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Fighting Obesity one Molecule at a Timeby Ruth SoRelle, M.P.H. Thousands of years ago, hunger was the predator. In humans, biological mechanisms evolved to insure that the species survived at a time when no one could be certain where or when his or her next meal would come. The ability to store fat meant survival. That ancient advantage, however, works against modern populations in a time of plenty. In the past 20 years, obesity in the United States has increased to the point that the U.S. Centers for Disease Control and Prevention estimates that 30 percent of adults are obese—60 million people. The diseases that accompany weighing too much—high blood pressure and fats in the blood, type 2 diabetes, heart disease, stroke, gallbladder disease, arthritis, respiratory problems and cancer—make this a significant pubic health issue. While physicians and social engineers work to change the physical and lifestyle factors that can cause obesity, scientists in laboratories around the world are looking at the problem at the cellular level. At Baylor College of Medicine, many of the College's foremost researchers are hoping to fight obesity one molecule at a time. Salih Wakil's Magic Mice
Dr. Salih Wakil For the past half century, Dr. Salih Wakil, immediate past chairman of the Verna and Marrs McLean Department of Biochemistry and Molecular Biology at Baylor College of Medicine, has studied the chemistry of food-—protein, carbohydrates, starch and fat. Today, his work concentrates on an enzyme called Acetyl-CoA carboxylase, or ACC. The enzyme exists in two forms—ACC1 and ACC2. If mice are genetically engineered to lack ACC1, the animals die before they are born. However, mice bred to lack ACC2 can eat 20 to 30 percent more food and weigh 10 to 15 percent less. They are healthy, long-lived and resist developing type 2 diabetes—even when they are fed high-fat, high-carbohydrate diets that cause the disease in normal animals. ACC2's role as a crucial element in the production of malonyl-CoA (the base that enables production of fatty acids) is the secret to the svelte bodies and the health of the ACC2-deficient mice. Malonyl-CoA inhibits the passage of fatty acid into the mitochondria (the cell's power source), where it is burned to make energy. When mice lack ACC2, there is no barrier, allowing fatty acid to continuously pass the membrane into the mitochondria, where it is burned. Ironically, ACC1—the brother enzyme to ACC2—is also key to the production of a pool of malonyl-CoA that resides elsewhere in the cell, but the two pools don't mix. This belt-and-suspenders approach evolved as a protective mechanism in organisms when the hunt for food was a constant uncertainty. "The idea is that if we find drugs that regulate the expression of the ACC2 gene and/or inhibit the enzyme, we can control obesity and prevent diabetes," said Wakil. Guardians of Fat
Dr. Lawrence Chan In the laboratory of Dr. Lawrence Chan, chief of the division of diabetes, endocrinology and metabolism at BCM, studies of proteins on the surface of droplets of lipids or fat have led to new understanding about how fats are metabolized or used by the body. Chan's work centers on the activity of these proteins that can stabilize fat. "Why do you get balls of fat? Why don't you get a sea of fat?" he asked. "Initially, we looked at these as building blocks of balls of fat. Now we find that they are not just mere building blocks. They are active participants." Work with a protein called perilipin found on the surface of lipid droplets showed that it somehow controls fat degradation or breakdown. "When you don't have perilipin, the fat is degraded much faster," he said. "It's the guardian angel of fat." Now, studies of another protein associated with fat droplets—adipose differentiation-related protein or ADRP—have shown that animals that lack the gene associated with this protein do not develop fatty liver, a disorder that can later lead to liver dysfunction and cirrhosis. "Fatty liver disease is a common problem for obese people," said Chan. He is still trying to determine how ADRP works to affect fat accumulation. "The main thing is to learn more about how we conserve energy and how we burn up our fat," Chan said. The Ghrelin Conundrum
Dr. Roy G. Smith Dr. Roy G. Smith's association with the protein ghrelin began even before it was discovered. Ghrelin is a short-lived protein that stimulates appetite and growth hormone release. Smith, director of the Huffington Center on Aging at Baylor College of Medicine, actually studied the path of ghrelin action in the cell while he was heading obesity research at a pharmaceutical firm. Today, he continues work on the molecule that seems to defy explanation. "Everyone thought antagonists (drugs that would block the effect of ghrelin) would be the key to obesity," he said. Animal studies, however, have proved disappointing. Obese animals have low ghrelin levels but continue to eat more than they need. Conversely, they have high levels of leptin, a protein believed to inhibit appetite. Giving obese animals leptin reduced weight gain, but its effect in humans was less positive. Now, he and others in the field are beginning to believe that people can be resistant to the effects of both leptin and ghrelin—just as people with type 2 diabetes are resistant to the effects of insulin. Studies are now ongoing in cancer patients who are losing weight rapidly (a problem called cachexia). "Can we increase appetite and body weight by giving more ghrelin?" said Smith. If the treatment overcomes cachexia, patients could then take more chemotherapy and have a better chance at control of their disease. By looking at people in the exact opposite condition from obesity, Smith and his colleagues hope to better understand ghrelin's effect on obesity. In earlier studies of compounds that acted on the same cellular receptor as ghrelin, he found that the drugs did not help people lose weight, but they did shift the composition of their bodies more toward muscle. People with more muscle tend to clear glucose from their systems more efficiently—a finding that could have implications for preventing type 2 diabetes. A Worldwide ProblemObesity is increasing around the world. The World Health Organization estimates millions of people will be affected by the excess pounds that create health problems and hasten death. BCM experts, intent on their work in the laboratory, relate it to this worldwide threat. On a recent visit to China, Chan saw thin and trim people in the rural areas where food is still scarce and people work hard to produce it. However, in Shanghai and other big cities, obesity is growing, and it does not portend well for those nations of the Third World that are becoming more industrialized. It puts the problem into context for Chan and his colleagues and gives impetus to their activities. "If every city in China becomes a Shanghai, they are in trouble," said Chan. "The idea is that if we find drugs that regulate the expression of the ACC2 gene and/or inhibit the enzyme, we can control obesity and prevent diabetes." |
Patient CareHealthy Living for a Thousand, Alex ResearchFighting Obesity one Molecule at a Time Doctors are from Jupiter, Patients are from Saturn EducationA Lot's Changed in 40 Years... Sort Of Community ServiceAlumni & DevelopmentBuilding BCM and Biochemistry History Following Father's Bedside Manner More than a Street Sign: Advocates for Medicine College NewsAn Artist in the Medical Arena
Educating the Next Generation of Leaders
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Volume 2, Issue 3, Fall 2006 |
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