A Zucker rat is undeniably fat. Weighing in at one kilogram, this fat rat, with two copies of a recessive allele, dwarfs its normal 500 gram siblings. George Crist, a graduate student in Kathryn LaNoue's lab in Penn State's College of Medicine, dubs the rats morbidly obese." The animals have fat in places you'd never even think fat could grow," he says.
Less visible health problems plaguing the Zucker rats include diabetes (the type II non-insulin-dependent variety) and abnormal heart function.These defects stem from a faulty protein in the hormone control center of the brain, the hypothalamus. The defective protein is called the leptin receptor. Each receptor has a specific shape. When a molecule comes along that fits the receptor like a letter into an envelope, changes occur within the cell to which the receptor is attached. In this case, the matching molecule is leptin, and it tells the brain not to be so hungry anymore.
Except the message goes undelivered in Zucker rats. "Over the long term," says Crist, "the interaction between leptin and its receptor helps to regulate the balance between energy storage and energy expenditure, a balance we see as a 'set point' of body weight." Without a functional receptor, leptin circulates like a letter addressed to a nonexistent place -- and the Zucker rats eat every waking hour.
An insatiable appetite can get in the way of fight-or-flight versus repair-and-repose responses. Explains Crist, When you are eating food, you divert your blood flow to the intestines because you want to concentrate on absorbing the maximum amount of nutrients. When you are being chased by an animal, you don't want to worry about digesting your food." Trouble is, that is precisely all the fat rats worry about; they are in an eternal state of repair and repose. In physiological terms, this means that their fight-or-flight sympathetic nervous activity isn't quite up to par.
Normal effects of the sympathetic nervous system are an increased heart rate and stronger heart contractions. When Zucker rat hearts are stimulated with the sympathetic hormone norepinephrine, they never beat as fast nor as hard as normal rat hearts on norepinephrine do. Crist monitors their heart responses with a contraption made of 2-foot-long, 5-inch-wide transparent tubes harboring a continuous series of hourglasses. "This all looks kind of medieval," he admits, smiling toward the contraption. The function of this heart perfusion apparatus is to perfuse, or feed, a living tissue with all the essentials to keep it alive. The liquid running through the hourglasses is a simulation of blood, complete with just the right amounts of essential gases, sugar, and salts. The solution is kept at 37°C, body temperature. Says Crist, "It's like blood, except without the cells." A rat heart, suspended beneath one of the perfusion chambers, lives for hours. During that time, Crist tests the effects of various hormones and drugs on heart rate and on the force and rate of contraction.
Based on his experiments, a caffeine-like drug, BW1433, shows promise for potential treatment of heart problems experienced by human patients with type II diabetes. The hearts of fat rats treated for one week with BW1433 responded significantly better to sympathetic stimulation with norepinephrine than did untreated fat rat hearts.
Crist would like to know exactly where and how BW1433 exerts its influence. Says Crist, "It may have a direct effect on cardiac tissue, or the improvement in cardiac function following treatment with BW1433 may actually be due to effects on the pancreas or some other endocrine organ." It probably acts somewhere along the leptin receptor pathway, since it overrides some effects of the defective leptin receptor.
Yet while BW1433 does improve the fight-or-flight responsiveness of the Zucker rats, it does nothing for their obesity problem. "This suggests that the site of action of BW1433 is downstream from the central nervous system centers that control body weight, and located somewhere in the pathways controlling the sympathetic function," he notes. Finding out how it works may also tell Crist just how, on a biochemical basis, "the natural propensity we all have for skinniness or obesity affects our ability to handle physiological stress."
George H. Crist is a graduate student in the department of cellular and molecular physiology in the College of Medicine. His adviser is Kathryn F. LaNoue, Ph.D., professor of physiology, College of Medicine, Milton S. Hershey Medical Center, 500 University Dr., Box 850, Hershey, PA 17033; 717-531-8155. Their work receives funding from the National Institutes of Health.