Wednesday, January 21, 2009

Deb Zoran's Presentation, July 2008

Obesity Management: Diet, Exercise and Now Drugs?

Debra L. Zoran, DVM, PhD, DACVIM

Obesity is the excessive accumulation of adipose tissue in body, and has been defined to occur when dogs or cats are >20-30% over their optimal body weight. In humans, criteria have been established for what defines "overweight" and what is "obese", however, in general, dogs are reported to be overweight when their body weight is 15% over their optimal body weight, and obese when they are >30% over the optimum. Using these criteria, the incidence of obesity in dogs and cats in the United States is reportedly between 30-40%. More important is the suggestion that the incidence of obesity in our pet population is increasing despite the many attempts to control weight with diet and exercise programs. This paper will review our current understanding of obesity in dogs, its important role in the development of many diseases in dogs, and discuss the approach to management of obesity from dietary, lifestyle and behavioral alterations, to newer, pharmacologic options for management.

The Causes of Obesity
The primary reason for development of obesity in any animal is that they are consuming more energy than they are expending. This can occur when a dog has excessive dietary intake of calories (food and treats) or when there is a reduction in energy expenditure (reduced activity, illness or injury resulting in less exercise, etc). There are some medical conditions and drugs that are associated with obesity: endocrinopathies, such as hyperadrenocorticism and hypothyroidism, and drugs such as steroids and anticonvulsants. But the primary reason that weight gain occurs in dogs on steroids or with hypothyroidism is that they have either increased food intake or decreased energy expenditure (or in some cases, both). Nevertheless, in both instances, the primary reason for the development of obesity is still a positive energy balance. While genetic factors are also likely involved (e.g., Labrador retrievers have a higher incidence of obesity than is seen in other breeds of like size), the role of inheritance in canine obesity needs more study. In both dogs and cats, neutering is an important risk factor due to the hormonal changes that occur that result in changes in levels of leptin, progestins, and other hormones that result in increased appetite, and reduced energy metabolism and metabolic rate. The key factors for prevention of obesity in neutered animals appears to be careful control of intake immediately after neutering (no free choice feeding, reduction of intake by 25% to account for the hormonal changes resulting in reduced energy needs), and close monitoring of body weight and BCS to allow adjustments in intake if needed. In dogs, there are a number of dietary factors that are also associated with obesity: including the number of snacks fed, especially table scraps, and the number of meals. Dogs that were allowed to be near their owners at mealtime also had a greater tendency to be obese due to the increased likelihood of receiving table scraps and human food treats. In addition, because feeding dogs is a social interaction, feeding and food interaction with the dog can become a daily social interaction that can become a problem resulting in overfeeding and inappropriate food intake patterns. It has been shown that in households where the owners are health conscious (conscious of diet and nutrition, who exercise regularly, and watch their own weight) they tend not to have obese dogs. Thus, there are clearly human behavioral and "food is love" issues that have to be considered in the development of obesity in dogs, and these must be addressed for successful weight control to be achieved.

The Importance of Obesity as a Disease
Obese humans generally do not live as long as their lean counterparts, and are much more likely to suffer from obesity-related diseases such as type II diabetes, coronary artery disease, osteoarthritis, hypertension, and some cancers. Dogs and cats are susceptible to the same detrimental effects, including decreased longevity, and development of a variety of disorders that are associated with being obese. In a recent study, dietary calorie restriction was clearly shown to increase longevity in a group of 24 Labrador retrievers. In that study, the dogs in the energy restricted group were fed 75% of their counterparts, and the dogs lived an average of two years longer and had a reduced incidence of hip dysplasia, osteoarthritis and glucose intolerance. Other problems that were found to be more common in obese dogs compared to the dogs that were of ideal body condition, include heat intolerance, increased anesthetic risk, increased difficulty with routine clinical procedures (catheter placement, palpation, imaging), and prolonged surgical procedures.

In order to understand the role of obesity in disease development, it is necessary to first understand the role of adipose tissue in energy balance and metabolism. The expansion of adipose tissue was long thought to be simply a depot for the deposition of fatty acids (triglycerides) that occurred because of the excess energy intake. However, research in the past decade has revealed that adipose tissue is not just a storage site, but also is responsible for production of many key hormones (e.g., leptin) involved in energy balance and a variety of other processes. Leptin was first identified in 1994 and its discovery opened the door to a whole new world of understanding about white adipose tissue. Leptin is an inhibitor of food intake--primarily through suppression of neuropeptide Y and orexin in the brain, and plays a role in the regulation energy expenditure. In obese mice that lack leptin or have leptin resistance, appetite suppression mechanisms are non-functional and energy metabolism abnormal. However, despite the importance of leptin in appetite suppression and energy expenditure, it is not the "silver bullet" of obesity management: simply replacing leptin does not result in weight loss or changes in the metabolism of obese animals. Further research in recent years has elucidated an entire list of adipokines secreted by fat cells. These adipokines are involved in a wide variety of metabolic and physiologic, as well as inflammatory changes that are implicated in the pathophysiology of obesity. Why did it take so long to understand the importance of fat cells in disease? The key reason is their apparent simplicity--in histologic appearance as well as metabolically--that belied their important role in energy metabolism and as an endocrine organ. Adipose tissue is a major secretory organ--and does not just release fatty acids during fasting--the tissue also releases a wide variety of lipid based moieties: cholesterol, retinol, steroid hormones and prostaglandins. However, fat cells also secrete many pro-inflammatory cytokines (e.g., tumor necrosis factor alpha was the first to be discovered), including interleukins (IL-1, IL-6, IL-10), chemokines (such as monocyte chemoattractant protein-1), proteins involved in hemostasis (platelet activator inhibitor-1) and blood pressure (angiotensinogen). What does this mean for the obese dog? Obesity is a metabolic disease that results in major changes in appetite control, energy expenditure, and induces a chronic, low-grade, pro-inflammatory state that may be responsible for many of the diseases associated with increased body weight.

There are a number of diseases in dogs and cats are reported to be associated with obesity, including orthopedic diseases, diabetes, heart disease, abnormal circulating lipids, certain cancers, urethral sphincter mechanism incompetence, dyspnea due to compromised ability to breathe (e.g., laryngeal paralysis, brachycephalic syndrome, tracheal collapse etc), heat intolerance, decreased immune function, and dystocia to name just a few. Further, we do not have a complete understanding of the inflammatory role of obesity hormones in our pets, and this could lead to an even greater connection between obesity and disease. Finally, as we have previously shown from the prospective study of calorie restricted dogs, dogs that are obese also do not, on average, live as long as their leaner counterparts. The bottom line is that prevention of obesity in dogs can increase both the quality and quantity of their life.

Dietary Therapy
There are two important goals in establishing an appropriate dietary therapy regimen: 1) it must be tailored to the individual animal (diet needs for allergy, renal disease, GI issues, etc), and 2) caloric restriction must occur without concurrent protein starvation to prevent loss of lean muscle tissue during weight loss. The first step in making a diet plan is to obtain a complete dietary history that gives an accurate accounting of all foods fed to a pet on a typical day. In some cases, it may be necessary to have the owners keep a diet log for a week, writing down the meals, the treats, the table foods, etc. consumed by the dog during that time. This is especially helpful in households where the dog may receive foods from more than one individual (especially children). In addition, it should be noted if the dog has access to any other foods (other pets in the family, outside scavenging), if the pet received medications in foods, and if there are other food items available to the dog (chew treats, dental chews, etc).

The next step in designing a diet plan is to decide upon a weight loss goal. The goal does not necessarily have to be that the pet achieves its ideal body weight--this goal should be based on the pet, the owner's situation and goals, and the ability to reach the goal. It is important to set reasonable goals that can be achieved, rather than overly ambitious goals that are not likely to be achieved and result in the client becoming discouraged because their pet is not meeting the expected goal. A step down approach to weight loss is much more likely to result in success and continued owner persistence, than a goal that is too ambitious and results in the owner abandoning the process due to lack of progress. Once you have set the appropriate weight loss target for that pet, then you can calculate the energy restriction that will be required to achieve the goals you have set. Ideally, the best way to set the new energy intake is to reduce intake to 60-80% of the pet's current intake. If the pets intake is not known (or cannot be calculated accurately), then it is necessary to calculate an estimate of intake for the target weight. There are a number of different equations recommended for calculating maintenance energy requirements, and ones the most frequently used are given in Table 2. Finally, another way that you can calculate calorie reduction is to calculate the energy content of the amount of fat mass you wish the pet to lose (e.g., 1 kg adipose tissue = 7700 kcal) Take this number and divide by the number of days you plan to feed the weight reduction diet. That number is subtracted from the dog's current intake to achieve a new, lower number of calories for intake. This method is more cumbersome, but is based on a more precise estimate of fat loss. Nevertheless, no matter which approach is used, the key to success is first to have complete client cooperation, then to monitor the pet frequently (e.g., every 3-4 weeks), and finally to make adjustments in intake as needed based on the plan you have developed. To be sure of accuracy in the weight loss period, it is important to weigh the pet on the same scale. To provide safe, but efficient weight loss, the dog should not lose more than 1-2% of its body weight/week.

In addition to reducing the energy intake of pets that are overweight, it is also possible to increase weight loss by increasing energy expenditure through increased exercise. In obese dogs, as in obese humans, it is important to start slow with an exercise program, and only very gradually and slowly increase the duration and intensity of the exercise. In some dogs, exercise may be impossible, due to severe joint problems or exercise intolerance or due to inability of the owners to exercise with their pet. In these dogs, very minimal activity, or low impact activity, such as a tread mill or water treadmill may be needed to allow safe, non-painful activity. Consultation with a veterinary physical rehabilitation specialist is often very helpful in determining appropriate activities for the dog. This can also be part of the overall diet and weight reduction plan, as the weigh-ins and evaluation of the pet's progress can occur in conjunction with the visits to the rehabilitation program.

Many dogs become obese due to the social bonding that occurs with owners and their dogs during feeding. This human animal bond activity results in a strong behavioral component to the development of obesity that must be addressed. In order to achieve success in changing these behaviors, it is important to substitute low calorie treats, games, or grooming activities for table scraps or other high calorie treats. Begging for food is more of a behavioral problem than a hunger problem, and if this relationship is not considered in weight loss programs, the plan is doomed to fail. In some cases, consultation with a veterinary behaviorist is an important part of the overall plan for weight loss.

Pharmacologic Options for Obesity Management
In addition to traditional therapies used for weight regulation or weight loss, there is increasing interest in other modalities (drug therapy, surgical options, nutraceuticals) that may improve the odds of success. The surgical approach has become increasingly important in the management of the disease in humans, but in veterinary medicine this approach carries considerable ethical grey areas and will not be discussed in this forum. However, there are currently three different pharmacological approaches to weight management currently available for use in humans: 1) drugs that reduce fat digestion from the intestine, 2) drugs that reduce appetite, and 3) drugs that increase metabolism (fat burning). Of these different types of drugs, two are currently approved for use in humans in the US and they are: 1) Orlistat (Xenical®), and 2) Sibutramine (Meridia®, Reductil®). Orlistat is a derivative of a lipostatin (isolated from a bacterium in the soil) that inhibits gastrointestinal lipases. In contrast to Orlistat, Sibutramine is a noradrenergic and serotoninergic re-uptake inhibitor that enhances both satiety and thermogenesis (energy metabolism). This effect is identical to the effect produced by fenfluramine (one of the drugs in the previously available, now off the market, combo drug Fen-Phen (Phentermine) in that it reduces hunger and increases satiety. The most important potential risk from the use of sibutramine is its sympathetic activity, as it has been shown to increase heart rate and blood pressure, which is very important in patients that have preexisting heart or kidney disease, or hypertension. At this time, there is one drug approved for use in the United States (and one in Europe) for weight loss in dogs (another one is in the approval process). Dirlotapide (Slentrol®) is the drug approved for weight loss in dogs and is a selective (intestinal) microsomal triglyceride transfer protein (MTP) inhibitor. However, unlike non-selective MTP inhibitors, whose mechanism of action is reduction of lipid metabolism in the liver, dirlotapide works primarily by preventing formation of chylomicrons in intestinal cells, an effect that induces an increase in peptide YY secretion. Peptide YY is a potent appetite suppressant whose effect is on the satiety center in the hypothalamus, and this accounts for 90% of the action of the drug. The reduction of fat absorption in the small intestine that results due to prevention of formation of chylomicrons is responsible for only a small fraction of the effect, and thus steatorrhea and other side effects related to fat malabsorption are minimal. Because of the difficulty in achieving weight loss in extremely obese dogs, it is likely that pharmacologic options for obesity management will become an increasingly important part of the overall approach to the problem.

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Debra L. Zoran, DVM, PhD, DACVIM Texas A&M UniversityCollege Station, Texas, USA

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