'm Hungry?
Your body likes to keep itself in stable conditions, with stable blood sugar, stable fat content etc.

We've already talked about how fat cells secrete leptin to tell you how fat you are. If you have lots of fatty stores, the leptin produced by these stores should tell your brain to not eat so much. If there is not that much leptin around (I.e. if you've been starved for a while, or just have a low body fat content) then you will seek out fatty foods.

Your stomach also tells you when you are hungry, especially if you keep to a regular daily meal schedule. The Stomach produces a hormone known as ghrelin. This hormone reacts in an opposite way to leptin, in that it increases those hunger pangs you feel, rather than decreases them.

It has been found that the levels of ghrelin increase just before a meal [6] , and there is evidence that it is influenced by the circadian rhythm of the body. This would be advantageous, because ghrelin increases acid production in the stomach in preparation for a meal. Studies have shown that the brain can induce expression of ghrelin when it expects food to be served [8], and there is a sharp increase in ghrelin at customary meal times. So to some extent, ghrelin production is trained at an early age to orient towards meal times. But these rhythms can be changed via habituation. If you are used to having 5 meals a day, your brain trains itself to be hungry at those times of day.

There is a rare syndrome, prader -willi syndrome, which is one of the few forms of genetic obesity around. One of the ways of characterising it is that sufferers have 2-3 times more ghrelin production than normal people. so they feel much more hungry than a normal person.

In contrast, in normal obese patients , the levels of ghrelin are in fact lower, as it's production is believed to be in some way inhibited by leptin.

I have only named two hormones which are involved in hunger, but there are probably more out there which have yet to be discovered.

How do My Organs Tell me That I'm Full Up ?
This is a bit more complicated, as there are different reactions at different organs.

The Stomach: The Stomach is a muscular mass which churns up the food. the splanchnic and the sensory vagal nerves are heavily involved in telling you when you've had enough to eat. There are stretch receptors in the stomach that signal to the vagal and spinal sensory nerves that there is food in the stomach[9]. However, this is not usually a significant effect, because food is regularly taken out of the stomach and dumped into the intestine, so there isn't much opportunity for the stretch receptors to be stimulated in this way.

The Intestine: It is here that satiation can be best controlled. Unlike the stomach, the intestine has eneteroendocrine cells, which are able to detect the nutrients within the food, and therefore whether more or less food needs to be eaten. many of the signals produced by the intestine inhibit the emptying of the stomach, which leads to a build up of food within the stomach, activating the stretch receptors.

CCK (Cholecystokinin) is one of the main hormones secreted by the intestine. This is produced in the duodenum and the jejunum, and is produced by I cells. There have been attempts to turn this peptide into a viable treatment, but a single dose only protects against hunger for about half an hour.

GLP-1 (Glucagon-like peptide 1), this is expressed in the L cells of the lower GI tract, and in the pancreas as well. It acts to decrease food intake. More importantly, it has been found to accentuate insulin, and inhibit glucagon secretion. It is currently being developed as a drug to treat diabetes. Exenitide is a drug which stimulates the receptor for GLP-1 in the hypothalamus. However, there are GLP-1 receptors in the amygdala, which when stimulated, cause feelings of nausea.

Oxyntomodulin: this is also produced in L-cells, and it has been shown to not only decrease appetite, but also increase activity levels, although it is not known how it does these things.

PYY (Pancreatic polypeptide fold) is also mainly produced by L-cells in the intestine, and is secreted after a meal in proportion to the amount of calories within the meal. The intersting thing about this peptide is that when it is administered via the body to people, it is an inhibitor of food intake, but when it is administered via the brain, it is a stimulator. The reason for this is due to the administration of PYY to the brain allowing for receptors access to the hormone that they would not get through peripheral administration.

I could go on for years about all the different hormones that are stimulated. But basically, your intestine detects nutrient levels and sends messages to the brain. Each of these signals has been studied, and they are currently developing a whole swath of drugs based on these signals to combat obesity.

How Do People resist these signals and become Obese ?

This is a quite difficult question, mainly because it's not the same for everybody. I've already talked about Leptin deficient children, whom eat a lot because they have no leptin to tell them that they've had too much to eat. People with Prader-Willi syndrome have excess ghrelin production, and a deformation in their vagus berve which means that not only are they more hungry, but they are less able to tell when they are full.

But genetic diseases represent the extreme minority of cases of obesity. 50% of people in the UK are classed as overweight. It is predicted that by 2010 (2 years away) 12 million adults and 1 million children will be obese. This is not just about genetics, something significant in the environment has changed over the past hundred years which has caused obesity (it's not global warming)

The most obvious thing to point out is the existance of "fast food". Fifty years ago, there were no ready meals, or junk food outlets. The food we get from those shops is very different from what we would cook in our own kitchens. Try making burgers yourself, and then compare the ingredients you've used with those and those you see on the back of a burger meal.

So why doesn't your body immediately stop you eating a whole "super fun" meal from your local junk food outlet. Why doesn't the level of hormones in your intestine tell you exactly when you've reached your correct caloric intake? How come after eating at a junk food store, you find that you are still hungry?

Well, the effects of food extend beyond the hypothalamus of the brain. We have a whole gamut of emotions and behaviours associated with food. The touch, sight, smell and sound of food can stimulate hunger centres within our higher brain, which ends up dialling the pizza restaurant before the hypothalamus has anything to say about it. The fact that we attribute emotions, such as good feelings with some foods, can dictate a lot of our food habits. [10]

The memory of food has an effect on how much we behave towards it. You can catch a whiff of your favourite food on the air, and immediately you think about how it tastes, how it smells, its texture and you find yourself wanting to have it. (Do you feel hungry now? all this talk of food is making me hungry...I'll go off for a snack..)

The mu-opiod receptor is one of the receptors in the brain which affects this "want reflex". In mice injected with mu-opiod show a particular requirement for sucrose and fat rich foods. it is believed that opiods have some effect on the "pleasure" response involved in eating food [11]. This is response is likely to be due to the nucleus accumbens , a complicated structure within the brain which is also an integral region in drug reward.

So essentially, the brain gets "rewarded" every time it eats fatty foods. The desire for a person to get this reward can overrule other signals from your stomach and hypothalamus. Your higher brain has multiple inputs into the hypothalamus, which are theorised to "move the goalposts" of energy requirements.

They do this by interfering in the arcuate nucleus, and disabling the POMC/CART receptors, which are needed to tell you when you are full up [12]. This was found through an experiment in which mice had their nucleus accumbens stimulated by a neuropeptide (Muscimol, a GABA-ergic receptor agonist). It was found that these mice had increased food intake. Moreover, histochemical staining revealed that the cells in the arcuate nucleus of the hypothalamus were affected. The activity of these neurones was measured through their Fos expression (fos is an important transcription factor for hormones.) it was found that POMC/CART neurones had a lower Fos expression, and NPY/AgRP neurones had greater expression of POMC. this experiment demonstrates how higher brain functions can override the hypothalamus.

Companies who sell you foods want them to be as tasty and as palatable and as cheap as possible, so we find ourselves bombarded by literrally hundreds of products designed to elicit a positive response from our brains. Delicious, sweet, fatty unhealthy food has never been more readily available to the masses. There are adverts blaring on our TV screens, all targeted to elicit a reaction from our amygdala. Watching an advert about a delicious food can elicit an emotional response from your memory, and this stimulates the orbitofrontal cortex and your nucleus accumbens, making you desire that food.

The reward/pleasure circuits in our brains mean that we can get addicted to food very easily. (for more on addiction, look at my world of warcraft post). People who are depressed self medicate themselves with food, so as to stimulate the pleasure centres in their brains to combat the negative emotions they are feeling at the time. This is , of course, a Primary Addiction.

And while this happens, we find ourself in a society that requires us to sit at a desk more and more, and not do any sort of exercise to counterract the increase in nutrient intake [10] The very domesticity of our life is causing our waistlines to expand. Not only at work, but at home, our forms of entertainment are becoming less physical (unless you buy a wii). Even our pets are becoming fatter.

Is it any wonder that we have people who weigh half a ton in our society, when it seems so geared into tricking us to eat big and eat fast ?

It makes me wonder whether there is some alien conspiricy which has infiltrated our government, so that the fattest of our society can be shipped off to a far off world where they could feed millions of starving aliens. of course, this is incredibly unlikely. Fat humans are quite poor nutritionally, and even aliens need to watch their weight. We'd probably end up as engine fuel.

1. "Experimental hypothalamic obesity."KENNEDY GC Proc R Soc Med. 1951 Oct;44(10):899-902.

2. "The Role of Depot Fat in the Hypothalamic Control of Food Intake in the Rat"G. C. KennedyProceedings of the Royal Society of London. Series B, Biological Sciences, Vol. 140, No. 901 (Jan. 15, 1953), pp. 578-592

3. "A mutation in the human leptin receptor gene causes obesity and pituitary dysfunction"
Karine Clément, Christian Vaisse et al ,Nature 392, 398-401 (26 March 1998) doi:10.1038/32911

4. "Effect of three treatment schedules of recombinant methionyl human leptin on body weight in obese adults: a randomized, placebo-controlled trial." Diabetes, Obesity & Metabolism. 7(6):755-761, November 2005. Zelissen, P. M. J. 1; Stenlof, K. 2; Lean, M. E. J. 3; Fogteloo, J. 4; Keulen, E. T. P. 5; Wilding, J. 6; Finer, N. 7; Rossner, S. 8; Lawrence, E. 9; Fletcher, C. 9; McCamish, M.

5. "Region-Specific Leptin Resistance within the Hypothalamus of Diet-Induced Obese Mice" Heike Münzberg, Jeffrey S. Flier and Christian Bjørbæk , Endocrinology, doi:10.1210/en.2004-0726

6.A Preprandial Rise in Plasma Ghrelin Levels Suggests a Role in Meal Initiation in Humans David E. Cummings, Jonathan Q. Purnell, R. Scott Frayo, Karin Schmidova, Brent E. Wisse, and David S. Weigle, Diabetes 50:1714-1719, 2001

7. "Ghrelin Stimulates GH But Not Food Intake in Arcuate Nucleus Ablated Rats" Hideki Tamura, Jun Kamegai, Takako Shimizu, Shinya Ishii, Hitoshi Sugihara and Shinichi Oikawa, Endocrinology Vol. 143, No. 9 3268-3275

8. "Spontaneous 24-h ghrelin secretion pattern in fasting subjects: maintenance of a meal-related pattern ", G Natalucci, S Riedl, A Gleiss1, T Zidek2 and H Frisch , DOI: 10.1530/eje.1.01919European Journal of Endocrinology, Vol 152, Issue 6, 845-850

9. "Gut vagal afferent lesions increase meal size but do not block gastric preload-induced feeding suppression" Gary J. Schwartz, Cynthia F. Salorio, Chris Skoglund, and Timothy H. Moran Am J Physiol Regul Integr Comp Physiol 276

10. "Interactions between the “cognitive” and “metabolic” brain in the control of food intake " Hans-Rudolf Berthoud , Physiology & Behavior Volume 91, Issue 5, 15 August 2007, Pages 486-498 doi:10.1016/j.physbeh.2006.12.016

11. Enhanced intake of high-fat food following striatal mu-opioid stimulation: microinjection mapping and Fos expression
M. Zhang and A. E. Kelley Neuroscience Volume 99, Issue 2, 9 August 2000, Pages 267-277 ,doi:10.1016/S0306-4522(00)00198-6

12 . "Appetite-inducing accumbens manipulation activates hypothalamic orexin neurons and inhibits POMC neurons"
Zheng, H.a , Corkern, M.a , Stoyanova, I.a , Patterson, L.M.a , Tian, R.a , Berthoud, H.-R, American Journal of Physiology - Regulatory Integrative and Comparative Physiology Volume 284, Issue 6 53-6, 1 June 2003, Pages R1436-R1444

No comments:

Post a Comment

Markup Key:
- <b>bold</b> = bold
- <i>italic</i> = italic
- <a href="">FoS</a> = FoS