Stopping Food Fat from Becoming Body Fat - A New Drug Target

Fat-filled calories – how would you like to eat as many as the next guy, while he balloons out and you don’t? That idea might not be as far-fetched as it sounds. A new fat-fighting strategy comes from Robert Farese Jr., MD, a scientist with the UCSF-affiliated Gladstone Institute of Cardiovascular Disease. Farese is probing a fat-morphing enzyme called MGAT. He says MGAT might one day be targeted to prevent fat storage and obesity. MGAT is found in cells lining the small intestine. It is a gatekeeper for the absorption of fat from nutrients in the gut. “If you were a caveman, and calories were few and far between, you would want this enzyme,” Farese says, “because it helps you take up that energy as quickly as possible and bank it in storage.” But for modern men and women constantly surrounded by calories, MGAT – with its contribution to fatty weight gain – loses its luster. Another gut enzyme, pancreas lipase, already is the target of a weight loss drug called orlistat (Xenical, Alli). Orlistat prevents this lipase from breaking down dietary fats into smaller bits that can be taken up by the intestinal cells. Instead, the fat is excreted. However, excessive fat consumption while consuming orlistat may result in diarrhea and other unpleasantries. While fat passes right through people taking orlistat, mice lacking MGAT still absorb fat, Farese finds. But instead of storing the fat molecules in fat tissue, the mice burn it up. To do the research, reported in the March 15 online edition of Nature Medicine, Farese’s lab team cloned the MGAT gene and developed a strain of mice that lack the enzyme. “If they eat a diet that is low in fat, there are no apparent effects. The mice weigh the same as normal mice,” Farese says. “However, as soon as we feed the mice a high-fat diet, the wild-type mice gain weight, but the mice that lack this enzyme gain much less weight and accrete much less body fat.” A svelte physique is one thing, but physicians focus on healthy metabolism. The MGAT-lacking mice fared well in this regard too, Farese notes. “They have much less susceptibility to disorders associated with obesity, such as insulin resistance, fatty liver or hypercholesterolemia, and high levels of blood lipids,” he says. This higher metabolism of mice missing MGAT is evidenced by measurements of greater oxygen consumption and slightly elevated body temperature.

Fat-Burning Mysteries

Fats in food are broken down by enzymes, such as lipase, secreted by the pancreas. Broken-down fats are taken up by the cells lining the small intestine and reconfigured into triglycerides, a form of fat that the body can easily use. The first step toward triglyceride synthesis within these cells involves MGAT. “We don’t know exactly how the lack of this enzyme triggers the effects we observe, but we think it has something to do with the timing of the taking up of the fat,” Farese says. “In the absence of the enzyme, the fat enters the bloodstream more slowly through the intestine.” As a result, Farese suggests, molecules that normally work together in a coordinated way to store fat efficiently might become uncoupled. Translating these new findings from lab rodents into drugs that work in clinical trials, and then for the average Joe, may take a decade or more – if the idea pans out at all. But Farese has an established track record of investigating fat metabolism and storage and identifying potential drug targets. A decade ago, Farese and members of his lab group discovered how an enzyme called DGAT might be targeted to keep weight under control in mice fed high-fat diets. DGAT is another enzyme involved in the creation of triglycerides. Mice deficient in DGAT eat as much as, but are more active than, their genetically unaltered brethren. As a result, they are less fat. That work now has led to the first phase of human clinical trials to test a weight control drug that targets DGAT.

Deficiency of the Intestinal Enzyme Acyl CoA:Monoacylglycerol Acyltransferase-2 Protects Mice from Metabolic Disorders Induced by High-Fat Feeding

Chi-Liang Eric Yen, Mei-Leng Cheong, Carrie Grueter, Ping Zhou, Junya Moriwaki, Jinny S. Wong, Brian Hubbard, Stephen Marmor and Robert V. Farese Jr.
Nature Medicine 
(Published Online: March 15, 2009)
Abstract | Full Text

Related Links:

Robert V. Farese Jr., MD
Gladstone Institute of Cardiovascular Disease

Weight Management Program
UCSF Medical Center

Pfizer and BMS to Fight Fat Together
Pharmafocus, Sept. 1, 2007