Progress Report 2009: The Obesity Problem
When Our Hormones Betray Us


by Scott P. Edwards

January, 2009

Research during the past two decades has raised public awareness of the brain’s role in regulating how much food we eat, but our current picture of appetite and food intake emerged much earlier, when in the 1950s nutritionist Jean Meyer discovered that glucose levels in the blood regulate hunger. Meyer went on to study obesity, which he called a “disease of civilization,” and he helped to link excess weight to other substances in the blood and to structures in the brain.

Neuroscientists have since taken up Meyer’s fight. In 2008, researchers reported findings that provide a greater understanding of the role of two (out of a dozen or so known) important appetite-related hormones, ghrelin and leptin. Researchers also determined how a popular class of anti-obesity drugs can affect brain wiring and found evidence of a potential link between obesity, diabetes, and Alzheimer’s disease.

The Basics of Appetite

The U.S. Centers for Disease Control and Prevention designates the labels “obese” and “overweight” for ranges of weight greater than what is generally considered to be healthy for a given height. Bodymass index, or BMI, measures body fat based on a person’s height and weight. Clinicians consider a BMI of 25–29 to be overweight, while anything over 30 is obese.

Meyer helped to identify the brain’s hypothalamus as a regulator of appetite, but that brain structure influences a number of other bodily functions as well, including body temperature, blood pressure, and fluid and electrolyte balances. A collection of neurons in an area of the hypothalamus called the arcuate nucleus coordinates our need to eat in relation to how well our body is fed via cross talk with signals arising from the gastrointestinal system and adipose (fatstoring) tissue. Two specific neural circuits within the arcuate nucleus promote or suppress appetite, regulating our body’s nutritional state and helping to provide balance to our body weight, respectively.

In addition to the hypothalamus, the brain’s limbic structures and reward circuitry contain information on food preferences acquired over our life span based on aspects such as taste and smell. Our sensory organs send food-related signals to the brain that release dopamine, a neurotransmitter that plays an important role in motivation and reward. More than food itself, our expectations—what we associate with certain tastes and smells—cause the secretion of dopamine. Thus, eating really starts in our brain before we even put food in our mouths.

PR09_CH05_Connections_spotlight

In a study of neural connections between brain regions, neurons from the arcuate nucleus (bottom left), which has been linked to appetite control, extend axons toward the paraventricular nucleus (top right). (Sebastian Bouret, Ph.D. / University of Southern California) 

Several factors contribute to the world’s obesity epidemic. A growing number of people find themselves unable to defy the desire to eat more food than is healthy. While many of us know that the food we eat adds inches to our waistlines, some people cannot control themselves at the dinner table. And despite spending countless hours and millions of dollars on diets and weight-loss products and services, many people lose weight only to gain it again.

Leptin and Ghrelin: Two New Players in a Large Arena

Research on appetite control in the 1970s and 1980s focused on two neurotransmitters, norepinephrine and serotonin. Both are messenger chemicals that travel across the synaptic gap between neurons. Doctors prescribed amphetamines to enhance the release of norepinephrine and thereby control appetite, and targeted serotonin for its role at the hypothalamic control centers for appetite. However, the discovery of two important hormones in the 1990s led to a finer understanding of how appetite is controlled and how, when something goes awry, obesity can occur.

In 1994 Rockefeller University researcher Jeffrey Friedman and his colleagues published a landmark paper in Nature that identified a hormone called leptin (Greek for “thin”) produced by the obese (ob) gene.1 Leptin is made by the body’s fat cells, which help to regulate food intake and energy expenditure (the amount of calories we burn). Friedman showed that mice lacking the ob gene do not produce leptin and become extremely obese. After both normal and ob-deficient mice were injected with synthetic leptin, they became more active and lost weight.

High levels of leptin activate nerve cells in the brain and create a feeling of fullness, while low levels signal hunger. Friedman alsoshowed that humans who lack the ob gene and eat large amounts do not experience that feeling of fullness and end up extremely obese.

Five years after Friedman’s discovery, Japanese researchers identified another hormone, ghrelin, which they called the “hunger hormone.” Ghrelin is made in the stomach and tells our brain when it’s time to eat. Ghrelin levels rise just before mealtime and fall after we eat.2

These two hormones played an important role in 2008 research aimed at discovering how to regulate food intake in obese and overweight people.

In 2007, researchers at Harvard Medical School developed what they call a “right brain hypothesis” for obesity. The right hemisphere of the brain’s prefrontal cortex (PFC) plays a critical role, they say, in the cognitive control of food intake, which refers to our capacity to process information and make decisions regarding what we eat. The PFC controls a number of complex behaviors that separate humans from other species.

The Harvard researchers say that a certain amount of activity in the right PFC is required to control appetite. While the PFC is not damaged in obese people, they say, activity in this area of their brains is diminished. In addition, the right PFC is critical for what the researchers call “moral cognition,” our ability to give values to different foods, which influences our decisions about what we eat. Dysregulation of the right PFC, the Harvard researchers say, could lead to inappropriate conclusions about food choices, which could contribute to obesity.

As more research supports hypotheses that emphasize the involuntary processes that lead to obesity, many scientists now view addiction as a potential contributing factor to our growing waistlines. Research studies are currently under way to examine the underlying psychology and biology behind this hypothesis. Some of these studies have focused on the neurotransmitter dopamine, which plays a role in the brain’s reward circuit. In 2001, researchers at Brookhaven National Laboratory reported that obese people have fewer receptors for dopamine than people without weight problems, implying that obese people may eat more to try to stimulate dopamine pleasure circuits in their brains, just as drug addicts do by taking drugs.3 Others, however, believe that factors such as poor eating habits, lack of exercise, and genetics contribute more to overeating than do either physical or psychological dependence.

In 2008, scientists at Eli Lilly and the University of Texas Southwestern Medical Center independently discovered an enzyme that is responsible for putting a fatty acid on ghrelin, the so-called hunger hormone.4, 5 Without this fatty acid, ghrelin might not have the same effect on appetite. The identification of this enzyme, called GOAT, or ghrelin O-acyl transferase, is the first step toward developing medications to treat obesity.

Ever since ghrelin was discovered, scientists have sought ways to manipulate the hormone to help tame hunger. With the discovery of GOAT, researchers are now testing compounds that block the enzyme from attaching to ghrelin. One promising approach uses antibodies to sop up the enzyme and block ghrelin signals to the brain.

Hardwired to Be Obese?

In February 2008, researchers at the University of Southern California showed that a predisposition to obesity might be hardwired in the brain at birth.6 The researchers selectively bred rats that were prone to becoming obese and found that the regions of their brains that control appetite were abnormal. The arcuate nuclei of the obese rats were defective, leaving their brains less receptive to leptin, a hunger-suppressing hormone. These abnormalities showed up in the mice as early as the first week after they were born.

Under the direction of Sebastien Bouret, the USC researchers discovered that the obesity-prone rats had fewer neural projections from the arcuate nucleus, a problem that continued into adulthood. These projections enable leptin to signal from the arcuate nucleus to other parts of the hypothalamus. Bouret’s team said that appetite and obesity are built into the brain during development and that the propensity to gain weight cannot be reversed. Scientists are trying to determine how to treat this abnormality during early, critical phases of development by rewiring the brain so that leptin signals are adequately relayed.

Researchers have begun to develop treatments to prevent children from carrying extra weight into their adult years. Scientists at the Massachusetts Institute of Technology (MIT), however, have found that anti-obesity drugs that suppress appetite by blocking so-called cannabinoid receptors in the brain could also interfere with children’s brain wiring during development.7 Synthesized in the brain, cannabinoids are structurally related to tetrahydrocannabinol, the active ingredient in marijuana and a known appetite stimulant.

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Bone density scans provide images of body composition in wild-type (left panel) and leptin-deficient (right panel) mice. Leptin deficiency is associated with increased fatty tissue. (Sebastian Bouret, Ph.D. / University of Southern California)

The anti-obesity drugs include rimonabant, marketed by Sanofi-Aventis under the trade name Acomplia, which has been approved for weight loss in Europe and awaits approval by the Food and Drug Administration (FDA) for use in the United States.

The MIT scientists used a well-known experiment to examine brain plasticity (its ability to change based on experience); they temporarily covered one eye in mice soon after they were born, inducing a loss of synapses in the covered eye. Even one day of vision loss caused the synapses to shift to the uncovered eye. Injecting the mice with a cannabinoid receptor blocker stopped the synapses from shifting, suggesting that the cannabinoids play a key role in the early stages of synapse development. Blocking cannabinoids, as anti-obesity drugs such as Acomplia do, could hinder this development process, the researchers say, suppressing the brain wiring necessary for normal development in children.

Researchers caution, however, that psychiatric problems, including severe depression and suicidal thoughts, may be a greater potential problem linked to cannabinoid antagonists than childhood brain development. In 2007, a panel recommended that the FDA not approve rimonabant for use in the United States because of this increased risk.

Approved treatments have limitations, as well. While many people on weight-loss plans successfully shed pounds, others, especially those who typically overeat, become hungry when dieting and increase their food intake even as they attempt to lose weight. Researchers at the Columbia University Medical Center/New York Presbyterian Medical Center reported in the Journal of Clinical Investigation that low levels of the hormone leptin cause changes in food intake and energy expenditure that lead to weight gain during dieting.8 Using visual food cues, the scientists showed that leptin-mediated changes in areas of the brain that regulate the emotional and cognitive aspects of eating led to overeating after weight loss. The researchers say their findings “support the pivotal role of leptin in body weight regulation as a primary ‘defense hormone’ against loss of body fat following otherwise successful weight loss.”

Other research gives extra incentive for researchers to reduce the prevalence of obesity. In the Cellular Neurobiology Laboratory at the Salk Institute, David Schubert has shown how obesity, type 2 diabetes, and Alzheimer’s disease may be linked.9 While the research is not directly related to obesity, Schubert’s findings show that people with type 2 diabetes, a leading cause of which is excess weight, are nearly 65 percent more likely than those without diabetes to develop Alzheimer’s disease.

Schubert’s research builds on other studies showing that obesity and Alzheimer’s are linked. In a May 2008 paper in Obesity Reviews,10 a team of researchers at the Johns Hopkins Bloomberg School of Public Health examined two decades’ worth of research that coupled obesity with an increased risk of Alzheimer’s and other forms of dementia. In most of the studies they analyzed, the researchers said obesity increased the risk of Alzheimer’s by 80 percent. Preventing or treating obesity at an early age, they said, could “play a major role in reducing the number of dementia patients.”

Global Initiatives to Combat Epidemic

As the 2008 research findings show, curbing obesity will require more than simply eating less and exercising more. Scientists continue to further their understanding of the biochemistry of appetite, and drug companies seek new drugs to help rid us of unwanted pounds. In the United States, policymakers push for better food labeling and nutritional information on food packages. An increasing number of schools alter their cafeteria menus to offer a more healthful diet. Many companies offer incentives to employees to lose weight (and thereby reduce the companies’ health-care costs).

Countries such as Brazil, Australia, and Singapore have started to address their growing obesity problem; however, it will take time for their strategies to be implemented and for results to become evident. The International Obesity Task Force, part of the International Association for the Study of Obesity, has established a program aimed at the prevention and management of obesity through raised awareness of the problem among governments, health-care professionals, and the community. And the World Health Organization, through its Global Strategy on Diet, Physical Activity, and Health, is helping to create public policies that promote the availability and accessibility of low-fat, high-fiber diets, as well as monitoring the response to the burden of obesity and associated medical conditions through clinical and training programs to ensure effective support of those afflicted with obesity.

They have their work cut out for them: currently there are more than 1 billion overweight people in the world—nearly one-sixth of the population—and 300 million of those overweight people are obese.

Notes

1. Zhang Y, Proenca R, Maffei M, Barone M, Leopold L, and Friedman J. Positional cloning of the mouse obese gene and its human homologue. Nature 1994 372(6505):425−432.

2. Kojima M, Hosoda H, Date Y, Nakazato M, Matsuo H, and Kangawa K. Ghrelin is a growth-hormone-releasing acylated peptide from stomach. Nature 1999 402(6762):656−660.

3. Wang G, Volkow N, Logan J, Pappas N, Wong C, Zhu W, Netusll N, and Fowler J. Brain dopamine and obesity. The Lancet 2001 357(9253):354−357.

4. Gutierrez JA, Solenberg PJ, Perkins DR, Willency JA, Knierman MD, Jin Z, Witcher DR, Luo S, Oniya JE, and Hale JE. Ghrelin octanoylation mediated by an orphan lipid transferase. Proceedings of the National Academy of Sciences 2008 105(17):6320–6325.

5. Yang J, Brown MS, Lian G, Grishin NV, and Goldstein JL. Identification of the acyltransferase that octanoylates ghrelin, an appetite-stimulating peptide hormone. Cell 2008 132(3):387–396.

6. Bouret SG, Gorski JN, Patterson CM, Chen S, Levin BE, and Simerly RB. Hypothalmic neural projections are permanently disrupted in diet-induced obese rats. Cell Metabolism 2008 7(2):179–185.

7. Liu CH, Heynen AJ, Hussain Shuler MG, and Bear MF. Cannabinoid receptor blockade reveals parallel plasticity mechanisms in different layers of mouse visual cortex. Neuron 2008 58(3):340–345.

8. Rosenbaum M, Sy M, Pavlovic K, Leibel RL, and Hirsh J. Leptin reverses weightloss induced changes in regional neural activity responses to visual food stimuli. Journal of Clinical Investigation 2008 118(7):2583–2591.

9. Burdo JR, Chen Q, Calcutt NA, and Schubert D. The pathological interaction between diabetes and presymptomatic Alzheimer’s disease. Neurobiology of Aging 2008 (March 27, 2008, online edition).

10. Beydoun MA, Beydoun HA, and Wang Y. Obesity and central obesity as risk factors for incident dementia and its subtypes: A systematic review and metaanalysis. Obesity Reviews 2008 9(3):204–218.