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.

About hunger

Much has been said about hunger. The sensation is often considered largely under cognitive control. An overweight person seeking counselling is asked to eat less, despite claiming to already be hungry most of the time. Hunger is in this case simply considered by the treating authority to be suppressed by a strong will of mind. Sadly, it doesn’t work that way.


Many theories have however been presented in an attempt to explain hunger through physiological processes. Amongst these are hunger and satiety centres, the glucostat and lipostat theory and body weight set point. Unfortunately most of these fail to explain the observations in a satisfactory way. There is however a less known hypothesis which manages to explain most observations quite well. The consequence of this hypothesis however, is that macronutrient intake may play a very important role. Not because they contain different amounts of energy, but because they influence our metabolism in different ways.


Hunger might seem easily understood, as we get hungry when we don’t eat and feel sated when we do. But this is a gross oversimplification. If we fast, we may feel extreme hunger during the first day or two, but then as ketone body production sets in and fat metabolism is up regulated, hunger is diminished despite the complete lack of food. In some cases people feel hungry most of the time and satisfying the constant hunger may cause obesity and even death. This makes no evolutionary sense. Why is a body creating hunger signals when it obviously has more than enough energy in its stores and is obviously consuming more than enough energy to maintain it’s weight? The simple answer is that stored energy is not necessarily available for use, and the amount of energy ingested also does not necessarily reflect the amount of energy available for use.

    
In the 1950s, Jean Meyer presented the glcostatic theory. This hypothesis was used (and unfortunately still is) to explain how our blood glucose level controls our sensation of hunger and satiety. It states that a low blood glucose level stimulates an increased hunger and food intake, while high glucose levels will stimulate satiety. The theory is not easily rejected and may indeed seem plausible. In early studies, scientists succeeded in inducing increased food intake in rats and increased hunger in humans, by using insulin to reduce glucose levels. In addition, hypoglycaemia (low blood sugar) in diabetes was known to be associated with increased food intake. Also, the knowledge that our brain is strongly dependant on glucose for fuel further increased the plausibility of the theory. But, although glucose level does influence our feeling of hunger it is however unlikely that it controls our total food intake and low glucose might just be an effect rather than a cause. One good argument against a glucostatic theory is that affecting fat metabolism, independent of glucose levels, can increase hunger.

As we grow our different body tissues grow in unison, but after we become adults most of the change in body size is due to changes in fat tissue size. The lipostatic hypothesis claims that any change in body fat is followed by a signal to either increase or decrease food intake.  I’ll admit that from an evolutionary point of view this seems plausible, but the number of observations that fails to be explained by this hypothesis are many. Unfortunately, many consider this hypothesis close to a fact even today, but now it goes under the name of the body weight set-point hypothesis.

One of the strongest arguments in support of the lipostatic hypothesis has been based on the hyperphagia (fancy word for great hunger or eating a lot) and obesity that result following ventromedial hypothalamic (VMH) lesions. During the 40’s and 50’s it was found that damage to specific hypothalamic areas (VMH lesions) provoked dramatic alterations in food intake and body weight. These lesions caused an increased food intake in most animals studied. As it was assumed that the hypothalamus was the control centre of hunger and satiety, the increased food intake in these studies was thus assumed to be a result of increased hunger. Also, people with the genetic condition known as Prader-Willi, are known to have a voracious appetite. This genetic condition affects the hypothalamus as well and it was once again assumed that this genetic error affected the hunger/satiety centre of the brain thus causing increased food intake.

Although VMH lesions were originally used in support of a lipostatic hypothesis, the very same studies provide evidence for the improbability of the same hypothesis. The fact that hunger occurs in rats with VMH lesions despite the presence of an internal excess of metabolic fuels suggests that the size of the fat depots becomes important to feeding only if the animal has access to them. Access is a key point here. 

It was later found that although VMH lesions did indeed cause increased food intake, the very same lesions also disrupted fat metabolism in favour of increased fat storage (partly due to increased insulin secretion) thus making fat depots unavailable. Hyperphagia has been associated with obesity and large energy storage in fat tissue, but it has also been shown that in most animal models, the increase in fat storage occurs prior to increases in food intake. In other words, increase in fat storage (the unavailability of fat for fuel) increases hunger and thus food intake. This is an extremely important point. Increased hunger may very likely be caused by increased fat storage and not the other way around, as is the general interpretation. In support of the above-mentioned, scientists has successfully increased both the power and the duration of satiety, simply by inhibiting fat storage.

Even in the Prader-Willy syndrome, the hyperphagia observed might very well be secondary to fat storage. They might be eating because they are getting fat, and not the other way around. They might be eating because most energy is locked away in fat depots, and the rest of the body is starving. Our body gets its energy either from its stores or from food. If the stored energy is unavailable the body is left with no other choice than to increase hunger. I have unfortunately only seen one study described where a low carbohydrate diet was administered to people with Prader-Willi, but it does provide some interesting clues. Remember that reducing dietary carbohydrates most often will cause a decrease in fat storage. If hunger is caused by large fat storage, reducing the storage would presumably decrease hunger, as has been done with medications in other studies. In the study described in ”The Prader-Willi syndrome”, by Holm et al it seems that carbohydrate restriction does indeed reduce hunger effectively, even in people with Prader-Willi. The mechanism behind the reduction in hunger is presumably the decrease in fat storage and thus an increased release of stored energy from fat tissue.

In the genetic rat models of obesity fa/fa rats and ob/ob rats, their defect genetics makes them overweight even with calorie restriction. The effect of their defects is an increased fat deposition. This increased storage of energy in fat tissue causes a concomitant hyperphagia and decreased energy expenditure.

Low blood sugar may also provide a strong stimulus for hunger, as the glucostatic theory claims. But, the reason for a fall in glucose levels may be caused by a low fat oxidation. If little fat is oxidized and ketone bodies are not being produced our body is more dependant of glucose for fuel, and blood sugar falls quickly. In the studies where insulin was used to stimulate hunger, it also stimulated fat storage. Insulin makes all fuels less available fore use. 

It may not even be the low glucose level in it self that makes us hungry. It may simply be the low total amount of energy available. A combined inhibition of fatty acid and glucose metabolism produces a far greater eating response than would be expected from inhibiting the metabolism of each component separately. A combined inhibition may even produce hunger when the metabolic inhibitors are given in doses that alone do not stimulate eating. This increase in food intake would not be expected if signals from glucose and fat metabolism controlled feeding independently, and indicates that changes in glucose and fat metabolism influence feeding through a common mechanism. The likely place for this regulation would be the liver.

Mark I. Friedman and Edward Stricker elucidated the mechanisms of how macronutrient composition affects hunger as early as 1976. They wrote that the stimulus for hunger and satiety were likely the result of alterations in oxidative metabolism within the liver. Their reasoning makes unnecessary previous hypothesis such as hunger and satiety centres, glucostat, lipostat, and body weight set point.

More recent work by Mark Friedman makes it clear that liver ATP production is an important regulator of hunger. Although intake of the different macronutrients affects hunger it doesn’t seem likely that quantitative changes in the use of these nutrients would provide a stimulus for hunger. Compensatory changes in the use of other fuels would limit the significance of this. It is more likely that hunger occurs whenever the immediate availability of utilizable metabolic fuels is reduced below some critical level.

The consequence of all this is that a diet with little carbohydrates and generous amounts of fat makes us lean much because this diet provides a constant flow of available energy for the liver, both from food intake and from body energy stores, and this makes us less hungry.

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.