Brain Control of Appetite and Weight
New research is providing insights as to how the brain and nervous system regulate body weight and control appetite and food intake. Exploring the effects of hormones that regulate eating, understanding the neurochemical signals involved in food-seeking behavior and examining brain and nervous system changes that accompany obesity are some of the ways scientists are investigating what the Centers for Disease Control and Prevention has called an American epidemic.
Rise in Obesity
According to the CDC, surveys conducted during the 1990s showed that obesity, defined as being at least 30 percent above ideal body weight, increased across the United States from 12 percent of the population in 1991 to almost 18 percent in 1998. The latest data for the first quarter of 2002 show that more than 24 percent of American adults aged 20 and older are obese.
The Food and Drug Administration says about 300,000 U.S. deaths a year are associated with obesity and overweight. The FDA also says the total direct and indirect costs attributed to these conditions amounted to $117 billion in 2000.
Scientists at Oregon Health Sciences University in Portland and the Imperial College of Science, Technology and Medicine in London, England, are studying a naturally occurring substance that signals the brain to stop eating.
Peripheral Hormone Peptide YY (PYY)
The compound, called peripheral hormone peptide YY (PYY) is secreted from the gastrointestinal tract in response to food. It acts on neurons in the arcuate nucleus of the hypothalamus, a particular region of the brain associated with energy balance and food metabolism.
Michael Cowley, PhD, and his colleagues at OHSU identified mouse pro-opiomelanocortin (POMC) neurons by using a jellyfish protein that induced these specific nerve cells to glow green. They observed that PYY activated the POMC neurons. After the scientists examined this effect, their London associates studied the clinical response to PYY in humans.
The researchers randomly assigned 12 healthy non-obese volunteers to receive intravenous PYY or saline infusions. Two hours after the infusions, the scientists measured caloric intake during a free-choice buffet meal. People who received PYY took in about one-third fewer calories than those in the placebo group. This reduction in appetite lasted for about 12 hours.
Drop in Appetite
“Not only did the PYY group experience a drop in appetite, they did not have increased appetite later, and did not ‘make up’ for the food they missed,” notes Cowley, with the OHSU Oregon National Primate Research Center.
But we sometimes show a desire for food in the absence of actual hunger. Ann E. Kelley, PhD, of the University of Wisconsin-Madison Medical School, is engaged in research efforts to understand the brain pathways and neurochemical signaling that underlie our motivations to procure and consume food.
“What is it that makes food so pleasurable and why do we eat when we’re not hungry?” Kelley asks. “Why is the desire for tasty foods, particularly sweet high-fat foods so strong? Can you be addicted to food?”
Nucleus Accumbens – Linked to Appetite and Food Drives
Her research efforts center on examining, in rats, a region of the brain called the nucleus accumbens. This collection of neurons connects directly to the hypothalamus, and may act as an interface between our emotions and food drives, she explains. The nucleus accumbens, she adds, also is involved in addiction to drugs, nicotine and alcohol.
GABA (gamma amino butyric acid)
Part of the system involved in food-seeking behavior also involves a particular neurotransmitter called GABA (gamma amino butyric acid), which acts like an “on-off” switch to pathways that trigger eating. “When we turn on this system artificially in rats, they show uncontrolled eating and the hypothalamus is highly activated,” Kelley says.
Enkephalins and Endorphins
Another critical part of the system is the release of opioid peptides called enkephalins and endorphins, which are released in response to highly palatable foods. “Our research has shown that if opioid receptors are overstimulated, rats eat up to six times the amount of fat they normally consume and they also increase their intake of sweet, salty and even alcohol-containing solutions, even in the absence of hunger,” she explains.
Associated investigations show that overeating can be overcome by blocking neural processing in the lateral hypothalamus. “We propose that the accumbens opioid system and its associated brain circuitry constitute the brain’s “food pleasure” system,” Kelley says.
Recent data also show that rats that overindulge in tasty foods show marked, long-lasting effects on brain neurochemistry similar to that seen in rats given morphine or heroin for extended times.
Do emotions also come into play where food is concerned? Sweet and fatty foods, sometimes referred to as comfort foods, alleviate anxiety and help produce temporary feelings of well-being. Kelley says a recent finding suggests the amygdala, which regulates positive and negative emotions, exerts direct control on how we behave in response to pleasurable tastes.
This brain mechanism may be an evolutionary holdover from humanity’s past when high-energy food sources rarely were encountered. “When early humans came across a positive taste their brains provided a “go” signal – ‘consume a lot now because you don’t know where or when your next meal is,’ or ‘you may need a lot of energy to escape from predators,'” Kelley says. “But in today’s modern societies this mechanism is maladaptive and may contribute significantly to the present obesity epidemic.”
But a continued high-energy diet may predispose only certain individuals to gain weight, notes Barry Levin, MD, of the New Jersey Medical School of the University of Medicine and Dentistry of New Jersey in Newark. “We work with a rat model of diet-induced obesity in which rats all gain the same amount of weight when fed a low-fat diet,” he says. “But there is a marked bimodal weight gain pattern when we give the rats a diet high in fat and energy content. Some rats become obese on such a diet while those that appear to be resistant gain no additional weight. Once the obese rats begin to gain more weight, they defend that higher body weight against over- and underfeeding.”
New Body Weight Set Points
Certain brain and nervous system reorganizations accompany the establishment of new body weight setpoints. Levin and his colleagues are investigating how the brains of obesity-prone rats develop in response to environmental and other influences, as well as ways they sense and regulate glucose, the basic food source required for nerve cell function.
The brain monitors glucose metabolism by means of specialized neurons that maintain energy balance. But, notes Levin, these metabolic sensor neurons are sensitive to outside influences, since their functions can be altered in obesity, diabetes and other metabolic diseases.
Raised Threshold for Metabolic Signals
“What our results suggest,” Levin says, “is that obesity-prone rats are programmed to store calories very efficiently and in abundance when an energy source is available. Thus, they appear to have a raised threshold for metabolic signals that would normally end a meal or inform them of eating too many calories. The hypothalamic neurons in these rats have reduced responses to glucose and leptin, a protein that helps the body manage its supply of fat.”
When the neurons are altered – either by genetics or environmental factors that affect brain development before and shortly after birth – it may be permanent, since it’s virtually impossible to get a genetically programmed rat to lose weight once it becomes obese. “This may be due to the plasticity in neural systems that regulate energy balance in the body and we have some preliminary data to support this,” Levin says.
This means these particular neurons may be important targets for therapeutic interventions in the treatment of human obesity, he adds.
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