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Obesity Caused by Non-Neuronal Cells (Glia) in the Brain

Treatment for obesity in the future may involve an X-ray beam to the brain.

Forget about stomach staples. Treatment for obesity in the future may involve an X-ray beam to the brain. This is what researchers have discovered to keep mice slim, trim, and energetic while gorging on a fatty diet. How it works offers a fascinating new insight into the cellular mechanisms of the brain in a spot where appetite is controlled.

Researchers Daniel Lee of Johns Hopkins University and colleagues found that cells in part of the brain called the hypothalamus, known to control hunger, thirst, and energy expenditure, were dividing. In any other organ in the body this would not be surprising, but in the brain this is a remarkable finding, because mature neurons cannot divide. They report their findings in the current edition of the journal Nature Neuroscience.

The researchers learned that the new neurons being born were not the offspring of other neurons, but rather the descendents of glia. Glia are non-neuronal cells that vastly outnumber neurons in the brain, but until recently most neuroscientists had little interest in studying them because glia do not fire electric impulses like neurons. We are now learning that glia communicate without using electricity; that they can control communication between neurons at synapses, and they are critically involved in nearly every aspect of brain function in health and disease.

The type of glial cells in the hypothalamus that were giving birth to neurons are called tanycytes. Looking at a molecular marker called c-fos that appears in the cell nucleus when neurons are stimulated, the researchers saw that these newborn neurons were activated when animals were fasting, proving that these neuronal newbies had worked their way into a functional circuit in the brain region that monitors hunger. Knowing that a high-fat diet during adolescence can lead to long-term increased food intake and weight gain as adults, the researchers fed the mice high-fat chow and looking later when the mice were adults, found that the population of new neurons in the hypothalamus had quadrupled. No changes were seen in the number of newborn neurons in mice fed normal diets. Thus, the high-fat diet had changed the circuitry in the brain region controlling hunger, by the addition of four times as many new neurons. This amped up circuitry controlling food intake in the adult brain might explain how high-fat diets in adolescence leads to obesity in adults.

To test the idea, researchers decided to cull the population of newborn neurons back to the original number in animals fed the high-fat diet. According to the hypothesis, restoring the neuronal numbers to normal should prevent the adult mice from overeating and becoming obese adults. To do that, they targeted the newborn neurons for destruction by using a beam of radiation focused on the hypothalamus, much as radiation therapy is used to kill rapidly dividing cancer cells. Radiation breaks the DNA of cells that are in the process of dividing, which is why radiation is effective in cancer treatment. The neurons in the hypothalamus that were not dividing were spared, but the tanycytes that were dividing to make new neurons were eliminated. The result was that the adults gained less weight when irradiated and their energy consumption and activity levels were much higher than the animals fed the high fat diet but not irradiated.

Why the brain would remodel its hunger center when exposed to an energy-rich diet makes sense in the wild where food is scarce. Pigging out when food becomes available and building fat reserves for the future will prevent starvation in lean times, but in the modern world where high calorie and fat-rich foods are just as accessible as leaner foods, the strategy becomes detrimental, leading to obesity.

Obesity is a serious health problem in the United States, and these new discoveries come from looking not at the digestive system, but rather from looking at the brain, the organ that controls feeding. And by looking inside the brain: not at neurons, but at the glial cells that give birth to them.

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