Update on Deb Zoran's Obesity Article, NAVC Conference 2009

OBESITY: THE BIGGEST ENDOCRINE
DISEASE
Debra L. Zoran, DVM, PhD,
DACVIM (SAIM)
College of Veterinary Medicine and Biomedical Sciences Texas
A&M University, College Station, TX
Obesity is the excessive accumulation of adipose tissue in body, and occurs due to an imbalance of energy intake versus energy expenditure in the body. There are many criteria for
defining overweight and obesity, but in general, dogs are defined as 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% and 40%, possibly higher in some regions. More alarming, however, 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 article reviews our current understanding of obesity in dogs, with a particular emphasis on understanding the metabolic, physiologic, and endocrine changes that occur in obese animals that influence their ability to lose weight and their overall health and well being.

THE IMPORTANCE OF ADIPOSE TISSUE IN HEALTH
The importance of white adipose tissue cells (adipocytes) in health has been elegantly demonstrated in a mouse model of lipoatrophy—the mice were genetically engineered to have virtually no white fat tissue—and as a result developed severe insulin resistance, hyperglycemia, hyperlipidemia, and fatty livers. The affected mice then received transplanted adipose tissue from healthy mice, and this resulted in a dramatic reversal of the changes in glucose and lipid
metabolism, insulin sensitivity, and other metabolic derangements. The key point these experiments illustrated that the absence of adipocytes is metabolically detrimental and provided the platform for future experiments that would demonstrate the many hormones secreted by white fat and the important role these hormone play in normal metabolism and health. One of the key early discoveries that dramatically changed our appreciation of the role of adipocytes in health and disease was the discovery of their complex and integral role in the hormonal regulation of metabolism, energy intake and fat storage. We now know that fat cells secrete over 50 adipokines that act in an antocrine, paracrine, or endocrine fashion to control various metabolic and endocrine functions. Of these, leptin and adiponectin have been the most closely studied and will be considered here more closely as well. Adiponectin, which is also called adipoQ, is specifically and very highly expressed in white adipose tissue. (Figure 1)*
Adiponectin enhances insulin sensitivity in both muscle and liver tissues, and increases the oxidation of free fatty acids (FFA) in several tissues, including muscle. In normal, lean mice, adiponectin also decreases serum FFA, glucose, and triglyceride (TG) concentrations. In humans, and also apparently in dogs and cats with increasing obesity the levels of adiponectin decrease concurrently—an effect that correlates with insulin resistance and hyperinsulinemia.
Furthermore, in humans with polymorphisms of the adiponectin gene there is an increased risk of type 2 diabetes, insulin resistance and development of the metabolic syndrome. Conversely to adiponectin, leptin influences food intake (direct effects on the hypothalamus) and energy expenditure. In the normal (lean) animal, increased leptin secretion from adipocytes is a key satiety signal that reduces intake after meals. Because leptin was the first adipocyte hormone identified, it was initially thought to be the key cause of obesity (either lack of the hormone or resistance to its effects) resulted in lack of controls on intake and obesity development. However, what has been discovered is certainly more complex: leptin levels in humans, rodents, dogs, and cats are clearly highly correlated with body mass index (BMI); however, it is not a cause an effect phenomenon. Increased levels of leptin occur with increasing fat mass, but the increased levels of leptin result in co-secretion of an inhibitor of leptin signaling (SOCS-3) that blocks the central effects of leptin (effectively causing leptin resistance—thus loss of appetite controls and alterations in energy metabolism). The key point is that clearly both adiponectin and leptin, as examples of just two of the many adipokines secreted by fat cells, are extremely important hormones with both central and peripheral effects on metabolism and energy balance.

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 (eg, reduced activity, illness or injury resulting in less exercise). 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 (eg, 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 body condition score (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 EFFECT OF OBESITY ON ADIPOCYTES
As adipocytes enlarge due to increasing obesity, the adipose tissue itself undergoes molecular and cellular alterations that affect the adipokines themselves and their influence on metabolism. First, with increasing obesity, there is an increase in whole body FFA levels and glycerol release from adipocytes which is known to promote insulin resistance. This is believed to occur as a result of decreased perilipin expression. Perilipins are gatekeepers on fat cells that regulate the hydrolysis of fat—in obese individuals the reduced amounts of perilipins results in increased release of FFA. Second, with increasing adiposity, a number of pro-inflammatory cytokines are produced in white adipose tissue. These pro-inflammatory cytokines, which include tumor necrosis factor alpha, interleukin-6, nitric oxide synthetase, transforming growth factor beta,
plasminogen activator inhibitor, and monocyte chemotactic protein, are not present in normal adipose tissue, but increase steadily with increasing adiposity. The presence of these inflammatory cytokines is an important protagonist of obesity-related diseases and complications.

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, life long 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, included heat intolerance, increased anesthetic risk, increased difficulty with routine clinical procedures (catheter placement, palpation, imaging), and prolonged surgical procedures. 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.

SUGGESTED READING
1. German AJ. The growing problem of obesity in dogs and cats. J Nutr. 2006;136:1940S-1946S.
2. Mawby DI, Bartges JW, d Avignon A, et al.Comparison of various methods for estimating body fat in dogs. J Am Anim Hosp Assoc. 2004;40:109-114.
3. Trayhum P, Bing C, Wood, IS. Adipose tissue and adipokines – Energy regulation from the human perspective. J Nutr. 2006;136:1935S-1939S.
4. Armstrong PJ, Lund EM, Kirk CA, et al. Prevalence and risk factors for obesity in dogs and cats. Proc ACVIM. 2004;22:6-7.
5. Kealy RD, Lawler DF, Ballam JM, et al. Effects of diet restriction on life span and age related changes in dogs. JAVMA. 2002;220:1315-1320.
6. Greenberg AS, Obin MS. Obesity and the role of adipose tissue in inflammation and metabolism. Am J Clin Nutr. 2006;83:461S-465S.
7. Trayhurn P, Wood IS. Signalling role of adipose tissue: adipkines and inflammation in obesity. Bichem Soc Trans. 2005;33:1078-1080.
8. Kahn BB, Flier JS. Obesity and insulin resistance. J Clin Invest. 2000;106:473-481.

*The above information came directly from Deb's outline and while I have her permission to post, I have been unable to transfer the "Figure 1" graphic to this site. The original graphic was used at her July 31, 2008 presentation on an overhead screen. The chart was adopted from another source, and included leptin; a grouping of PAI-1, haptoglobin, and serum amyloid A; NGF; VEGF; adiponectin; a grouping of MCP-1, MIF, and IL-8; another grouping of IL-1beta, IL-6, IL-10, and TGF beta; and lastly TNFalpha, for those who want to research into this further.