Have you ever had problems losing weight and wondered if you’re just genetically fat and doomed to your pudgy fate? If so, you may be in luck. Scientists studying nutrition and genetics in dogs are helping to debunk the myth that your genes set your physiologic fate in stone.
“Your DNA tells you everything you could be. It doesn’t tell you everything you are going to be,” says Dr. Steven Hannah, Director of Molecular Nutrition at Nestlé Purina PetCare.“There are many factors that modify the ultimate expression of an animal.” One such factor is diet.
New studies are finding that diets can alter the expression of genes. In other words, they can determine which genes are active. In fact, there’s now a branch of nutrition called “nutrigenomics” dedicated to the study of how nutrients affect gene expression.
In an active gene, a segment of DNA is transcribed to RNA, which can then be translated into many copies of a single protein. Each gene codes for a different protein and each protein has a slightly different job. Some proteins provide structure, such as the protein in muscle or collagen.Other proteins, called enzymes, drive the chemical reactions that create the various hormones, neurotransmitters and products needed by the body, as well as creating products that serve as energy to power the body.
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In humans, the study of nutrigenomics is slow because there are too many factors to consider in a person’s normal life—even in just their diet. But with dogs, researchers have already discovered diets that alter arthritis and obesity.
How does nutrigenomics come into play in developing these diets? First, the company or researcher identifies gene expression profiles in affected and normal dogs.Next, they figure out which ingredients they believe will change the gene expression profile from that of an affected dog to that of a healthy one. Then they formulate a mixture, feed it to the affected individuals and see if the gene expression profile changes in a positive way. For instance, in the case of arthritis or degenerative joint disease, researchers at Purina compared the gene expression profile of normal, healthy cartilage cells, called “chondrocytes,” to that of arthritic chondrocytes.
“We have constructed a gene expression array chip that has virtually every gene known in the dog,” states Hannah. “It has tens of thousands of genes on it. We took the chondrocyte cell’s RNA and applied it to the chip.” The chip, in turn, revealed every gene whose expression was affected.
“We were able to identify which genes in the tissue were up- and down-regulated in arthritis,” says Hannah.“Because those genes are codes for all of the proteins the cell was making, it’s a snapshot in time of what the cell is planning to do biochemically.” (“Up-regulation” and “down-regulation” are the processes by which cells increase or decrease, respectively, the quantity of a cellular component, such as RNA or protein, in response to an external variable.)
By examining the 325 up-regulated genes and the 25 down-regulated genes, Purina researchers were able to look at the biochemical decision of the arthritic cell compared to a healthy chondrocyte cell. What they found was that the arthritic cells were up-regulating specific enzymes that degrade the cartilage and down-regulating enzymes that inhibit the degradation process. That is, they were primed for cartilage destruction.
The next step was to determine what dietary changes might affect the joint. These tests started in petri dishes. First, the researchers grew chondrocytes in cell culture and added inflammatory mediators that would be seen with any joint injury. This made the chondrocytes look arthritic. Then they added nutrients at various concentrations to see which nutrients would help the cells repair.With that testing, they found that omega-3 fatty acids provided good results, and they were able to determine which levels worked best.
But, as Hannah points out, “We can’t feed the nutrient directly into an animal’s joint. There’s no cell culture dog food. Rather, we needed to next see if we could get the nutrient from the food in the same concentrations into the dogs’ joint.”They needed to know if the fish oil would be digested, absorbed and then the omega-3 fatty acids transported to the joint in concentrations shown to be effective in the cell culture.
“Luckily, at the time, Colorado State was conducting an arthritis study in dogs,” says Hannah.“We were able to put these dogs on test diets with different levels of omega-3 fatty acids and then analyze the joints.” They quickly found that they were indeed able to match the levels that they had gotten in the petri dish.
“That’s all nice,” says Hannah,“but the bigger question is whether the dog actually cares. Does it make a clinical difference?” That’s where force-plate analysis came in. This process determines whether a dog’s lameness has improved; researchers did find improvement in the dogs’ physical abilities.
“We were able to verify that the changes in the gene expression profile were accompanied by changes in the corresponding enzyme levels too,” says Hannah. “After the diet, the joints contained less metalloprotease, an enzyme that degrades the cartilage, and more protein that inhibited the metalloproteases. So the omega-3 down-regulated the enzymes that chew up cartilage and up-regulated factors that inhibit the degradation.”
Another major area of nutrigenomics research is in obesity. “We’ve looked at the gene expression profile in obese patients,” says Dr. Todd Towell of Hill’s Pet Nutrition.“We can see a huge difference in gene expression between dogs who are obese and those who are lean.”
What classes of genes are different? The short answer is that at the level of gene expression, obese dogs are up-regulated at systems that make them efficient at storing fat in adipose tissue. They are fat storers. Those who are lean are more efficient at burning fat for energy.
Armed with this information, researchers set out to answer the million-dollar question: Is it possible to design a diet that would both allow weight loss and change the gene profile? To find out, Hill’s researchers fed overweight animals a new weight-reduction diet and then looked at their gene expression profiles; they looked at percent of body fat and genomic analysis at the onset of the study and then again after four months on the diet. All the dogs went from overweight to lean, and those on the new diet showed a change in 254 genes—240 were down-regulated and 14 were upregulated. The diet had changed the dogs’ metabolisms from fat-storing to fat-burning.
Interestingly, in a similar study with dogs on a high-protein weight-loss diet, dogs also went from fat to lean, but their gene expression profiles remained those of metabolically obese dogs. So they were still fat-storers, which suggests they would gain weight back. Because it’s the gene expression in the fat cells that’s important, the downside to this study is that researchers tested the gene expression in blood cells but did not test it in the fat cells where fat is actually stored; their assumption was that gene expression was also changing in the fat cells.
Another researcher who has looked at gene-expression changes in fat is Dr. Kelly Swanson, adjunct assistant professor at the University of Illinois, Department of Veterinary Clinical Medicine. “We fed a fructooligosaccharide, which is a fiber-like substance that’s not digested by the host but preferentially stimulates the beneficial microbes in the gut.” In other words, the fructooligosaccharide hangs around in the gut, where it serves as food for beneficial microbes. As a result, it allows the beneficial microbes to flourish.
The results? The diet improved insulin sensitivity in fat cells of obese dogs. Several genes that coded for proteins important in lipid regulation and oxidation were up-regulated. These results suggest that a diet with fructooligosaccharides could be useful in diabetic patients.
These findings are just the start. Says Hannah,“Researchers are routinely using nutrigenomics to understand physiology and biology at a new level. Instead of just trying to find individual genes that predispose dogs to developing diseases such as diabetes or obesity, researchers are now asking, ‘What about all of the genes and corresponding pathways?’ It’s about understanding how a molecule or nutrient changes gene expression.”
Says Swanson, “With nutrigenomics, you often get to disease states you don’t understand. If you can identify the genes and pathways affected in the disease process and know the effect of nutrition on that same process, you can determine the biological mechanisms to target.”