Studying mice, they found that when the target protein was disabled, the animals became more sensitive to insulin and were less likely to get fat even when they ate a high-fat diet that caused their littermates to become obese.
The findings are published online in the journal Cell Metabolism.
The researchers studied how the body manufactures fat from dietary sources such as carbohydrates. That process requires an enzyme called fatty acid synthase (FAS). Mice engineered so that they don't make FAS in their fat cells can eat a high-fat diet without becoming obese.
"Mice without FAS were significantly more resistant to obesity than their wild-type littermates," says first author Irfan J. Lodhi, PhD. "And it wasn't because they ate less. The mice ate just as much fatty food, but they metabolized more of the fat and released it as heat."
To understand why that happened, Lodhi, a research instructor in medicine, analyzed their fat cells. Mice have two types of fat: white fat and brown fat. White fat stores excess calories and contributes to obesity. Brown fat helps burn calories and protects against obesity.
In mice genetically blocked from making fatty acid synthase in fat cells, Lodhi and his colleagues noticed that the animals' white fat was transformed into tissue that resembled brown fat.
"It definitely exists, and perhaps the next strategy we'll use for treating people with diabetes and obesity will be to try to reverse their problems by activating these brown fat cells," says senior investigator Clay F. Semenkovich, MD.
Semenkovich, the Herbert S. Gasser Professor of Medicine, professor of cell biology and physiology and director of the Division of Endocrinology, Metabolism and Lipid Research, says the new work is exciting because FAS provides a target that may be able to activate brown fat cells to treat obesity and diabetes. But even better, he says it may be possible to target a protein downstream from FAS to lower the risk for potential side effects from the therapy.
That is possible because the scientists learned that the FAS pathway involves a family of proteins known as the PPARs (peroxisome proliferator-activated receptors). PPARs are important in lipid metabolism. One of them, PPAR-alpha, helps burn fat, but the related protein, PPAR-gamma manufactures fat and helps store it.
Lodhi and Semenkovich noticed that in mice without FAS in their fat cells, activity of PPAR-alpha (the fat burner) was increased, while PPAR-gamma (the fat builder) activity decreased.
A protein called PexRAP (Peroxisomal Reductase Activating PPAR-gamma) turned out to be a downstream mediator of the effects of FAS and a key regulator of the PPAR-gamma, fat-storing pathway. When the researchers blocked PexRAP in fat cells in mice, they also interfered with the manufacture and buildup of fat.
"There was decreased fat when we blocked PexRAP," Lodhi says. "Those mice also had improved glucose metabolism, so we think that inhibiting either fatty acid synthase or PexRAP might be good strategies for treating obesity and diabetes."
Several pharmaceutical companies are working on FAS inhibitors. Meanwhile, the discovery that inhibiting PexRAP also makes the animals less obese and less diabetic has convinced the Washington University researchers to continue those studies.
"Because PexRAP is downstream, it theoretically might cause fewer side effects, but nobody knows what role the protein might play in different tissues in the body," Semenkovich says. "We need to conduct more experiments with the goal that we may be able to move into some sort of clinical trials relatively soon. It's very important to find new treatments for obesity and diabetes because these disorders aren't just an inconvenience, both can be lethal."
Lodhi IJ, Yin L, Jensen-Urstad APL, Funai K, Coleman T, Baird JH, El Ramahi MK, Razani B, Song H, Fu-Hsu F, Turk J, Semenkovich CF. Inhibiting adipose tissue lipogenesis reprograms thermogenesis and PPARã activation to decrease diet-induced obesity. Cell Metabolism, vol. 16 (2), Aug. 8, 2012.
Funding for this research comes from the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) and the National Heart, Lung, and Blood Institute (NHLBI) of the National Institutes of Health (NIH). NIH grant numbers DK088083, DK076729, F32 DK083895, KO8 HL098550, DK20579, DK34388, RR00954 and T32 DK07120.
Washington University School of Medicine's 2,100 employed and volunteer faculty physicians also are the medical staff of Barnes-Jewish and St. Louis Children's hospitals. The School of Medicine is one of the leading medical research, teaching and patient care institutions in the nation, currently ranked sixth in the nation by U.S. News & World Report. Through its affiliations with Barnes-Jewish and St. Louis Children's hospitals, the School of Medicine is linked to BJC HealthCare.
Jim Dryden | EurekAlert!
Penn studies find promise for innovations in liquid biopsies
30.03.2017 | University of Pennsylvania School of Medicine
'On-off switch' brings researchers a step closer to potential HIV vaccine
30.03.2017 | University of Nebraska-Lincoln
The Institute of Semiconductor Technology and the Institute of Physical and Theoretical Chemistry, both members of the Laboratory for Emerging Nanometrology (LENA), at Technische Universität Braunschweig are partners in a new European research project entitled ChipScope, which aims to develop a completely new and extremely small optical microscope capable of observing the interior of living cells in real time. A consortium of 7 partners from 5 countries will tackle this issue with very ambitious objectives during a four-year research program.
To demonstrate the usefulness of this new scientific tool, at the end of the project the developed chip-sized microscope will be used to observe in real-time...
Astronomers from Bonn and Tautenburg in Thuringia (Germany) used the 100-m radio telescope at Effelsberg to observe several galaxy clusters. At the edges of these large accumulations of dark matter, stellar systems (galaxies), hot gas, and charged particles, they found magnetic fields that are exceptionally ordered over distances of many million light years. This makes them the most extended magnetic fields in the universe known so far.
The results will be published on March 22 in the journal „Astronomy & Astrophysics“.
Galaxy clusters are the largest gravitationally bound structures in the universe. With a typical extent of about 10 million light years, i.e. 100 times the...
Researchers at the Goethe University Frankfurt, together with partners from the University of Tübingen in Germany and Queen Mary University as well as Francis Crick Institute from London (UK) have developed a novel technology to decipher the secret ubiquitin code.
Ubiquitin is a small protein that can be linked to other cellular proteins, thereby controlling and modulating their functions. The attachment occurs in many...
In the eternal search for next generation high-efficiency solar cells and LEDs, scientists at Los Alamos National Laboratory and their partners are creating...
Silicon nanosheets are thin, two-dimensional layers with exceptional optoelectronic properties very similar to those of graphene. Albeit, the nanosheets are less stable. Now researchers at the Technical University of Munich (TUM) have, for the first time ever, produced a composite material combining silicon nanosheets and a polymer that is both UV-resistant and easy to process. This brings the scientists a significant step closer to industrial applications like flexible displays and photosensors.
Silicon nanosheets are thin, two-dimensional layers with exceptional optoelectronic properties very similar to those of graphene. Albeit, the nanosheets are...
20.03.2017 | Event News
14.03.2017 | Event News
07.03.2017 | Event News
30.03.2017 | Health and Medicine
30.03.2017 | Health and Medicine
30.03.2017 | Medical Engineering