February 7, 2006

Genetically modified mice are resistant to obesity despite a high fat diet

Salk News

Genetically modified mice are resistant to obesity despite a high fat diet

La Jolla, CA – Ravenous mice that chomp down as if there were no tomorrow yet stay lean and mean? Shutting down two genes that modulate a body’s energy balance transformed these animals into fidgeting, highly efficient fat burning machines, report scientists at the Salk Institute for Biological Studies in this week’s issue of Cell Metabolism.

“Our finding emphasizes that the affected network is key to our understanding of obesity and will be critical for the development of future anti-obesity drugs,” said lead author Tony Hunter, Ph.D., professor in the Molecular and Cell Biology Laboratory at the Salk.

The equation sounds deceptively simple: People gain weight when their energy intake in the form of food exceeds their energy expenditure. But scientists parsing the intricacies of how the body regulates appetite, stores fat, and burns flab have discovered that the body’s energy balance is modulated by a complex network of brain signals, dozens of hormones, and physiological mechanisms.

Among them, is a family of receptor molecules that control the storage and burning of fat. Studied for nearly 15 years by Salk scientist Ron Evans, Ph.D., these receptors, called PPARs (peroxisome proliferator-activated receptors) are activated when free fatty acids, the main building blocks of fat molecules, drift into a cell’s nucleus. After grabbing the fatty acids, they clamp down on DNA together with a host of cofactors, including two named Src-1 and p/CIP.

Earlier in vitro studies had revealed that SRC-1 and p/CIP act as coactivators for multiple members of the nuclear hormone receptor superfamily but their specific role, if any, for a body’s energy balance remained unclear.

To identify their role, Hunter’s team resorted to technique popular among molecular biologists when they want to know what a protein’s function in the body is: Knocking out the corresponding gene that carries the DNA recipe for the proteins. In collaboration with Michael G. Rosenfeld, M.D., professor of medicine at the University of California, San Diego, the Salk scientists created mice lacking the genes coding for SRC-1 and p/CIP.

“The resulting animals were lean, active mice that were resistant to obesity even when we fed them the equivalent of a high fat McDonald’s diet,” reported postdoctoral researcher and first author Zhiyong Wang, Ph.D.

At closer inspection, these mice failed to turn on genes whose activity is selectively regulated by PPARy, a member of the PPAR family. With genes responding to PPARy silent, the mice lacking the genes for SRC-1 and p/CIP suffered from a range of effects.

The good

The lack of SRC-1 and p/CIP turned these mice into lean exercise aficionados. In white adipose tissue, the PPARy complex activates genes that are necessary to store fat. Unable to stockpile fat in times to of plenty, the double knockout mice had a significantly lower percentage of body fat compared to their wild-type counterparts.

“At first we wondered if these mice consumed less food than their normal littermates but to our surprise we found that they actually ate much more food,” said Wang. But even when fed a high fat diet that put their un-engineered siblings on the brink of morbid obesity – and to which they took with gusto – these mice hardly gained any weight.

That raised the question: Where did the additional energy go if not into fat stores? “We discovered that their basic metabolic rate was significantly higher and in addition, they were physically very active and worked the additional calories off,” explained Wang.

The bad

PPARy is not only found in white but also in brown adipose tissue. Located between the shoulder blades, brown fat works like a heating pad. It keeps newborn baby mice warm till they develop a sufficient layer of white fat and fur, but mice can count on this source of heat throughout their lives.

In response to falling body temperature or a high calorie diet, the PPARy complex revs up heat production in brown fat to keep the body’s temperature stable or to dissipate excess energy in a process known as adaptive thermogenesis. With SRC-1 and p/CIP missing, the mice had less brown adipose tissue and were unable to maintain their normal body temperature when researchers temporarily exposed the mutant mice to a cold environment.

And the ugly.

Within two to three weeks after birth, 70 percent of the mice were dead. The exact reason is being studied. The ones who survived this critical period, however, enjoyed a relatively healthy life.

“These mice lacked SRC-1 and p/CIP from the moment they were conceived,” said Hunter. “But there is hope that we might be able to replicate the beneficial effect on body weight without the negative consequence, by the careful dosing of future drugs targeting this network in adults to create a more nuanced effect,” he added.

Authors who contributed to this work include Pam Woodring and Ronald Evans at the Salk Institute, La Jolla, Chao Qi and Janardan K. Reddy at Northwestern University, Chicago, as well as Anna Krones, Xiaoyan Zhu and Michael G. Rosenfeld at the University of California San at San Diego, La Jolla.

The Salk Institute for Biological Studies in La Jolla, California, is an independent nonprofit organization dedicated to fundamental discoveries in the life sciences, the improvement of human health and the training of future generations of researchers. For more information: www.salk.edu.

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