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In 1994, a scientific finding shot through the research world and then raced far beyond. It inspired wonder and, particularly among discouraged people struggling with severe weight problems, great hope. The report described how a molecule, leptin (from the Greek leptos, meaning “thin”), which is present in humans and other animals, powerfully influenced eating in laboratory experiments with obese mice.1 With good reason, experts speculated freely about defeating obesity—while giving appropriate cautions about the need for more research—and the discussion filled the airwaves and pages of newspapers and magazines for months. But then, just as quickly, leptin was gone. Further research failed to demonstrate a beneficial effect in people, and the “next big thing” was dethroned. People who had hoped leptin would be their salvation were disappointed and frustrated.
But the breakthrough and subsequent experiments with leptin did not leave scientists disappointed—far from it. They had turned an essential corner on the road to understanding the brain and obesity, and researchers have discovered much more in the 15 years since. In this article, we will explain what we now understand about one of the master controllers of this very intricate brain-body relationship. We also offer a surprise ending—of the good news–bad news sort.
Understanding Energy Balance
When thinking about obesity, it is important to remember that consuming food to store energy is fundamental for survival—and nature has done all it can to thwart interference with this mechanism. Much of evolutionary development has been about preserving and synchronizing opportunities to obtain and consume food to maintain a precise balance between food intake and energy expenditure (energy balance).
In the wild, sources of food were few and dispersed widely; early humans had to travel great distances to find food and safe places to rest. Because agriculture developed later on the evolutionary scale (by most estimates, only 10,000 years ago), this migratory behavior required high levels of daily activity. Additionally, because food was scarce, it was essential for us to develop a biological system to store energy. In humans, the largest depot of stored energy is our fat—specifically, the white adipose tissue. Thus, for most of human history, the struggle for life was about seeking, consuming and storing food, and our brains and bodies adapted to thrive in these environmental conditions.
In contrast, humans in modern societies can obtain food on demand and, in many instances, they have low activity levels (low energy expenditure) resulting in what is called positive energy balance—we consume more calories than we burn. This chronic, positive energy balance leads to obesity (accumulation of fat tissue) and its associated problems, including diabetes, cardiovascular disorders, cancers and neurodegenerative diseases. A striking development is that in the last few decades, adults have not been alone in their struggles with obesity. Children have become fat at an alarming rate, making childhood obesity a major health issue for most societies.2 We are seeing an epidemic of positive energy balance.
The Role of the Brain in Maintaining Energy Balance
Several brain nuclei—identifiable groups of neurons functioning together in specific brain areas—regulate the coordination of food intake and energy expenditure. Some of these nuclei are housed within the hypothalamus, a structure that lies just above the brain stem and helps control essential processes such as metabolism, sleep-wake states, body temperature, blood pressure, hunger and thirst and, through connections to other brain circuits, helps regulate brain activities. The hypothalamus was one of the first brain regions to evolve.
One nucleus that helps regulate energy balance is located in the most basal (lowest) part of the hypothalamus and has the form of an arc, giving it its name, the arcuate nucleus (ARC). Researchers have focused their attention on the ARC in recent decades because it has a singular role in energy balance and because it is located in one of the few areas in the brain that is not protected by the blood-brain barrier, the tightly meshed cell structure of blood vessel walls that keeps most blood-borne molecules from entering nearly all brain areas.
Within the ARC is the heart of what scientists believe is the main system for regulating food intake, the melanocortin hormone system. During a meal, various substances are released in the blood, enter the ARC and signal the melanocortin system to end the meal. To sense these substances, the system uses two side-by-side groups of specialized neurons with opposing actions. One neuronal group produces melanocyte-stimulating hormones (MSH) that suppress appetite, while the other neuronal group produces molecules that inhibit these hormones’ actions and stimulate appetite.
MSH hormones signal the brain that no food is needed via a several-step process. The appetite-suppressing neuronal group produces a molecule called proopiomelanocortin (POMC). This molecule ultimately creates large peptides (the building blocks of proteins) that are then broken down by enzymes into small peptides including the appetite-suppressing MSH hormones. These hormones bind to and activate melanocortin receptors located on brain cell surfaces that will signal the rest of the brain that food is not needed.
Two appetite-stimulating molecules, however, oppose the action of these MSH hormones. These two molecules, neuropeptide Y (NPY) and agouti-related protein (AgRP), are produced by neurons adjacent to the POMC cells. These molecules successfully compete against the MSH hormones to bind to the same melanocortin receptors on brain cells and inhibit their activity, so that the rest of the brain no longer receives the signal that food is unnecessary. The interaction between NPY/AgRP (appetite-stimulating) and POMC (appetite-inhibiting) neurons, therefore, regulates food intake.
Moreover, the brain has a redundant system for promoting the urge to eat. Appetite-stimulating neurons also produce the chemical neurotransmitter gamma-aminobutyric acid (GABA), which inhibits the POMC neurons from producing MSH hormones. During periods of negative energy balance, therefore, appetite-stimulating NPY/AgRP molecules inhibit the message that no more food is needed in two ways: They limit production of MSH and they prevent existing MSH from signaling.
This redundant system, then, promotes eating by (1) directly prompting food intake via the appetite-stimulating molecules NPY and AgRP and (2) sending signals that inhibit POMC neurons from suppressing appetite. Strikingly, even though the predominance of appetite-stimulating activity in this system is driven by negative energy balance— the need for food—its influence over POMC neurons seems to be the brain’s default system. In other words, the human brain has the default wiring: “I am hungry.”
This system had profound evolutionary consequences. The redundant mechanism to promote eating aided in survival when food was scarce, yet today when food is available at our discretion and the energy stores (fat tissue) are sufficient to maintain the energy needed for the body’s metabolism, the brain’s default wiring still signals us to keep eating. This mechanism, therefore, might be a key contributor to the current worldwide epidemic of obesity.
Enter Leptin and Visions of Treatment
More than a century ago, British neurophysiologist Sir Charles S. Sherrington suggested that certain factors arising from the blood regulated food intake.3 Seven decades later, scientists discovered that a naturally obese mouse (named ob/ob because of its mutant genes) became leaner if it received some blood from a naturally lean mouse.4–6 These experiments provided convincing data that something about the blood was driving the physical characteristics of the ob/ob mice. Since then, growing evidence has shown that the tissues in the brain and the rest of the body communicate, almost certainly by the way of the bloodstream, to signal and to sense stimuli that regulate food intake.7
In 1994, Jeffrey Friedman and others at Rockefeller University discovered that ob/ob mice lacked leptin, a hormone produced by fat tissue. Researchers later found that leptin enters the brain and signals the ARC neurons to decrease food intake, thus inducing satiety.8, 9 Then, in 2004, innovative research revealed that leptin can induce a re-wiring of NPY/AgRP and POMC cells in the ARC in such a way that the network departs from its default signaling of hunger and adapts to a positive energy balance, thus decreasing appetite.10
Administering leptin to obese patients to decrease their appetites, however, proved ineffective. The leptin treatment cured only a few individuals with a rare, genetic type of obesity (due to mutations in the gene that produces leptin, as was the case with the ob/ob mice). Further investigation proved that, with the exception of patients with this rare genetic mutation, the brains of obese people somehow develop a resistance to leptin, and the cells in the brain stop sensing the levels of leptin in the blood.11 Thus, because the brains of the great majority of obese people cannot sense levels of leptin, using it to treat obesity is ineffective from the start.
Understanding the causes of leptin resistance in obese people, though, may help researchers identify new targets for treatment designed to restore their sensitivity to this hormone. Finding ways to heighten tissue sensitivity to hormone signals is difficult but not impossible, as diabetes management shows: People with type 2 diabetes are treated with compounds to increase their sensitivity to insulin. We hope for the development of a similar drug treatment for obese people, but, until we know what causes their resistance to leptin, investigation into such new compounds will remain in its infancy.
Researchers have found, in addition to leptin, several other hormones and molecules that regulate food intake by acting directly in the brain. For example, the gastrointestinal system has been a target of research because scientists believe it releases many hormones to signal a negative or positive energy balance. Investigators have taken a particular interest in the finding that the gut, mainly the stomach, produces the important appetite-stimulating molecule ghrelin, which also acts in the hypothalamus to prompt eating. Researchers found that ghrelin activates the NPY/AgRP appetite-stimulating neurons in response to negative energy balance (for example, when a person is fasting or following a low-calorie diet).12–14
Studies investigating how ghrelin affects the activity of NPY/AgRP neurons in the ARC have encouraged researchers by showing a cascade of events in these cells that ends by stimulating food intake.15 This sequence of events suggests several points of possible intervention for new therapies to treat energy balance disorders. First, ghrelin released by the gut enters the brain and stimulates a receptor on the NPY/AgRP cells that prompts secretion of growth hormone, thus increasing their appetite-stimulating activity. At the same time and related to this event, the mitochondrial machinery in the NPY/AgRP cells speeds up to deliver enough of the high-energy molecule adenosine triphosphate (ATP) for cell metabolism. The enhanced mitochondrial activity also increases the production of harmful oxygen molecules derived from mitochondrial respiration. These harmful molecules are free radicals that react with other molecules inside the cell and promote cell damage (for example, damage to the DNA). To protect the cell from such oxidative damage, the NPY/AgRP cells call on another mechanism to buffer these free radicals by activating the mitochondria’s uncoupling proteins. With appropriate buffering of free radicals by the uncoupling proteins, the NPY/AgRP cells can maintain high firing rates, thereby stimulating food intake.
Understanding this process may affect more than obesity research; it opens many lines of investigation to target cellular pathways to regulate energy balance—for example, by aiming at uncoupling proteins or the cells’ methods for buffering free radicals. In addition to suggesting an approach to solving eating problems, the possibility that free radicals play a role in modulating appetite and regulating energy homeostasis provides a promising avenue for the development of treatments for many diseases related to metabolism. Researchers can now test this promising theory with several newly developed compounds that act as antioxidants.
Moreover, scientists have identified several other molecules involved in regulating food intake. We won’t describe them, but they serve as a reminder of how intricately evolution built this regulatory network. For example, the gut produces several eating-related molecules in addition to ghrelin. Adipose tissue produces, in addition to leptin, immune system molecules with a role in diabetes and obesity. Lastly, classic regulatory hormones such as the glucocorticoids, produced by the adrenal glands and thyroid hormones, also control food intake.
The Feasibility of Treating Obesity with New Pharmacological Therapies
In the past two decades, researchers have worked hard to understand the biological abnormalities involved in obesity and to identify cellular pathways as possible targets for pharmaceutical treatments. The brevity of leptin’s shining moment dashed the hope that a single molecule could cure obese patients by counteracting their positive energy balance. This may be due to the different types of fuel utilization and overall metabolic consequences of the activity of NPY/AgRP versus that of POMC neurons. Fatty acids drive the firing of NPY/AgRP cells, while glucose drives the firing of POMC cells, showing that the former, which promote feelings of hunger and stimulate eating in response to negative energy balance, are a priority for survival.
Add this dominance—not to mention the default status—of the “get something to eat” component of the melanocortin system to the evolutionarily programmed rapid adaptability of brain circuits in response to the changing metabolic environment, and you can understand why it is a daunting and futile, if not counterproductive, task to attempt to develop a pill that will keep people from feeling hungry. Although a one-pill solution to obesity is unlikely, several avenues of research raise hope for new treatments for this widespread medical condition.
The first important step in managing obesity is to integrate disciplines. Based on the knowledge of the neurobiological basis of food intake, scientists could design a treatment using a mixture of compounds given at appropriate times. However, because of the influence of higher brain functions on the regulation of appetite—for example, the influence of the smell, taste and appearance of food on the stimulation of hunger—practitioners must also consider a psychological approach to treating obesity.
Indeed, we believe that obesity, like other disorders of energy metabolism (see “Anorexia Nervosa: a Mortal Clash between Reward and Hunger”), should also be treated as a psychological/psychiatric disorder. Additionally, because obesity involves not only elevated energy intake but also decreased energy expenditure, an exercise program is mandatory to its treatment. Finally, because obesity develops over many years, obese patients should expect a similar time scale to return to their ideal body weight after starting treatment.
This combination of treatment would take advantage of our new understanding of the brain’s role in obesity, going beyond the “silver bullet” visions that followed the discovery of leptin. As scientists continue to learn more about appetite stimulation and appetite suppression in the brain, as well as the hormones and other players that contribute to the process, we trust we will soon reach the goal of stemming the spread of obesity.
Anorexia Nervosa: A Mortal Clash between Reward and Hunger
Few disorders reveal the power of the brain’s cognitive circuitry more clearly than anorexia nervosa, a psychiatric disorder characterized by extreme undereating, loss of body weight, hyperactivity and hypothermia. Compared with other psychiatric conditions, this disorder has the highest mortality rate. We theorize that, in cases of anorexia nervosa, the brain’s ancient evolutionary wiring for adapting happily to low food availability is inappropriately activated and finds itself in a life-threatening battle with other brain signals demanding action to obtain nourishment.
One clue to the intensity of this clash is the elevated level of physical activity in patients with anorexia nervosa, a symptom that people have reported for more than 100 years. Several studies have established a relationship between obsessive-compulsive characteristics and exercise frequency in women with strenuous daily exercise routines and in hospitalized female patients with anorexia nervosa.16 In the patient group, preoccupation with weight was associated with both the frequency of exercise and pathological attitudes toward it. Addictive and obsessive-compulsive personalities contributed to excessive exercise because of their obligatory, pathological thoughts promoting it. Among anorexia nervosa patients, those who exercise excessively have more bulimic symptoms, higher levels of general psychopathology about eating and a greater degree of body dissatisfaction, anxiety, somatization (physical symptoms with a psychological origin), depression and irritability.
Scientists view the tendencies toward mental alertness and continued normal-to-high activity levels (despite insufficient nutrition and weight loss) as being relatively unique to anorexia nervosa patients, versus individuals who experience semi-starvation due to causes such as illness, chemotherapy or famine. For both of these tendencies, the most plausible explanation is activation of evolutionarily old circuitry leading to reward upon reduced energy intake.
A final clue is another characteristic of anorexia nervosa patients: 90 percent are women, mainly in their late teens. This leads us to propose that a cellular mechanism, in association with the changing hormonal milieu that is characteristic of anorexia nervosa patients, unifies and orchestrates activation of key brain circuits, which in turn leads to the behavioral and endocrine manifestation of anorexia nervosa. Our hypothesis is that anorexia nervosa occurs following shifts in the circulating hormones ghrelin, leptin and estradiol, which alter key groups of neurons. These alterations bring about sex-specific structural and functional changes in particular circuits of the midbrain that transmit the chemical dopamine to communicate. Dopamine then triggers a reward response in the prefrontal cortex and hypothalamus to undereating and overexercise.
We further hypothesize that rolling back this shift in reward response could reverse anorexia nervosa, and that either eliminating ghrelin signaling or suppressing the number of available long-chain free fatty acids in the brain could accomplish this. Neuronal cells normally activated by ghrelin use these acids for energy; thus, eliminating the fatty acids would silence the ghrelin-activated neuronal population. Patients who received controlled leptin and estrogen replacement therapy also might see their anorexic symptoms diminish. Moreover, we predict that if doctors help at-risk patients maintain estradiol and/or leptin levels during the initial phase of disease, the patients will be less likely to undergo the shift in reward responses that leads to anorexia nervosa.
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- A. M. Cali and S. Caprio, “Obesity in Children and Adolescents,” Journal of Clinical Endocrinological Metabolism 93(11 Suppl 1, 2008): S31–S36.
- C. Sherrington, “Cutaneous Sensation,” in Textbook of Physiology, ed. E. A. Sharpey-Schaefer, 920–1001 (Edinburgh: Young J. Pentland, 1900).
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