Killer fat Why a couple of extra Pounds complicates everything

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1 Killer fat Why a couple of extra Pounds complicates everything P. Jane Armstrong, DVM, MS, MBA, DACVIM (SAIM), College of Veterinary Medicine, University of Minnesota, St. Paul, MN, and Ryan M. Yamka, MS, MBA, PhD, Hill s Pet Nutrition, Inc., Topeka, KS fat as an endocrine organ The past decade has seen a revolution in our understanding of adipose tissue. The functions of fat have traditionally been understood as energy storage, thermal insulation, and structural support for some organs. It is now known that adipose tissue is metabolically active and constitutes the largest endocrine organ in the body with unlimited growth potential at any stage of life. Recognizing that adipose tissue is not inert has helped us understand the complex relationship between obesity and some of the diseases associated with obesity in humans (i.e., heart disease, diabetes and chronic degenerative joint disease). The relationship of obesity to other types of diseases, such as type 2 diabetes mellitus (T2DM), is not easily understood. The link is a group of proteins, collectively called adipokines, which are secreted by adipose tissue and adipose-resident macrophages and fibrocytes. Adipokines exert their effects in the central nervous system and peripherally, in tissues such as skeletal muscle and the liver. Leptin, adiponectin, resistin, visfatin, retinol-binding protein and tumor necrosis factor-alpha (TNF) are some of the main adipokines of interest. Enzymes such as lipoprotein lipase are also abundantly produced and released from adipose tissue. Finally, many pro-inflammatory cytokines and acute-phase proteins originate in adipocytes (Fig. 1). Figure 1: Adipose tissue Cellular components and molecules synthesized: Various mediators synthesized by adipocytes and resident macrophages might contribute to local and systemic inflammation. The overall adipocytokine cytokine cocktail might favor a pro-inflammatory milieu. IL, interleukin; TNF, tumournecrosis factor. Reprinted with permission. H. Tilg, A. R. Moschen. Adipocytokines: mediators linking adipose tissue, inflammation and immunity. Reprinted by permission from Macmillan Publishers Ltd: Nature Reviews: Immunology, Of the adipokines, leptin has received the most attention. In 1995, leptin was identified as the fat cell-specific secretory factor that mediates the hormonal axis between fat and the brain. Leptin concentrations increase with increased body fat in all species studied including dogs and cats. Adequate energy stores are signaled by leptin and permit reproduction and normal immune function. Leptin also functions to reduce appetite. Despite high hopes that leptin would be the long-sought lipostat, it is now known that leptin resistance develops with increasing obesity. The ability of low leptin levels to stimulate appetite is greater than the ability of high leptin levels to suppress appetite. Leptin, however, may provide a link between osteoarthritis and obesity. In humans, increased leptin in synovial fluid has been seen in patients with either rheumatoid arthritis or osteoarthritis.

2 PreValence of obesity in dogs and cats The number of pets that are overweight or obese has reached epidemic proportions in the US and other industrialized countries. There are various reports as to how common obesity is, but it has been shown that just over 35% of adult cats in the U.S. were overweight or obese. In addition, 45% of the cats age were considered overweight or obese. Studies investigating the prevalence of overweight/obesity in dogs have varied from 24% to 34% (Fig. 2). Figure 2: Obesity Epidemic 30 45% of pets are overweight or obese Obesity prevention in pets needs increased emphasis with focus on wellness plans through owner education. Significant health benefits to maintaining a normal to lean body weight have been shown in dogs and other species. The veterinary visit for spaying/neutering is an important, but often neglected, opportunity to reassess diet type and feeding management and make appropriate awareness of obesity issues to clients. risk factors for obesity in dogs and cats 1. Genetics a. Dogs Specific breeds are more likely to become overweight. These include but are not limited to Shetland Sheepdogs, golden retrievers, dachshunds, cocker spaniels, Labrador retrievers, Dalmatians, Rottweilers, and mixed breeds. b. Cats Mixed breed (DSH, DLH, DMH) and Manx cats were found more likely to be obese than most purebred cats. 2. Gender/neuter status a. Dogs Spayed female dogs are about twice as likely to be overweight than are intact female dogs. Similar trends have been seen in castrated male dogs. b. Cats Male cats are predisposed to being overweight. Neutering further increases the risk of obesity by decreasing the metabolic rate by at least 25%. Removal of estrogens may also increase food consumption independent of the decreased metabolic rate. This may also be accompanied by an increased appetite following surgery. 3. Age Risk increases with increasing age in both dogs and cats. 4. Activity Reduced activity increases risk for weight gain in both dogs and cats. 5. Food and feeding Highly palatable foods, free choice feeding and excessive treats. In particular, feeding high fat foods is associated with obesity. 6. Other associations In cats, other factors such as apartment dwelling, presumably due to decreased exercise opportunities. This is softer data, but seems to be a commonly observed association. Arthritis Difficulty breathing Diabetes Mellitus Conditions associated with obesity in pets Heart disease High blood pressure Greater anesthetic risk Some cancers Skin disorders Hepatic lipidosis Dystocia Reduced immune function 2

3 nutrition myths and truths, facts and fallacies health risks of obesity Figure 3: Weight Tracking Chart Owner compliance may be enhanced by the use of weight tracking tools Gene expression profiles for obese dogs are clearly different from lean dogs Studies investigating overweight dogs and cats have identified many of the same health problems observed in humans. In cats, T2DM, neoplasia, dental disease, dermatologic diseases, and lower urinary tract problems have been associated with obesity. In dogs, obesity has been linked with diabetes, pancreatitis, cruciate ligament rupture, hypothyroidism, hyperadrenocorticism, lower urinary tract disease, oral disease, neoplasia dyslipidemia, osteoarthritis, hypertension and altered kidney function. In addition, although harder to measure, obesity exacerbates existing musculoskeletal problems, respiratory distress from upper airway obstruction, pregnancy complications, and is associated with delayed wound healing, increased anesthetic/surgical risk, and reduced life expectancy. Obesity also makes tasks such as collecting blood samples and placing intravenous catheters much more difficult. Preventing or treating obesity may delay and/or prevent many of these obesity-related diseases. A successful weight loss program requires a reduction in caloric intake (owner compliance) and an increase in physical activity (Fig. 3). Weight loss studies in dogs have found positive associations on biomarkers associated with obesity-related diseases. Weight loss in dogs has been associated with a reduction in triglycerides, cholesterol, thyroxine and leptin. In addition, weight loss in dogs lead to an increase in insulin sensitivity and lowering of adipokines linked with insulin resistance (tumor necrosis factor alpha and insulin-like growth factor-1). genomics and obesity Fat Lean i Free fatty acid receptor 2 i Long-chain-fatty-acid CoA ligase 1 i Fibronectin type III domain containing 3B i Growth factor receptor-bound protein 2 i Hypoxia-inducible factor 1 alpha Figure 4: Gene Expression Heat Maps Gene expression profiles for obese dogs are clearly different from lean dogs As indicated earlier, the relationship of obesity to other diseases is complicated and only recently began receiving recognition as a key factor affecting overall health. New research tools such as genomics have enabled scientists to shed some light on the underlying mechanisms which link obesity with other diseases. By performing microarray analysis on lean and obese adipose tissue and lymphocyte samples, scientists have begun to understand the processes behind obesity and, importantly, how obesity links to other diseases. When comparing lean vs. obese adipose tissue, the gene expression of obese adipocytes showed a down regulation of PPAR-gamma, uncoupling protein-2, carnitine O-palmitoyltransferase 1 A and acyl-coa synthetase. When functioning properly these genes are important in the beta-oxidation of fatty acids. The down-regulation of these genes may explain why obese animals are fat storing instead of fat burning (Fig. 4). In addition, the obese adipose tissue also has down-regulation of genes 3

4 associated with glucose metabolism. Down-regulation of pyruvate dehydrogenase kinase-4 and glucose-6- phosphatase may be a potential link between diabetes and obesity. Many of the same pathways altered in the obese adipose tissue have also found to be altered in lymphocytes from obese dogs. Microarray analysis of lymphocytes revealed that overweight dogs had decreased carbohydrate metabolism, interleukin signaling, PPAR signaling, IGF-1 signaling, insulin receptor signaling, amino acid metabolism, branch chain amino acid degradation and lipid metabolism, compared to results of similar analyses in lean dogs. These observations of both adipocytes and lymphocytes may explain why obese animals become insulin resistant and have increased circulating glucose, insulin, IGF-1 and inflammation. A recent study researched the effects of weight loss on the gene expression profiles of obese dogs. These dogs (> 35% body fat by DEXA) were fed a dry low-fat, fiber-enhanced therapeutic food (33.2% crude protein, 8.7% crude fat and 26.7% total dietary fiber on dry matter basis) for a period of four months. On average, dogs lost 2.8 ± 0.8 kg body fat (41.2% of initial fat mass) in four months. The nutrigenomic effect of the food can be seen in the shift from an obese to a lean gene expression profile (Fig. 5). Of the genes identified, there was a down-regulation of genes associated with fat accumulation (i.e., leptin and IGF-1) once the dogs lost weight. This data suggests that obese dogs fed the weight loss food had a shift in metabolism to a lean genomic profile. However, weight loss alone does not alter gene expression. Changes in gene expression occur as a result of foods with specific nutrient profiles and weight loss working together. Gene expression comparison (before) Increased levels of identified ingredients: Lysine, L-carnitine, soluble fiber Gene expression comparison (after overweight pets ate enhanced r/d Canine) Overweight dogs Lean dogs Key Up-regulated gene expression Down-regulated gene expression Overweight dogs after weight loss Lean dogs Figure 5. The nutrigenomic effect of the food can be seen in the shift from an obese to a lean gene expression profile The effect of weight loss on the gene expression profiles percent of obese cats has also been examined. In one study, obese cats (> 30% body fat by DEXA) were fed Hill s Prescription Diet r/d Feline Dry for a period of four months. On average, cats lost 0.61 ± 0.13 kg body fat (30.7% of initial fat mass) in four months. The nutrigenomic effect of the food was associated with the down regulation of genes associated with inflammation, obesity and T2DM. These data suggest that weight loss can correct the systemic effects of obesity. 4

5 Summary In summary, obesity is not just a weight issue. The biochemical changes occurring with obesity result in an increased susceptibility to other diseases. Genomics may provide valuable insights into the underlying mechanisms which link obesity with other diseases. The biochemical changes which occur in the adipocyte influence the adipokines released which ultimately will affect the body systemically. These changes can be quantitated by studying the genomics of lymphocytes and adipose tissue and by measuring circulating adipokines. Weight loss appears to reverse many of the changes that occur with obesity. Selected readings Scherer PE. Adipose tissue: from lipid storage compartment to endocrine organ. Diabetes 2006;55,1537. Henson MS and O Brien TD. Feline models of type 2 diabetes mellitus. ILAR Journal 2006;47:234. Hoenig M. The cat as a model for human nutrition and disease. Curr Opin Clin Nutr Metab Care 2006;9:584. Lund EM, Armstrong PJ, et al. Prevalence and risk factors for obesity in adult cats from United States private veterinary practices. Intern J Appl Vet Res 2005;(3):2. Laflamme DP. Understanding and managing obesity in dogs and cats. Vet Clin Small An Pract 2006;36; ,vii. Center SA, Harte J, Watrous D et al. The clinical and metabolic effects of rapid weight loss in obese pet cats and the influence of supplemental oral L-carnitine. J Vet Intern Med Nov-Dec;14:598. Rand JS, Marshall RD. Diabetes mellitus in cats. Vet Clin Small Anim Prac 2005;35: Yamka RM, Friesen KG and Frantz NZ. Identification of canine markers related to obesity and the effects of weight loss on the markers of interest. Intern J Appl Res Vet Med. 2006;4: Yamka RM, Frantz NZ and Friesen KG. Effects of three canine weight loss foods on body composition and obesity markers. Intern J Appl Res Vet Med. 2007;5: Diez M, Michaux C, Jeusette I, et al. Evolution of blood parameters during weight loss in experimental obese beagle dogs. J Anim Physiol Anim Nutr 2004;88: Blanchard G, Nguyen P, Gayet C, et al. Rapid weight loss and a high-protein low-energy diet allows the recovery of ideal body composition and insulin sensitivity in obese dogs. J Nutr 2004;134:2148S-2150S. Yamka RM and Friesen KG Identification of markers related to feline obesity. J Anim Sci 84 (Suppl. 1): (T31). Yamka RM, Friesen KG, Gao X, Malladi S, Al-Murrani S and Bernal L. The effects of weight loss on gene expression in dogs ACVIM Meeting, San Antonio.

6 P. Jane armstrong, dvm, ms, mba, dacvim, is a professor of clinical nutrition and internal medicine at the University of Minnesota College of Veterinary Medicine, and is currently president of the American College of Veterinary Internal Medicine ACVIM (Small Animal) and the Comparative Gastroenterology Society. Dr. Armstrong is a graduate of the Ontario Veterinary College, earned a master s degree from Michigan State University and is ACVIM board certified. Her interests within small animal clinical nutrition include obesity and gastrointestinal disease, as well as integrative medicine, hepatology and canine genetic disorders. ryan m. yamka, Phd, ms, mba, is a Senior Nutrition Scientist at Hill s Pet Nutrition where his current research is conducted in the field of genomics, weight management, amino acid metabolism, carbohydrate metabolism, fiber utilization and alternative testing. Dr. Yamka received a BS in animal science, a BS in biology, an MS and PhD in animal science (canine nutrition) and an MBA. In 2003, he joined Hill s as a nutrition scientist in Product Development where he helped develop a urine ph model that helped reduce levels of animal testing. Dr. Yamka has published over 30 scientific abstracts, 17 peer-reviewed articles, two book chapters, an AVMA book review and is the inventor of more than 25 patents (pending). / Trademarks owned by Hill s Pet Nutrition, Inc Hill s Pet Nutrition, Inc. 6