Nearly everyone knows that AIDS is due to a viral pathogen. Recently discovered severe acute respiratory syndrome (coronavirus) and West Nile also are viral. In fact, from adenovirus (common cold, uncommon ills) to yellow fever, a dozen vaccines immunize the public against infectious viruses. Think hepatitis A and B, influenza, polio, measles, mumps and rubella.
There's no vaccine for one worldwide malady, namely obesity. Recognized by the World Health Organization as a health problem of pandemic proportions, "Obesity is a metabolic disorder of multifactorial etiology, which often leads to insulin resistance, dyslipidemia, hypertension and impaired fibrinolysis, [among other things]."
At the University of Florida at Gainesville, virologist Sergei Zolotukhin makes a point concerning cancer and obesity. "The basic reason why so many people are obese has to do with their lifestyle and genetic inheritance," he said.
He is senior author of a paper in the Proceedings of the National Academy of Sciences (PNAS) released online Nov. 4, 2003, and titled "Sustained peripheral expression of transgene adiponectin mediated by recombinant adeno-associated virus offsets the development of diet-induced obesity in rats."
"The general message or finding from this paper," Zolotukhin observed, "is that it's a transgene for adiponectin and expressed from a vector that was delivered to the liver by intraportal vein. So this vector was allowed to change, to transduce, into hepatocytes, fat cells in liver. This presence prevents the development of diet-induced diabetes obesity.
"Adiponectin is a hormone in adipocytes, in fat cells. It is secreted from fat and circulates in plasma. Apparently it interacts with its respective receptors that were recently discovered in a Science paper. At the present point, the function of this hormone or its receptor are not known. What is known is that there is a lot of this anti-obesity adiponectin hormone in circulation, as opposed to leptin. Leptin is also a hormone secreted from fat. Its function is well characterized at this point."
Obese Who Pop Leptin Already Have Too Much
"Leptin supposedly causes less obesity," Zolotukhin observed, "but it's not really true because the more fat obese people have the more leptin they have. And at some point they become leptin-resistant. Nobody knows the exact mechanism of leptin resistance. It could be mediated in the brain, or it could be peripheral. Probably it's both. The reason you cannot use leptin to treat obesity is because these people already have lots of leptin.
"On the other hand, adiponectin is quite different. The more fat obese individuals have the less adiponectin. So there is a reverse relationship. That was why we decided to do these in vivo experiments in the first place. We asked: if there was less adiponectin and we supplement these animals with more liponectin, would they lose weight? It turned out to be true; however, there is a catch here, which is important to stress. We did these experiments in a preventive mode. That is, we injected these vectors before animals developed obesity.
"So it is not clear whether the same treatment would help animals - or a human for that matter - to reverse obesity if we injected this vector into the person or animal. Or if they are over the halfway mark, would they lose weight or increase it?
"We have several groups and we feed these groups different diets. One is a normal chow regimen and the other group a high-fat diet. People call it cafeteria diet.' It has a higher content of fat and is more tasty. So the rats and mice tend to eat more of this tempting high-fat diet. Obese people, humans, who overeat, get diet-induced obesity. And these animals are not as uniform as humans. Some of them do develop more diet-induced obesity, and some of them do not. We didn't separate these diet-inducing animals from diet-resistant ones. We're going to do that in our next experiment. When we purchase these animals they are usually three months old. After a couple of weeks to settle down, we inject them with this therapeutic vector. Another group is inoculated with another vector with reporter genes. We feed these animals a high-fat diet, then compare them to animals injected with control vectors. If there is a difference, we can tell that it is an effect of this treatment."
Wakened From Long Sleep, Protein Goes Into Action
"As for the effects in the body of adiponectin," Zolotukhin continued, "apparently it increases insulin sensitivity. This is all that is known right now. Adiponectin was discovered by a number of people independently in different labs at different times in the past. Actually it was identified quite a while ago but left sitting dormant until recently when people started looking at it more closely. A close synonym to adiponectin," he went on, "is Acrp-30.' Its acronym stands for adipocyte complement-related protein.' And 30 stands for 30 kiloDaltons of molecular weight.
"The gene-therapy vector that delivers the adiponectin hormone (or Acrp-30) to our experimental mice and rats," Zolotukhin recounted, "is a small DNA-containing adeno-associated viral vector, which is non-pathogenic. It normally integrates into chromosomes and stays there for a lifetime. The gene or sequence that the vector delivers consists of adiponectin or Acrp-surrogate - two different names for the same compound. It's delivered to mice and rats by injecting the vector virus that contains this sequence under the control of the promoter. Once it's injected and infects hepatocytes, it integrates into chromosomes and starts promoter-directed expression of this transgene.
"Normally, concentration of this hormone is pretty high in plasma. You would need a lot of it to do replacement protein therapy. Also, as opposed to other proteins, it has to be purified from the mammalian cell culture. So you cannot make this hormone in bacteria and then inject it into human patients."
Asked if there is extrapolation or homology of rats to humans, Zolotukhin responded: "I wouldn't dare to answer, because humans don't have the same genes but genes that are highly homologous to murine or rat adiponectin. We haven't tried it yet experimentally. We will seek a bigger preclinical animal, a canine model, and if it works, we'll think about the next step."