Working with genetically engineered mice, Johns Hopkins scientists have interfered with the brain's ability to control an animal's response to a high-fat diet. The report, to be published in the latest issue of the Proceedings of the National Academy of Sciences online the week of May 1, is based on the identification of a gene - CPT1c - the brain needs to manage body weight.
According to the researchers, the CPT1c gene protects against weight gain caused by a high-fat diet. So-called knockout mice lacking the CPT1c gene gain more weight than their littermates carrying normal copies of the gene.
"We think our study reveals a direct weight management pathway," says Michael Wolfgang, Ph.D., a postdoctoral fellow in the Department of Biological Chemistry at The Johns Hopkins University School of Medicine and an author of the report. "CPT1c seems to allow the body to respond immediately to the level of nutrients and fat in the bloodstream."
Hopeful that the discovery has broad implications for understanding the genetic underpinnings of obesity and weight management, the Hopkins investigators say the work affirms the central role of the brain in managing hunger and satiety and offers up new targets for drugs that manipulate CPT1c. But none have been developed so far, says Wolfgang.
The newly discovered gene makes a protein found only in the brain, notably in the region that controls hunger, thirst and metabolism - the hypothalamus. Proteins similar to CPT1c are known to help break down fat to release energy to feed cells. Mice lacking the CPT1c gene are the same length as their littermates who carry normal copies of the gene but on average weigh 15 percent less when fed a low-fat diet.
Further analysis revealed that when deprived of food for four hours prior to feeding with standard laboratory mouse chow, the knockout mutant mice ate about 25 percent less food than their normal siblings. Therefore, the researchers concluded, CPT1c must play a role in feeding behavior and appetite control.
And when fed a high-fat diet (mouse chow laced with lard) for 10 weeks, mice lacking CPT1c still ate less than their normal littermates, but they were much heavier.
What scientists already know about the regulation of body weight helps explain why the absence of CPT1c may have its seemingly paradoxical effect.
Under normal circumstances, says Wolfgang, body weight is maintained by a combination of food intake and energy expenditure, how hungry the body is, and how much energy cells need. Many cells in the body use a sugar called glucose as a source of energy. When the body is starved, the body literally feeds on itself, breaking down fat to form fatty acids that fuel energy needs. When the cells of the body are well fed and energy is in ample supply, molecular signals from the brain tell cells in the body to store the excess energy by converting it to fat. Weight gain results when food intake greatly exceeds energy expenditure. But when the brain's appetite/energy regulator is out of whack, so are the rules for gaining and losing weight.
"How do you know when to stop eating?" asks M. Daniel Lane, Ph.D., senior author of the study and a professor of biological chemistry in the Institute for Basic Biomedical Sciences at Hopkins. "The liver sure isn't going to tell you, it just keeps storing fat as long as the body is well fed." Instead, he notes, it is the control regions of the brain, namely the hypothalamus, that governs eating behavior.
Previously, the same researchers showed that a molecule called malonyl-CoA is critical for fat metabolism. And as it turns out, malonyl-CoA interacts with CPT1c, according to Lane.
Increasing the amount of malonyl-CoA in the liver causes those cells to synthesize fat, which is stored. Increasing malonyl-CoA in the hypothalamus somehow tells the cells in the body to break down fats for energy and the muscle cells to use more energy. Therefore, identifying molecules that interact with malonyl-CoA will help scientists understand how energy balance and body weight is controlled.
"We are beginning to understand what the hypothalamus inputs are, but unlike the liver, where nearly the whole organ is involved in the same thing, the brain is very specialized and only a few neurons do very specific things," says Lane. The researchers hope to further understand how malonyl-CoA and CPT1c function to control body weight and appetite.
Funding for this study was provided by Astellas Pharma Inc. Tsukuba.
Authors on the paper are Wolfgang, Yun Dai, Seung Hun Cha and Lane, all of Hopkins, and Takeshi Kurama, Akira Suwa, Makoto Asaumi, Shun-ichiro Matsumoto and Teruhiko Shimokawa, of Astellas Pharma Inc. Tsukuba of Japan.
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