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Veterinary Forum September 2009 (Vol 26, No 9)

Clinical Report — Nutrigenomics: overcoming genetics with diet?

by Sophia Yin, DVM, MS (Animal Science)

    Almost every veterinarian has encountered an owner of a portly dog who claims that his or her dog's obesity must be a result of genetics, not improper feeding.

    To some extent, the owners might be correct. There are dogs that have a gene expression profile that predisposes them to being fat. However, according to recent research on how diets can alter gene expression, also called nutrigenomics, scientists are showing that an animal's genes do not necessarily seal its fate.

    "Your DNA tells you everything that you could be," says Steven S. Hannah, PhD, director of molecular nutrition at Nestlé Purina Petcare. "It doesn't tell you everything you are going to be. There are many factors, including diet, that modify the ultimate expression of an animal."

    For example, a pilot study published in the Proceedings of the National Academy of Sciences in 2008 suggests that diet and lifestyle modifications in humans can alter gene expression related to prostate health. In the study, 30 men with low-risk prostatic cancer who declined surgery were placed on a strict low-fat diet supplemented with 3 g of fish oil each day. Most fish oil formulations contain between 300 and 500 mg of fish oil, so the study supplements contained 6 to 12 times the normal dose. The study participants also were placed on a strict regimen of exercise and stress management.

    After 3 months, the participants showed reductions in weight and body fat as well as the upregulation of 48 genes and the downregulation of 453 genes. Among the modulated genes, some had critical roles in tumorigenesis.

    Studies in humans can be quite challenging because some environmental variables can be difficult to control. Animal studies of this type, however, can be less challenging.

    First, the researcher identifies gene expression profiles of unhealthy and healthy dogs. Next, he or she hypothesizes about which ingredients can change the profile from that of an unhealthy dog to a healthy one. Then a test product is formulated and fed to the study animals to test whether the gene expression profile changes in a particular tissue.

    In the case of arthritis or degenerative joint disease research, scientists at Nestlé Purina compared the gene expression profile of arthritic chondrocytes to that of normal, healthy chondrocytes.

    "We constructed a gene expression array chip that contains virtually every gene in the dog," Hannah says. "It has tens of thousands of genes on it. We took RNA from chondrocytes cells and applied it to the chip." The chip, in turn, revealed the expression level of every gene with an affected expression.

    Researchers identified more than 300 upregulated genes and about 30 downregulated genes in the arthritic vs. nonarthritic populations. In general, the arthritic cells upregulated the expression of enzymes that degrade the cartilage and downregulated enzymes that inhibit the degradation process. In essence, the arthritic cells were primed for cartilage destruction.

    The next step was to determine which dietary changes might affect the joint. These tests began in petri dishes. The researchers grew chondrocytes in cell culture and added inflammatory mediators that would be present with any joint injury. This process made the chondrocytes appear arthritic. The researchers then added nutrients at various concentrations to see which would help the cells to repair themselves. These tests revealed that omega-3 fatty acids provided good results, and the researchers were then able to determine which levels worked best.

    Hannah explains the next step: "We can't feed the nutrient directly into an animal's joint, so we needed to see if we could get the nutrient from the food into a dog's joint at the correct concentration." The researchers wanted to see if fish oil could be digested and absorbed into the joint and if the omega-3 fatty acids were transported to the joint in concentrations shown to be effective in cell culture.

    In a subsequent study conducted at Colorado State University, researchers fed a diet high in fish oil to arthritic dogs and examined the dogs' joint fluid. It was quickly found that the omega-3 fatty acid levels were similar to the levels that had proven effective in the petri dish.

    In a separate study, force-plate analysis was used to show that dogs fed high levels of fish oil did benefit in terms of lameness.

    "We were able to verify that the changes in gene expression profile were accompanied by changes in the corresponding protein level as well," says Hannah. "After being fed the diet, the dogs' joints contained less metalloprotease, an enzyme that degrades the cartilage, and more proteins that inhibited the metalloprotease. So, the omega-3 downregulated the enzymes that chew up cartilage and upregulated factors that inhibit the degradation."

    Nutrigenomics and obesity

    Another major area of nutrigenomics research focuses on obesity. Several pet food companies, including Nestlé Purina, Royal Canin and Hill's Pet Nutrition, are investigating this area of study.

    "We've looked at the gene expression profile in obese ­patients," says Todd Towell, DVM, MS, DACVIM, of Hill's Pet Nutrition, "and we can see a huge difference in gene expression between dogs that are obese and those that are lean."

    Dogs that are obese at the level of gene expression have upregulated systems that make the animals more efficient at storing fat in adipose tissue. The animals that are lean are more efficient at burning fat for energy.

    Knowing this, the researchers attempted to design a diet that could encourage weight loss and change the gene profile. They studied overweight animals and fed them a new weight reduction diet, then looked at the gene expression profiles.

    Body fat percentage measurements and genomic analysis were conducted at the beginning of the study and then 4 months later.

    The dogs on the test diet went from being overweight to being lean and had a change in 254 genes — 240 were downregulated and 14 were upregulated. The diet had changed the dogs' metabolisms from fat storers to fat burners.

    In a similar study, dogs fed a high protein weight loss diet changed from fat to lean, but the gene expression profiles were still those of metabolically obese dogs. The dogs were still fat storers, which suggests the weight would easily be gained back.

    Unfortunately, researchers tested the gene expression in blood cells but did not test the gene expression in the fat cells, where fat is actually stored. Nevertheless, the results are promising, and nutrigenomics is proving to add insight to our understanding of medicine and physiology.

    For more information:

    Ornis D, Magmanua MJM, et al. Changes in prostate gene expression in men undergoing an intensive nutrition and lifestyle intervention. Proceedings of the National Academy of Sciences, 2008;105(24):8369-8374.

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