Food reward, a factor in obesity

 “I think food reward offers the most compelling explanation for the US/global obesity epidemic.” 

Stephan Guynet 
In studies where the food intake and energy expenditure of subjects are carefully monitored over a period of weeks to months (which tends to average out day-to-day fluctuations) a remarkable balance between calories consumed and calories burned was observed. When various mammals, from mice to monkeys, are either overfed or starved for a few weeks, their weight soon returns to normal levels when free access to food is resumed. Crucially, our mammalian bodies seem to be able to regulate feeding based on the amount of energy available in the food we consume, not just on the volume of that food.

The above quote David Linden, suggests the body controls body weight by registering the amount of energy in food. This theorizing usually leads to the white adipose tissue derived hormone leptin and particularly its effect on the hypothalamus. Leptin, in general, correlate with adipose tissue mass. But the energy the body needs comes from two places: food and stored energy. Increasing use of stored energy will make animals and human eat less. Any energy-sensing control system must register the total amount of energy available, both from foods and from fat and glycogen stores. From this point of view, obesity could to be caused by the body not having access to its own stored energy and so continues to signal for food intake. Alternatively, the stored energy is readily available, but somehow an obese person experience feelings of hunger and craving that overpower any signal telling the brain that there is enough energy available. This scenario makes it likely that obesity is caused by a malfunctioning control system.

Stephan Guyenet has created quite a stir lately with his posts about food reward. Several of the posts have over 100 comments, some more rational than others, but people clearly have strong feelings about this. I think one of the reasons some people feel personally offended by his writing, is that they feel food reward lends support to overweight being caused by lack of willpower. This is definitely not Stephan’s intent, nor does his reasoning indicate willpower as a major factor. Nevertheless, willpower is a major part of food reward, as one of the opposing forces to a physiological drive to consume rewarding foods.

The theory of food reward is a theory of how foods affect our feelings, stimulate our behavior and how some foods appear addictive and promote addictive behavior. This seems lost on many. Food reward does not and cannot explain how we fatten. To find the answer to this we need to look at the physiology of the fat cells. Basic biochemistry still applies and some foods are more fattening than others, although as it seems, Stephan does not think so and he even uses his belief that macronutrients doesn’t matter as an argument in favor of the food reward theory. But the theory itself is a theory of why we (over)eat, not a theory of how we gain fat.

Even though the theory of food reward is not about willpower, willpower invariably enters into the equation. Many physiological drives can be affected by conscious thought. Stick your hand in ice water and your head tells you to pull it out (or your spine), but you can keep it submerged by willpower, some longer than others. Highly rewarding foods do, according to Guyenet, cause obesity in susceptible people, just like drugs may make addicts of some (often the same people). Still, I cannot see that food reward argues more strongly for willpower as a part of obesity, than other rational theories.

The theory of food reward is actually mostly about carbohydrates as most of the data relating to it is from the studying of sweet foods. As Hans-Rudolf Berthoud put it 

For nonsweet palatable foods (typically high-fat foods), there is less convincing evidence for development of dependence…” [1]
So it seems the key questions are:

– do sweet foods cause addiction and increased energy intake with subsequent obesity?

or
– do sweet foods cause obesity (fat storage) with following addiction or addiction like behavior possibly caused by metabolic clues?

As we undoubtedly fatten differently and not everyone becomes obese despite similar obesogenic environments, we can conclude that addiction to high palatability foods is 1) genetic and that preexisting differences in reward functions cause obesity; 2) intake of palatable foods is in itself addictive and leads to obesity; or 3) obesity (the excess storage of energy in fat tissue) cause changes in reward functions thus further accelerating obesity.

As many lean people also eat large amounts of highly rewarding foods, it seems unlikely that the food itself can be to blame. So, either food reward is secondary to the harmful effects of sugars/grains (sweet food not found in hunter gatherers): these foods create excessive fat storage in obesity prone people and this cause addictive behavior towards the very same foods; or it is the primary cause of obesity: people prone to weight gain have physiological measurable differences in parts of the brain that cause an addictive intake of fattening foods.

Although I enjoyed the posts about food reward I was left with very many unanswered questions after reading:

The reasoning 
Stephan uses the fact that hunter-gatherers are lean in support of rewarding foods causing obesity in non HG societies, arguing that one of the reasons hunter gatherers are lean is because their diets are bland (although I think many HG’s would disapprove of their diets being called bland). This argument could go both ways. Because if the foods that drive fat gain also promote addictive intake of the same foods, then traditional diets can be as tasty as any, just as long as they do not contain these particular foods. As long as they don’t, there is no reason to think blandness is the cause of leanness.

Although lean traditional people’s diets are more unrewarding then say a SAD diet, this does not mean that we in the west become obese because our foods are not.

Also we have to ask: if obese people remove fattening foods, which are the same as those considered highly rewarding, will the addictive behavior/strong cravings for the fattening foods subside? I know from experience that many who struggle with strong cravings, lose their cravings when switching to a LCHF diet. The fact that some feel cravings even after some time on low carb diets, does not favor a set-point hypothesis. It could just indicate a dietary insufficiency, like the lack of salts or some fatty acids. As the cravings usually disappear before a considerable weight is lost, it is unlikely that the cravings were caused by the obesity itself. Often, it seems that cravings disappear when people regain the ability to burn fat.

Burning fat, or having a functional metabolism will make us eat less. The oxidation of fat in the liver offers a strong satiety signal [2]. So, even if lipolysis is high in obese, hunger will not go down if somehow the burning of fat in the liver is restricted. This is sort of a “metabolism argument”: One of the things that separate those prone to obesity and insulin resistance from the rest, is a poor and broken metabolism. They rely on glucose (glycogen) for fuel and have poor fatty acid oxidation in combination with blood sugar fluctuations and cravings, so fat is stored rather than burned as it should. Resolving the metabolism issues will in many reduce the cravings and rewarding foods are no longer an issue.

Another important question to ask is: how often during the day and how much hyperpalatable, highly rewarding foods do people who become obese actually eat?

If people become obese without consuming highly rewarding foods (something I consider very possible) then the theory of food reward argues strongly that this type of obesity is mostly due to lack of willpower, as there is no addiction to blame.

The “bland food” study from 1965 Stephan writes of can be used to support a “food reward” theory, but there are many other ways of explaining why the overweight people lost weight while the lean did, not. If the obese ate high sugar/grain and franken-fat diets, that also happen to be palatable once you get used to it, then of course they lost weight on the liquid diet.

The first volunteer continued eating bland food from the machine for a total of 70 days, losing approximately 70 pounds. After that, he was sent home with the formula and instructed to drink 400 calories of it per day, which he did for an additional 185 days, after which his total weight loss was 200 lbs. The investigators remarked that «during all this time weight was steadily lost and the patient never complained of hunger or gastrointestinal discomfort.» This is truly a starvation-level calorie intake, and to eat it continually for 255 days without hunger suggests that something rather interesting was happening in this man’s body.

This isn’t really that interesting. With all likelihood the man could have lost an equal amount of weight eating real foods that are far more rewarding but not fattening. It has been known to happen.

I think decreased fasting insulin occurs as a result of weight loss…

Stephan Guyenet 

Another important point is that the body fat “setpoint” is still a theoretical point, and any theory based on the setpoint hypothesis is equally hypothetical. 

As one would expect if food reward influences the body fat setpoint, lean volunteers maintained starting weight and a normal calorie intake, while their obese counterparts rapidly lost a massive amount of fat and reduced calorie intake dramatically without hunger. This suggests that obesity is not entirely due to a «broken» metabolism (although that may still contribute), but also at least in part to a heightened sensitivity to food reward in susceptible people. This also implies that obesity may not be a disorder, but rather a normal response to the prevailing dietary environment in affluent nations.

Lean people have good access to their own body fat and high fat oxidation rates. They have a better working liver than obese, and they definitely had a better pre experiment diet than the obese. The above results can be explained exclusively by a broken metabolism theory. There is no need to involve food reward.

Some people may be inclined to think «well, if food tastes bad, you eat less of it; so what!» Although that may be true to some extent, I don’t think it can explain the fact that bland diets affect the calorie intake of lean and obese people differently.

Most diets affect lean and obese differently. These people are per definition quite different metabolism wise, and foods affect metabolism. Once again, the fact that one of the many diets that affect lean and obese differently are bland, does not lend much evidence for palatability playing a major part in obesity.

Although the rewarding abilities of different foods might explain some of the reason we overeat on fattening foods there are very many other ways you are likely to gain weight. As David Pier points out in the comments section:

Excess fructose? Too high an omega-6/omega-3 ratio? Too much omega-6? Too little omega-3? Too much polyunsaturated fat in general? Too little saturated fat? Micronutrient (choline, minerals, etc.) deficiencies? Excess total carbohydrate? Superstimulating hyperpalatibility? Over-availability? Excess insulin (cause and/or effect)? Gut flora (cause and/or effect)? Lack of fiber (insoluble and/or soluble)? Multi-generational epigenetic changes? Artificial sweeteners? Endocrine disruptors? Sleep disturbances? Psychological causes essentially independent of all hormonal homeostatic mechanisms?

In his third post, Guyenet writes about the review of low fat non energy restricted diets where overweight lost more weight than lean:

In other words, low-fat groups reduced their calorie intake by an average of 271 calories per day, and lost 7.5 pounds (3.2 kg). When they considered only people who started off overweight, they lost 12.8 pounds (5.8 kg). The investigators noted that the results were similar no matter what the duration of the trial, because weight loss plateaued fairly quickly.

Then he writes

This is all without any instruction to reduce calorie intake, therefore we can assume these dieters were eating to fullness.

No you can’t assume that. These are participants included in non blinded weight loss trials. I would say it’s a safer bet that they were in fact restricting their food intake.

The best low-carbohydrate diet study I’ve seen was published in 2008 in the New England Journal of Medicine (3). 322 «moderately obese» participants were placed on a low-carbohydrate diet, a calorie-restricted low-fat diet, or a Mediterranean diet, for two years. The low-carbohydrate group’s carbohydrate intake decreased by 130 grams per day, which is about half of a typical person’s total intake, and neatly corresponds to the reduction in calories of 561 per day, despite not being instructed to reduce calorie intake.

At two years, the low-carbohydrate group had lost 10.4 lbs (4.7 kg), which is very similar to the average weight loss seen in low-fat diet trials.

There are two major issues here. 1) The study by Shai et al is a horrible study: The Atkins based diet came with recommendations of getting fat from vegetable sources; By 24 months, carbohydrates constituted 40% in the low carb group and 50% in the low fat group. The low fat diet went from baseline fat intake of 31,4% to 30% (no reduction at all); the aurhors left out baseline energy intakes and only reported reductions; The study also used intention to treat analyses. The weight loss in the low carb group for the 272 who completed the study was 5.5kg in the “low carb” and 3.3kg in the “low fat” group. After 6 months the study diets were not very dissimilar.

If this is the best low-carbohydrate study Guyenet has read, he needs to read the other studies. Low-carbohydrate diets usually outperform low fat diets, as long as carbohydrate intake is kept restricted. This outperformance is despite low fat groups having caloric restrictions while low carb groups can stuff themselves as much as they want. His reasoning that low carb and low fat perform equally is flawed in so many ways, and he uses this reasoning to support a food reward hypothesis.

I think the reason very low-carb ketogenic diets cause fat loss is the same reason extreme low-fat diets cause it: they have a greatly reduced reward value.” 

Stephan Guyenet 

The fact that participants in the Lindberg study lost weight without caloric restrictions does not mean food reward had anything to do with it. Once again, if certain foods themselves cause fattening, and we restrict these foods, weight loss is likely to occur. There is no need to blame blandness.

Messing about with dopamine signaling can cause obesity in animal models, and there are differences in dopamine receptors between «normal» people and those prone to addictive behavior. It is not strange that messing about with the brain will cause all sorts of things, but it does not mean obesity is caused by food reward.

There is more reasoning to discuss, but this post is getting way to long. Is there really enough available evidence to justify calling food reward a dominant factor in obesity? If there is, I can’t say I found evidence of this in Stephan’s posts.

And as Paul Jaminet pointed out:

Likewise, we’re all familiar with young people who eat massive quantities of junk food and remain slender. The high food reward diets, even toxic and malnourishing diets, seem not to cause weight gain until some kind of metabolic damage occurs.

It seems that metabolic damage – the disease of obesity – is a prerequisite for food reward to matter.

Obese people should eat boring diets
Guyenet even offers tips on how to make food less palatable and more bland. But does this mean that there are people out there who have tried all the obvious ways to lose weight, like reducing inflammation and cutting back on carbs, who have not succeeded and are left with trying to make food not taste good?

The most palatable foods are those packed with fat and sugar. These foods are the first to go on any dietary strategy. Do we need to make the rest of the diet bland?

Guyenet offers a range of advice for losing weight based on food reward theory. For example:

Don’t snack. In France and many other countries with strong food traditions, snacks are for children. Adults eat at mealtime, in a deliberate manner.

And yet, if snack in itself do not seem to cause obesity, why not snack?

Don’t add fat to your food. That doesn’t mean don’t eat fat, it just means keep it separate from your cooking. If you want to eat butter, eat it separately rather than mixing it in with your dish.

…I don’t know what to say about this…but I know I don’t like it.

Some of his advices are meant mostly for those who struggle to lose weight, but I fear if anyone would follow them, they would die of boredom instead:

Eat only single ingredients with no flavorings added. No spices, herbs, salt, added sweeteners, added fats, etc. If you eat a potato, eat it plain. If you eat a piece of chicken, eat it plain. It can be in the same meal as other foods, but don’t mix anything together. If you would like to keep salt in your diet, dissolve it in water and drink it separately.

There are more of course. Most make sense, but they also make sense without considering food reward.

Importantly, all the studies used to support the award theory can also be used to support different theories. While they do no not falsify a reward theory they do not provide strong supportive evidence. But this is how science works. Stephan is right in offering the theory and he might turn out to be spot on. It will be interesting to see what future studies will reveal. We need some RCT’s to enlighten the causation between food and dopamine response and function, well any kind of RCT in this field would be important. I would like to make foods that are highly rewarding (measured by dopamine response or something fancy, that make people crave them, and that does not contain anything inherently fattening. Then I would give people free access to it to see if they got fat. Wonder what it could be?

«Some people have lost fat simply by avoiding carbohydrate or fat. I’ve heard people say that a low-carbohydrate diet in particular curbs their cravings and allow them to have a healthy relationship with food again (although others have developed strong cravings on low-carbohydrate diets). I believe this is mostly, if not exclusively, driven by the fact that carbohydrate and fat are major reward factors.»

Stephan Guyenet

References

1. Berthoud HR, Lenard NR, Shin AC: Food reward, hyperphagia, and obesity. Am J Physiol Regul Integr Comp Physiol 2011, 300: R1266-R1277.

2. Friedman MI, Harris RB, Ji H, Ramirez I, Tordoff MG: Fatty acid oxidation affects food intake by altering hepatic energy status. Am J Physiol 1999, 276: R1046-R1053.

Fat people are liars

Obviously! Obesity is a remarkably simple problem to solve. Eat less and move more. When energy expenditure exceeds energy intake, you lose weight. Many people claim to have tried eating less and exercising more and claim that it does not work. As this would be a violation of the laws of thermodynamics it is quite unlikely.

Not only do overweight people claim to break the fundamental laws of nature they also constantly lie about how much they actually eat.

Elaine Prewitt and coworkers examined the effect of a 37%-fat (HF) diet for 4 weeks followed by a 20%-fat diet (LF) for 20 weeks on body composition and weight in 18 premenopausal women with body mass index (BMI) of 18-44. They found that

Despite adjustments in energy intake to maintain weight throughout the study, by the end of the LF period, energy intake had increased significantly in comparison with the HF diet (119% of the HF intake, P < 0.0001). 

The authors knew what kind of people they were dealing with and wrote

We have no means of assessing the degree of food waste by subjects when meals were taken out but there was no reason to attribute the magnitude of energy increase we observed to overreporting of dietary infractions. By contrast, one would expect the subjects, particularly obese subjects, to underreport extra foods eaten.

W. Daniel Schmidt and coworkers exercised overweight women. All study groups were put on an energy restricted diet. The control group only dieted without changing exercise routines, but somehow they didn’t lose any weight. The authors write:

The fact that the control subjects in our study did not lose weight is perplexing and conflicts with other research that generally supports weight loss with caloric restriction [17, 18]. One explanation may be that subjects simply underreported the amount of calories consumed, thus making this an issue of noncompliance. 

Not only are fat people liars, but fat people on low fat diets are the worst. James Krieger, everyone’s favorite researcher, suggests that:

…subjects on low-fat diets systematically underreport energy intake compared with subjects on low carbohydrate diets.

In support of his theory he cites a study where weight loss from a low fat diet did not turn out as predicted.

Fat people on low fat diets are not only the worst liars around, they are also not very smart. Kelly A. Meckling and coworkers compared a low fat diet to a low carbohydrate diet in overweight men and women. They write:

Energy restriction alone predicted a weight loss of 5.5. and 6.9 kg, respectively, in the LF and LC groups, which was close to the observed values of 6.8 and 7 kg for the same groups. Slight differences, particularly for LF subjects might be explained by underreporting of habitual diets, as the subjects became better able to estimate their intakes and keep better food records as the trial proceeded. 

Those put i a low carb group obviously nailed the food reporting task right away, even before they actually were put on the diet, and missed the predicted weight loss by a mere 100 grams.

Everyone knows low fat fatties are the worst. Thermodynamics applied to food and the body is very simple, yet predicted weight loss are often not achieved by low fat fatties.

Writes Jennifer B Keogh and colleagues (when a low carb group lost more weight than a low fat group in their study):

Greater weight loss with a low-carbohydrate diet than with a conventional low-fat diet has been reported previously (2– 4, 57). Subjects in these studies reported similar energy intakes despite differences in weight loss, which suggests that the conventional diet group underreported their intake (3, 4, 57).

A group of Dutch researchers set out to test the extent of underreporting in 30 obese men. Their conclusion:

Total underreporting by the obese men was explained by underrecording and undereating. The obese men selectively underreported fat intake.

Not only did these men lie about how much they were eating, they didn’t even eat as much as they should have. They underrate. Those bastards!

If by chance you are wondering if the methods of the Dutch researchers were bulletproof, they weren’t. Still…

It is possible that overweight people under report more than lean people. But people seem to think that the under reporting somehow is the reason they are fat. They don’t know how much they eat and so they stuff themselves and grow fat. It is also possible that low fat diets does not work very well and that the human body is more metabolically complex than the simple energy calculations used predict.

But if overweight people do really under report more than «normal» weight people, are they then fat because they under report and lie, or are they perhaps under reporting because they are fat and afraid of being stigmatized as gluttonous and desperately trying to keep some of their dignity?

You want cognitive dissonance? I’ll give you cognitive dissonance!

The latest issue of Obesity offers both welcome rationality, important discussions and good chances of some decent hair pulling.

It features an editorial by Jean-Pierre Flatt from the Department of Biochemistry and Molecular Biology, University of Massachusetts.

Flatt gives us an insight into some important misconceptions about obesity. He even made us a list of contents:

1. Problems in applying the energy balance concept  

2. Problems with the metabolic efficiency concept 

3. The misleading emphasis on the importance of low resting metabolic rates 

4. Misleading expectations about the importance of adaptive thermogenesis 

5. Problem in judging the importance of de novo lipogenesis and of its metabolic cost 

6. The irrelevance of the “nutrient partitioning” concept 

7. Failure to recognize the greater impact of energy intake than energy expenditure 

8. Difficulties in understanding food intake regulation 

9. Conditions for body weight stability: settling point vs. set point 

10. Problems with the application of the RQ/FQ concept 

11. The “defense of body weight” concept 

12. The different roles played by CHO and fat in energy metabolism 

13. Food intake regulation and carbohydrate balance 

14. The difficulty in obtaining experimental evidence about the role of carbohydrate balance in food intake regulation 

15. The need to distinguish between the role of carbohydrate balance in food intake regulation and the role of habitual glycogen levels in body weight regulation 

16. Understanding the recent increases in the preponderance of obesity 

17. Why don’t people eat even more? 

18. Confusion about the leverage of exercise on body weight 

19. Is dietary fat or is dietary CHO the major culprit in causing weight gain? 

20. How can inherited traits influence body weight regulation? 

21. The leverage of inherited vs. noninherited factors 

22. BMI vs. % ideal body weight 

Lots of interesting stuff right? Right. There is lots of interesting food for thought in the editorial and much is welcome food. For instance the problems with the energy balance concept, and:

The use of settling point rather than set point:

This corresponds to a “settling point” (20). Such a view accommodates the fact that circumstances cause weight stability to occur for various degrees of adiposity. Thus it seems to fit reality much better than the concept of a «set point» or «ponderostat». 

It has sometimes been considered that “set-points” are reset for different conditions, but in effect this argument reduces the set-point phenomenon to a settling point. 

I agree with him that saying the body is «defending» itself against body weight change is not a very helpful thing to say:

The common tendency of individual body weights to return to their original value after a weight-changing intervention is often explained as the manifestation of a mechanism tending to “defend” a particular body composition. The problem with this concept is that it appears to imply that mechanisms exist to actively drive the fat mass to a particular level, much as one would expect if a set-point mechanism existed (21). It fails to take into consideration that before the intervention, body composition for a given individual had already evolved until a steady state of weight maintenance had become established. 

He even mentions Mark Friedmans work on how liver substrate oxidation rates affect hunger, work I have previously written about on this blog. 

And he even acknowledges that exercise reduces weight by glycogen depletion and increased fat oxidation rather than by acutely increased energy expenditure.

But most of all, he talks about the importance of glycogen storage in obesity.

Thus, the role which increased habitual glycogen levels will play in promoting obesity in humans needs to be recognized! 

And the dissonance?

After elaborating thoroughly on the importance of glycogen stores:

“In view of the considerations made above, it is not surprising that a high incidence of obesity is typically encountered in sedentary populations consuming diets providing substantial amounts of fat.” (my bold) 

You can pull your hair now. It never seizes to surprise me how so much smart and something so incredibly stupid can be crammed into the same text.

Heres another brainmusher for you:

Thus the answer to the question asked above is that the major culprit is the unrestricted and ubiquitous availability of a mixed diet, offering numerous appetizing foods, often in large portions, in which sugar, and to an even greater extent fat, contribute to raise the energy density.

Leptin and local cellular hunger – uniting the theories

Leptin

About 15 years ago the 167 amino acid peptide hormone leptin was discovered by Jeffrey M. Friedman and colleagues through work with genetic mouse models. It is primarily expressed in adipose tissue and there is thus a close correlation between the blood level of leptin and the size of the fat tissue. A small fat tissue size, as in anorexia nervosa, correlates with low leptin levels. Since its discovery leptin has commonly been known as an appetite hormone. Because of its correlation with fat tissue size it was considered an important step in obesity research from the very beginning.

The ob/ob mice strain (the very strain that helped us isolate leptin) produce no leptin. They are extremely fat and have a voracious appetite. If injected with leptin, they eat less and loose weight. The initial results from mouse trials created an air of optimism in the obesity research area. Leptin was thought to stimulate satiety. Imagine a substance that when injected would simply turn you off food. But, as always, the human body proved more complex than first assumed. It turned out that unlike the ob/ob mouse, overweight humans often had high leptin levels. Consequently leptin injections in overweight humans, not surprisingly proved a poor treatment.

4deaf-leanobese_mice400
Leptin deficient mouse to the right with normal mouse to the left. From: www.ohsu.edu/Bouret/ images/leanobese_mice400.jpg

Leptin circulates in a free form and binds to leptin-binding proteins. It’s secreted in a pulsatile fashion and secretion varies with night and day. The main regulating factors for serum leptin concentration seem to be short-term food intake and the amount of energy stored in adipocytes. Although leptin correlates positively with body fat size and supposedly down regulates hunger, the overweight and obese humans still experience strong hunger. This apparent paradox sparked the term “leptin resistance”.

Leptin resistance was thought to be much like insulin resistance and thus caused by long term high levels of serum leptin. Despite high serum leptin levels, the cerebrospinal fluid/serum leptin ratio is lower in obese compared to lean individuals, suggesting that a lower central nervous system leptin transport may explain part of the supposed leptin resistance in obesity (Eckert 1998).

Local cellular hunger

Before I delve deeper into the world of leptin I need to do a quick recap. I’ve written more substantially about this before here and here, but will try to summarize the most important points (Alternatively read thisthis and this).

Our sense of hunger is strongly dependant upon the state of our metabolism. For example, if we manipulate the fat tissue (by drugs or low carbohydrate diets or even exercise) into releasing larger amounts of fatty acids (energy), we don’t feel very hungry. Even more so if in addition glucose production is up regulated and glycogen breakdown is on. We also know that in most animal models, an increase in fat storage occurs prior to increases in food intake. It is thus more likely that we feel hungry and eat because we are storing fat, than it is that we are storing fat because we feel hungry and subsequently eat more.

Of course we don’t feel very hungry when we have a high fat oxidation. As humans we get the energy we need to sustain life and locomotion from two sources; food or stores in our body. When the stores provide a larger part of the energy needed the need for acquiring it from food declines. Hunger declines, metabolism is turned up and energy stores in our body shrink.

If, we on the other hand manipulate the fat tissue in the direction of storage, for example through increasing insulin levels we shut down fat release from adipose tissue. This effect takes place whether the insulin comes from injections or your own pancreas. The energy provided by the body stores is no longer enough to sustain high metabolism. The result is increased hunger, lower body temperature and no drive to exercise (fatigue). Many overweight people recognize these symptoms and meet them at a daily basis. These are the symptoms of a hungry body in a storage mode. It is hungry because much of the energy it needs is stored away. In this mode, if we don’t eat and don’t fill the energy gap with energy from food, the body will starve. It will starve no matter how much energy we’ve got stored as fat. What matters is if or how much of the energy stores are available for use.

Starving the body (even if you are overweight) will cause a great deal of things. In females, amenorrhea or loss of menses, the shutting down fertility is common. Fertility (and sex drive) is one of the first things to go when the body feel its starving. The simple explanation for why an energy deficit causes disruption of the reproductive function is that reproductive function has a low priority in the survival of mammals. Functions essential for survival are those of basic cellular maintenance, keeping correct body temperature and locomotion to obtain food. These functions are maintained at the expense of other functions (e.g. reproduction).

In the words of George Wade et al (1996):

” …it is worth noting that the low priorities of both reproduction and fat storage vis-a-vis processes necessary for survival could account for their habitual association. Exercise, exposure to low temperatures, excessive fat storage, or poorly controlled diabetes mellitus illustrate this second point.”

Take a strong note of the “excessive fat storage” part. Fat storing is from the body’s view not necessarily considered a state of energy surplus, but often that of energy deprivation. What is deprived, are all the tissues of the body, and even fat tissue itself. For as long as energy is being locked into the form of triacylglycerols and the hormonal environment hinder its release, no tissues can use it.

In animal studies, feeding a high-fat diet (which increases the energy flow from fat tissue to other tissues) may ameliorate reproductive deficits. Energy deficits resulting from inadequate energy intake are also more extreme when consuming a high carbohydrate diet.

Decreased reproductive function is but one symptom of starvation. When deprived of energy, even muscles may brake down to a larger extent to supply glucose for fuel. Supporting this theory are observations of sudden increases in muscle mass in ketogenic diet studies, and findings that the muscles in obese woman act very much like muscles in a starving person (Hittel 2009).

The major point here is that energy availability of the whole body does not reflect the energy availability of specific tissue cells. And hunger is largely the result of our metabolism, the regulatory point seem to be the production of ATP in liver cells (Friedman 1999).

Uniting the theories

Now for how leptin relates to hunger and our metabolism.

Leptin as an energy flux indicator

Leptin was thought to be a satiety signal. But, according to resent research, leptin’s main function is not simply to directly regulate hunger and satiety, but to inform the organism that there is enough energy to sustain life. The major physiologic role of leptin seems to be to signal available energy to the hypothalamus.

Increasing leptin increases fat oxidation. The finding is of great importance because increasing fat oxidation by any means, reduce hunger. Arch et al probably hit the nail on its head when they proposed that leptin is not raised in obese individuals because of leptin resistance, but because leptin is opposing other forces that promote obesity. Because of the opposing forces that drive fat storage, leptin is desperately trying to get the energy stored as fat transported to other tissues.

In anorexia nervosa leptin levels are low, very low (Eckert 1998). The oxidation of stored fuels is kept at a minimum and consequently the body is no longer signaling that it has energy surplus, which it hasn’t. It needs energy from food.

When fasting, leptin levels decrease rapidly before and out of proportion to any changes in fat mass, thus likely signaling an energy gap. A gap existing because the oxidation of stored fuels is not in itself enough to keep metabolism high. Consequently the body need energy from food and lack of leptin is signaling just that.

Expression of leptin from adipocytes is directly related to the glucose uptake by adipocytes. Glucose uptake is directly related to insulin level, and glucose level is directly related to fat oxidation. When fat oxidation is low, as with a high carbohydrate diet, the body relies heavily on glucose for fuel. The strong reliance on glucose increase the probability of low glucose levels with consequent decreased leptin secretion and increased hunger.

Ketones are produced to spare glucose. Most of the cells that can metabolize glucose can also metabolize ketone bodies. When people are fasting they commonly experience a great hunger the first days, but as glucose level drops, fat metabolism is turned up and keton production is increased. When ketone body production is increased, hunger declines, even though a person is still fasting. Thus hunger is controlled by the total rate of oxidation of fuels and not by the amount of energy ingested.

The same mechanism comes into play on a low carbohydrate diet when insulin is decreased and ketone body production is increased (Johnstone 2008Boden 2005).

When fat oxidation increases, whether it is by eating less (calorie restriction) or specifically reducing glucose and insulin load (low carbohydrate diet), leptin decreases. But this may not mean increased hunger. There may no longer be a need to overpower other fat storing effects. A decreased sensation of hunger may actually appear simultaneously with decreased leptin levels, further supporting the notion that leptin is not simply a hunger signal.

Leptin is decreased with dieting also because total fat mass is decreased. But, leptin concentration decrease after weight loss has been found to be disproportionate to changes in adiposity. These observations suggest that other factors in addition to adipose mass modulate leptin secretion. On low calorie diets, the individuals who experience the greatest increase in hunger, and therefore those who probably have the lowest fat oxidation rates, are also those who have the larges decrease in leptin (Keim 1998).

When the overweight person is hungry, this seems a paradox to those only preoccupied with total body energy expenditure and intake. It is not a paradox. It is a completely natural response to specific tissues starving because too much of the energy ingested is stored in the adipose tissue. The overweight person may also have a high level of leptin in combination with high level of hunger, because some tissues are in fact starving. Leptin is perhaps increased in this condition to increase energy availability, but does not in itself down regulate hunger. Hunger is reduced only if fat oxidation is properly increased.

In one study (Cooling 1998) the researchers found that subjects habitually consuming a high-fat diet had raised leptin concentrations and a higher basal metabolic rate (BMR) than subjects with the same BMI and adiposity habitually consuming a low-fat diet. In this case leptin seem to be high in the individuals on the high fat diet because it signals an energy surplus. A high fat intake leads to less fat storage than do high carbohydrate intake. The finding also shows how diet and thus metabolism influences leptin secretion independent of fat tissue size.

Leptin resistance

Evidence for leptin resistance was first based solely on the finding that obese humans generally have elevated serum or plasma leptin concentrations compared to lean subjects (arch 1998). Because the theory was not supported by experimental data, Arch et al (1998) proposed that that leptin concentrations are not raised in obese individuals because of leptin resistance, but because leptin is opposing other forces that promote obesity.

But does leptin resistance really exist? Or can the findings which lead to the theory perhaps be explained through the local cellular hunger – energy oxidation hypothesis? The question proves difficult to answer.  In 1998, roughly two years after the discovery that overweight individuals had high levels of leptin, some researchers already considered this hypothetical resistance to be nonexistent.

There still are several indications that a form of leptin resistance might exist. For one there is the fact that cerebrospinal fluid/serum leptin ratio is lower in obese compared to lean individuals. Although, this may just be a transport problem not related to an actual resistance. Several rat studies have shown increased fat oxidation rates by skeletal muscles when exposed to leptin. In humans however it is not quite that easy. One study (Steinberg 2002) showed a greatly increased fatty acid oxidation in muscles from lean individuals in vitro. Muscles tissue from overweight individuals however, did not show an increase when exposed to leptin. The finding is of course considered to be an indication of leptin resistance in the overweight, but remember these cautioning word from the authors;  “it should also be noted that the non physiological conditions imposed in such a preparation (i.e., high leptin, absence of insulin and other hormonal factors) make it difficult to extrapolate our findings to the in vivo condition.”

Also, animal studies have demonstrated that 4 weeks of high fat feeding can induce leptin resistance in skeletal muscle, as demonstrated by the elimination of leptin’s stimulatory effect on fat metabolism. If the stimulatory effect is gone we do indeed need to call it a resistance.

Leptin may be increased in obese individuals and so representing an attempt to overpower fat storing processes as well as possibly representing a leptin resistance. When weight is lost there seem to be a decrease in leptin either because of a reduced need for its effect on fat metabolism or because of an increase in leptin sensitivity. In any case, a high level of leptin in overweight do not likely cause overweight. It is there to reduce fat storage rather than to drive it.

Blüher et al (2009) argues that leptin resistance or hyperleptinemia causes not only an increasing degree of obesity, but is also associated with increased lipid storage in muscle, liver, and other tissues, dysfunction of several neuroendocrine axes, including the reproductive, thyroid, and adrenal axes, as well as abnormal function of the immune and autonomic system i.e. thermoregulation, energy expenditure, and others. Looking at this cluster of symptoms, we are looking at any metabolic resistant overweight person. All symptoms can be easily explained without leptin and it is thus unlikely that leptin play the causal role.

Uniting

Leptin was originally believed to control hunger, although it was never actually clear if it “controlled” it, or was simply a part of the intricate physiological interaction that is hunger. Leptin was later discovered to also be a part of the regulation of reproduction and the hypothalamic-pituitary-gonadal (HPG) axis. Animals that lack leptin (ob/ob mice) or have obvious leptin resistance (db/db mice and fa/fa rats) fail to achieve puberty and are infertile.

This is where we most easily see the theories unite. Reproduction is, as Wade shows us, highly sensitive to fluctuations in energy as is leptin. Leptin acts as a signal informing the different tissues of the energy state of the body, rather than itself controlling the energy metabolism.

The features of hypothalamic hypogonadism in women (low levels of sex hormones) and it’s associated disturbances can be restored by leptin administration. The question is, do we simply trick the body into believing there is more energy than there actually is, or do we actually increase energy availability?

Amenorrhea, the lack of menses, may also be induced by exercise. Endurance trained athletes have a higher prevalence of amenorrhea or dysmenorrhea than non exercising controls. It is normalized with leptin injections. Administering leptin may increase fat oxidation and thus, as Friedman et al has reported, also increase hepatic ATP levels and by doing so may restore fertility function.

Both increased levels of leptin, as in obesity, but also low levels act inhibitory in the HPG axis. Blüher el al claims that: “These results underline a pivotal role of leptin in regulating reproductive function and strengthen the hypothesis that leptin is one of the factors mediating reproductive abnormalities in several disease states.” But it may not be this way. Leptin is not necessarily “controlling” fertility. It may simply be the messenger informing the body of its energy status. Reproduction is regulated in accordance with energy status.

Blüher et al continues: “We have shown that leptin may serve as a signal to convey information to the reproductive system that the amount of energy stored in the body as fat is adequate not only for the survival of the person but also for carrying a pregnancy to term.”

This claim however, rests on the assumption that the energy stored as fat is available for use. This is not always the case.

When leptin resistance seem to be causing obesity in rodent models and the rare cases in humans, it is likely because the different body tissues and the hypothalamus constantly experience an energy shortage. Metabolism with all its manifestations, fertility included, is adapted. The body does what it can when it senses energy to be in short supply. It increases hunger, decreases the metabolic rate and effectively shuts down unnecessary processes.

 

32729-leptintreatment

Effects of recombinant human leptin treatment in a patient with congenital leptin deficiency. (A) Before treatment. (B) After treatment. From: Leptin: a pivotal regulator of human energy homeostasis, Farooqi 2009.

States of congenital leptin deficiency because of mutations of the leptin gene have been associated with severe obesity, glucose intolerance, and insulin resistance in humans. All expected symptoms if fat oxidation is low.

Despite the initial hopes, placebo-controlled trials in obese persons over periods of several weeks with leptin-treated subjects have not shown impressive results on weight loss. This is not surprising, considering that many obese persons have high leptin levels, high glucose level and high insulin resistance, and thus a fat tissue which reluctantly gives away energy. A slight increase in fat oxidation with leptin replacement therapy is expected to reveal nothing but small decreases in fat tissue, as long as nothing else is done with the fact that the tissue is in a storage mode.

Even in patients with severe lipodystrophy (inability to store fat/loss of fat tissue) leptin replacement decreases fat mass. The decrease in fat mass is an indicator that fat oxidation is increased and in accordance symptoms of starvation are improved (Oral 2002). At least in the short run. Women with anorexia nervosa and with cachexia resulting from cancer or severe chronic infections also show many of the symptoms of a starving body, including low leptin levels. Despite the fact that leptin would have the highly undesirable effect of inducing weight loss in these patients leptin treatment is still recommended (Friedman 2009). It is another example of a treatment aimed at ameliorating symptoms, without positively (probably negatively) effecting the underlying cause.

Control by food intake

Seen together the current data point to leptin as a signal informing the hypothalamus of the availability of oxidizable fuels.

If leptin is secreted in response to the energy metabolism, we would expect macronutrient intake to influence leptin level. Several studies have found such an effect, while others have not.

An increase in dietary protein from 15% to 30% of energy at a constant carbohydrate intake has produced sustained decreases in caloric intake, hunger and leptin levels (Weigle2005).

60315-leptin
Concentrations of circulating leptin (adjusted for adiposity) in 12 women during a prolonged energy deficit. Means with different superscript letters are significantly different, P < 0.05. From Relation between circulating leptin concentrations and appetite during a prolonged, moderate energy deficit in women, Keim et al 1998.

Havel et al (1999) reported acutely decreased leptin concentration after ingestion of a high fat, low-carbohydrate diet. Jensen et al (2006) found that persons in the highest quintile for whole-grain intake in a prospective study had 11% lower circulating leptin compared to those in the lowest quintile. It is intriguing to think that lower in this case could mean increased hunger response due to lower fat oxidation, but we must consider the possibility that it simply reflects and reduced leptin resistance. Volek et al reported a 42% decrease in leptin with a low carbohydrate diet (12%CHO) and 18% decrease in leptin with low-fat diet (24% fat) for 12 weeks in overweight subjects. Once again, the results could indicate a lack of energy availability or improvement in leptin resistance.

But, because we know that carbohydrate restriction greatly increases fat oxidation, reduces hunger and may even increase heat production and locomotion, it seem most likely that the larger decrease in leptin on a low carbohydrate compared to a high carbohydrate diet represents a decreased need to overpower fat storing mechanisms. The significant decrease in leptin found by Volek et al persisted after normalization of body and fat mass.

Expression of leptin from adipocytes is directly related to the glucose uptake by adipocytes. This could in itself explain why leptin is reduced more with carbohydrate restriction. Leptin also decreases with decreasing weight, because fat tissue is the main secreting organ. This means that in an overweight person with hyperleptinemia a reduction in leptin level is expected with weight loss and is not negative just because high leptin may reduce hunger.

It seems that increases in leptin usually signal a surplus of energy, but not in the obese. In the obese the high levels seem to be caused by the body’s desperate attempt to increase fat oxidation.

In support of this are the findings that injections of leptin increase fat oxidation in combination with reduced food intake. That dieting which increase fat oxidation cause reduced levels of leptin in the overweight.

Summing it up

Believing that leptin may prove to be an important treatment for obesity, trough down regulating hunger, is nothing short of crazy. There is little doubt left in the literature that the hunger experienced by an overweight person, stems from the unavailability of oxidizable fuels. Hunger is not what must be improved, rather we must increase the release and oxidation of the fat situated in adipose tissue stores, and hunger will decrease.

Although leptin is expressed in relation to adipose tissue mass, its main function is not so signal adipose tissue size, but fluctuations in available oxidizable fuels. When leptin treatment ameliorates adverse symptoms related to conditions of low fat mass, i.e. anorexia nervosa or lipodystrophies, the mechanism is likely an increase in fat oxidation and thus a small increase in oxidizable fuels. Treating these conditions with leptin is counterintuitive and may even cause adverse effects over time. Blaming leptin is equivalent to killing the messenger.

Local cellular hunger

I once wrote a short paper about menstrual disturbances in female athletes. Menstrual disorders seem to be more prevalent in athletes than sedentary controls and more prevalent in sports emphasizing leanness. Elite athletes also have higher menarche age compared to non elite athlete controls. Menstrual disorders increase the risk of low bone mineral density, stress fractures and infertility. One hypothesis put forth to explain the apparent increased risk of menstrual disturbances was “the body fat hypothesis.”

The body fat hypothesis originates from observations showing that females with extremely low body fat where amenorrheic (absence of menstrual cycles for more than 90 d) and that amenorrheic athletes had lower body fat percentages than eumenorrheic (normal menstrual cycles) athletes. But, when simply matching eumenorrheic and amenorrheic athletes for body fat, it was found that the body fat hypothesis could not explain the prevalence of menstrual dysfunction in athletes. Amenorrhea often occurs in the general adolescent female population, even in the absence of substantial undernutrition or underweight, and there are many underweight and lean athletes who still maintain their menstrual function.

Sudden strenuous exercise induces amenorrhea in humans and more so if the exercise is compounded by weight loss. This caused scientists to speculate if a negative energy balance is a causal factor in menstrual disturbances. It was in researching this I stumbled over the work of George Wade, and he really opened my eyes. Starving an animal will cause it to lose its reproductive function. The simple explanation of why an energy deficit causes disruption of the reproductive function is that reproductive function has a low priority in the survival of mammals. Functions essential for survival are those of basic cellular maintenance, keeping correct body temperature and locomotion to obtain food. These functions are maintained at the expense of other functions (e.g. reproduction, storage of energy as fat and growth).


Wade et al. points out that;” …it is worth noting that the low priorities of both reproduction and fat storage vis-a-vis processes necessary for survival could account for their habitual association. Exercise, exposure to low temperatures, excessive fat storage, or poorly controlled diabetes mellitus illustrate this second point.

When energy balance is discussed, it is implicit that we are discussing the whole body. But the theory of energy balance is inaccurate when simply defined as “energy intake minus energy expenditure.” It is inaccurate simply because the energy availability of the whole body does not necessarily reflect the energy availability of specific cells (e.g. the ovarian cells). So the important question is not necessarily if the body is in a negative energy balance, but rather what factors may cause a local energy deficit independent of total energy balance?

In a study by Tomten and Høstmark, 20 long distance runners were compared. 10 of the athletes had regular menses (control) and the other 10 athletes reported irregular menses. In the latter group a statistically significant negative energy balance was found. But the energy deficit was primarily because of a lower intake of dietary fat. Tomten and Høstmark conclude; “Present results might indicate that a high CHO/low fat diet could promote an inadequate EI (Energy Intake; my explanation) in recreational or sub-elite athletes and could cause energy deficit and endocrine disturbances.

Although a restriction in dietary fat intake is often found in athletes, it is not often referred to as an independent hypothesis. This might seem odd, given that there do exist a perfectly reasonable physiologic explanation for the link between dietary fat and menstrual disorders.

A diet comprising of mostly carbohydrates is more likely to give higher insulin load than diets with more fat and protein.

Injected insulin disrupts reproductive function in animals. In the words of Wade et al. “When food intake is limited or when an inordinate fraction of the available energy is diverted to other uses such as exercise or fattening [my bold], reproductive attempts are suspended in favor of processes necessary for individual survival”. In animal studies, feeding a high-fat diet may ameliorate reproductive deficits. Energy deficits resulting from inadequate energy intake are also more extreme when consuming a high carbohydrate diet.

Obese women also seem predisposed of menstrual disturbances. Many women get pregnant only after loosing weight. This may seem counterintuitive. Wouldn’t nature prefer a mother with large energy stores and thus a grater chance of caring for her young through hard times? Well, as it seems, nature would prefer a certain amount of extra available energy, as illustrated by the loss of menses with extreme leanness. But, in the case of overweight and obesity we are fooled by an apparent surplus of energy. To be more precise, the fat cells have a surplus of energy, but that tells us nothing of the energy available for other tissues. The menstrual disturbances in athletes are in part likely caused by low energy availability for the ovarian cells, and when we are talking reproduction, these are the cells that count.

Yet another indication that a local starvation may exist is a finding that myostatin secretion is may be close to 3 times higher in insulin resistant obese subjects than in lean controls. Myostatin is a natural regulator of muscle tissue growth. Removing myostatin will make you look like a human version of the Belgian blue (just type myostatin in Google). Increased myostatin secretion is seen with fasting, hunger and very low energy intakes. This might be an important evolutionary adaptation by which our body breaks down superfluous muscle protein for glucose production.

When muscles are insulin resistant, they cannot take up sufficient glucose. In addition a high insulin level may make stored fat unavailable. So from the muscles point of view the body is starving independent of the amount of stored energy in the body. For an overweight insulin resistant person this may become a downward spiral with a gradual decreased ratio of muscle mass to fat mass.

Insulin resistance and polycystic ovarian syndrome are commonly associated. PCOS is a condition characterized by excessive cyst growth on the ovaries and will often cause infertility. Funny thing is that this condition is best improved by carbohydrate restriction. One explanation is an improved energy flow to the ovaries.

As a final closing argument several studies of carbohydrate restriction have reported muscle growth without increases in exercise level. It is as if the muscles are finally given the energy they need to respond and grow to mechanic stimuli.

A scale model of obesity


Whatever the individual cause of obesity is, in the absolute majority of cases, carbohydrate restriction works effectively at reducing adipose tissue weight. This is a common observation in most human and animal studies. Carbohydrate restriction for the most part works because it influences insulin and glucose. In addition it affects our sensations of hunger and satiety and affects the energy flow to the individual tissues. This might be a simplification, but it’s a fair simplification. The increased fat storage and insufficient fat release apparent in overweight must in most cases be explained by the specific disease or condition’s influence on insulin and glucose metabolism, simply because insulin and glucose are the main regulators of fat metabolism.


I’ve often pictured the adipose tissue as a scale. All the factors that influence energy release from this tissue rest in one cup and all the factors influencing storage of energy rest in the other. Tipping the scale to one side symbolizes fat storage, tipping to the other symbolizes fat release. If the scale is in perfect equilibrium, the storage of energy matches the release of energy and the fat tissue remains roughly the same size.



Most people are more or less weight stable most of the time. The behavior of our fat tissue is, like most other physiological processes, a process seeking equilibrium (although not likely due to a set-point). Imagine any factor that is known to influence fat metabolism. Take dietary carbohydrates. Let us ad an increased intake of dietary carbohydrates as a factor on one side.


The factors contributing to the storage of energy now overpower the factors contributing the release of energy. Increasing carbohydrate intake will cause a decrease in lipolysis (fat release), mainly through the increased insulin release and increased glucose levels. Tipping the scale in this way (provided all other factors remain constant) will cause a net storage and we will gain weight in the form of fat. A larger fat storage in relation to the fat release will cause a more rapid weight gain. Of course, the scale that is our fat tissue goes up and down during the day and night. It does not remain in a fixed position for any amount of time, but the more time spent below horizontal position on one side in relation to the other, the larger the effect.

Adding an increase in exercise level to the scale will once again tip it towards equilibrium. 

Exercise improves the glucose tolerance of our skeletal muscles. Exercise might increase the level of LPL (lipoprotein lipase) in muscles and reduce the level in fat tissue. It might increase glucose uptake in muscles both by reducing glycogen stores, increasing glucose transporters or simply increasing muscle size. The net effect of exercise is that blood glucose and insulin levels are kept at a lower level and the scale is tipped in favor of fat release. Although exercise very often does not make us leaner, it may also do so and the above-mentioned mechanisms are likely explanations.


Exercise and diet are two lifestyle factors with large impact on our imaginary scale. Lifestyle factors do however affect us differently because of our different genetic heritage. Genetic factors may also more easily be understood using a scale model. Looking at fat storage this way, might give us a simple way of explaining many of the often-cited paradoxes of overweight.

Imagine for example that you are overweight while your brother is not, despite having an apparently similar lifestyle. It seems that your scale is tipping in the opposite direction of that of your brother (or sister, friend or whoever). As fat storage most often must be explained through insulin and /or glucose metabolism and not through energy intake or energy expenditure, we can imagine several scenarios that could explain the brotherly differences. Perhaps your brother has been genetically equipped with a more effective glucose uptake in skeletal muscles or that he needs a smaller stimulus (physical activity) in order to improve glucose uptake. A better glucose uptake would mean smaller increase in blood glucose after ingestion of dietary carbohydrate, a smaller insulin release and thus a smaller fat storage with an ensuing better fat release. This small difference would mean that your brother could consume more dietary carbohydrate without tipping the scale too far in direction of fat storage. It might also make your brother more physically active. It is not fair, but it is how it is. We are not all equipped with the same physiology or the same potential for changing our physiology.

I don’t suspect my scale contributes to the knowledge and understanding of health and nutrition, but it has helped me picture how our body works and it reminds me that overweight is about fat tissue size and not body size or body weight. When faced with a non responder (e.g. a person not losing much weight with carbohydrate restriction) we know the factors working against fat storage overpower the factors working for fat release. Knowing the effect of different factors on our physiology we can easily investigate the less common factors like cortisol, thyroid hormones or perhaps myostatin for that matter. The scale may help remind us that we are built differently and respond differently to any external factors.

I am still surprised by the way people often talk about overweight as if we were all physiologically identical. Most people will for example have no difficulty admitting that we tan differently and have different skin complexions from birth, but somehow when it comes to weight it is often expected that we are all created equal. Well, we’re not. Although the underlying cause of overweight and obesity are pretty much the same in all of us, we all have different potential to gain weight both locally and systemic. The scale model may illustrate our genetic differences and answer the poor, but often encountered argument «If carbohydrates make us fat, why isn’t everybody consuming carbohydrates fat?» Our scales are loaded differently from birth. Carbohydrates in a certain amount definitely do have the potential to make most of us fatter, but from a physiological point of view, we are not created equal.

The important question

By defining overweight as excess storage of energy in fat tissue (and consequently to little use of energy from the same tissue), we are only one simple question away from understanding what causes overweight and obesity, and ultimately how to treat and prevent it.

What factors control storage and release of energy in fat tissue?

Believe it or not, but this is actually common knowledge in physiology. Any physiology textbook will give you the answer, and the answer is even right. There are two main factors responsible for the storage of and consequently the use of energy in fat tissue. These factors are glucose and insulin, or more accurately the amount of glucose being metabolized and the level of glucose and insulin in your blood. Glucose is what most dietary carbohydrates are broken down to in your body and is what is known as blood sugar. Insulin is a very potent steroid hormone largely responsible for controlling blood sugar levels.

In order to understand how glucose controls storage and release of fat we need to understand how fat is stored. Fat is used as energy in the form of free fatty acids. These are long hydrocarbons that are broken down to create energy. When animals (humans are also animals) store energy for later use, it is mostly in the form of triacylglycerols in fat cells. Triacylglycerol is made up of three fatty acids bound to a glycerol molecule. So when the body has excess fatty acids that can be stored for later use, they are transported into the fat cell where they are bound to glycerol to form triacylglycerol (a.k.a. triglycerides). So far, so good. This all makes sense in that our fat tissue is supposed to work as an energy storage for when less food is available. Fat tissue is thus a very important evolutionary mechanism that ensures survival when food availability is not constant.

The thing is that for the body to make triacylglycerol, a molecule known as alfa-glycerolphosphate (glycerol-3-phosphate) is needed to provide the glycerol backbone of triacylglycerol. Alfa-glycerolphosphate is made in the body when carbohydrates are broken down. To put it simply, if little alfa-glycerolphosphate is made, fat tissue will lack glycerol molecules to make triacylglycerol and the fat cells cannot store energy. When the fat cells aren’t storing energy, they are more likely to release energy that can be used instead of dietary energy.

But the fat tissue is not only an important energy storage, it also functions as an important regulator of blood glucose levels. Glucose is not only providing the glycerol backbone for triacylglycerols, but is also made into fatty acids. This way, the fat tissue will absorb blood sugar when or if it gets high. This function is especially important when skeletal muscles are insulin resistant and absorb little glucose. If blood sugar is dropping the fat tissue releases fatty acids for use as fuel by the cells that can metabolize fat, thus making glucose available for the cells that need this particular fuel. There are some cells in the body that depend on glucose for fuel, but the total amount needed is so small our body can make it from scratch even without getting any dietary carbohydrate.

I am talking a lot about glucose and insulin, but what about how much we eat? Doesn’t that also control how much is stored? No, it doesn’t, it’s actually the other way around. How much you consume depends on how much is stored. It’s a complicated topic, but there are two important things I’ll say now and I’ll elaborate later. Firstly, energy expenditure and energy intake are highly dependent factors. This means that messing around with one factor will cause a compensatory change in the other (more elaborate in Norwegian here:http://www.forskning.no/artikler/2009/januar/207538 and in English here: http://nymag.com/news/sports/38001/). It’s the same in all animals. Secondly, our sensation of hunger is largely regulated by the energy available for (or rather the energy metabolized by) the liver cells at any moment. The amount of energy available for these cells does not necessarily reflect the amount of energy consumed. Worst case scenario, parts of your body might be starving despite large energy stores in fat tissue. Even though we might have a lot of energy stored, it doesn’t mean this energy is available for use.

Let us sum this up. Overweight is a condition characterized by excess storage of energy in fat tissue. The main regulators of storage in and release of energy from fat tissue are glucose and insulin. Ah, we are closing in. Now we are only one question away from understanding overweight and obesity and what we can do about it. And this time it will work.